Articles de revues : « Mosaic genetic anomalies »

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Xing, Huan-xia, Peng-bin Li, Li-min Cui, Jian-ye Jiang, Ning-ning Hu et Xiao-bin Zhang. « Whole Exome Sequencing Facilitated the Identification of a Mosaic Small Supernumerary Marker Chromosome (sSMC) ». BioMed Research International 2021 (2 juillet 2021) : 1–8. http://dx.doi.org/10.1155/2021/6258527.

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Small supernumerary marker chromosomes (sSMCs) are a group of rare chromosomal anomalies, which pose challenges in the clinical practice of prenatal diagnosis and genetic counseling. This study enrolled an extended family with an underage male patient displaying infantile seizures, intellectual disability, and retarded speech and psychomotor function. A series of multiplatform genetic detections was conducted to explore the diagnostic variation. Whole exome sequencing (WES) and chromosomal microarray analysis (CMA) indicated a mosaic sSMC derived from the pericentromeric region of chromosome 8 in the patient, which was confirmed using cytogenetic methods. The proband and his mother, who carried this mosaic variant, exhibited strong phenotypic variability. We also ruled out the pathogenicity of a KDM5C variant by extended validation. Our results emphasized the capacity of WES to detect mosaic SMCs and the importance of mosaic ratios in the appearance and severity of symptomatic phenotypes.

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Vinkšel, M., M. Volk, B. Peterlin et L. Lovrecic. « A systematic clinical review of prenatally diagnosed tetrasomy 9p ». Balkan Journal of Medical Genetics 22, n^o 1 (28 août 2019) : 11–20. http://dx.doi.org/10.2478/bjmg-2019-0012.

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AbstractTetrasomy 9p was first described in 1973 and approximately 68 cases with a variable phenotype have been reported to date with 22 of them being detected prenatally. The objective of this study was to review prenatally-reported cases of tetrasomy 9p thus far and to identify ultrasound phenotypes that may be suggestive of this specific syndrome. A PubMed database search was done in February 2018 without any restriction of publication date orjournals, with the use of the following keywords: tetrasomy 9p, tetrasomy 9p prenatal, mosaic tetrasomy 9p, mosaic tetrasomy 9p prenatal, isochromosome 9p, duplication 9p prenatal, trisomy 9p prenatal. Reported cases were included if the clinical presentation and diagnostic approach of each case was clearly described. The most common characteristics of prenatally-detected tetrasomy 9p are intrauterine growth retardation (IUGR, 57.0%), central nervous system (CNS) abnormalities (59.0%), skeletal anomalies (29.0%), genitourinary and renal anomalies (29.0%) and cardiac defects (29.0%). The phenotypic spectrum of tetrasomy 9p is rather unspecific as these findings are commonly associated with other chromosome anomalies, as well as microdeletion/microduplication or monogenic syndromes. The combination of early fetal morphology and diagnostic genetic testing enables a definite tetrasomy 9p diagnosis and effective further pregnancy management.

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Milicevic, Srboljub, Jasmina Tadic, Stasa Krasic et Stevan Repac. « Autopsy findings in a fetus with monosomy 20 mosaicism ». Srpski arhiv za celokupno lekarstvo, n^o 00 (2024) : 17. http://dx.doi.org/10.2298/sarh231112017m.

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Introduction. Mosaic monosomy 20 is a rare chromosomal aberration, without characteristic clinical features. We present a case of a fetus with monosomy 20 mosaicism revealed after prenatal ultrasound detection of anhydramnios and multiple anomalies. Case outline. The second pregnancy of a 33 years old woman, was terminated at 23rd gestational week, because of the multiple fetal anomalies and anhydramnios, detected by ultrasound. The autopsy of a female fetus revealed multiple congenital anomalies: ventriculomegaly, bilateral choroid plexus cysts, perivascular gliosis in periventricular region of cerebri, hydropericardium, severe cardiomegaly, severe myocardial hypertrophy, hydrothorax, glandular/canalicular stage of fetal lung development, bilateral renal and ureter agenesis (Potter syndrome), bladder aplasia, agenesis of the uterus, fallopian tubes and proximal vagina and valgus deformity of left foot (pes valgus). Fetal growth was adequate for gestational age with no craniofacial dysmorphy or radiographically visible anomalies of the skeleton, without signs of infection. The umbilical cord was too much length for gestational age-48cm. Analysis of fetal karyotype from fetal blood sampling revealed monosomy of chromosome 20 in 10% of analyzed cells in metaphase. Conclusion. Revealing the genetic basis of fetal anomalies is at outmost importance not only for further evaluation of pregnancy, but also for proper genetic informing of patients.

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Vorsanova, S. G., I. V. Solovyev, O. S. Kurinnaya, V. S. Kravets, A. D. Kolotii, I. A. Demidova, V. O. Sharonin, Yu B. Yurov et I. Yu Yurov. « The Y chromosome disomy syndrome (47, XYY) in children with mental retardation, deviations of sex development and different genome anomalies : molecular cytogenetic studies ». Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics) 65, n^o 2 (15 mai 2020) : 40–48. http://dx.doi.org/10.21508/1027-4065-2020-65-2-40-48.

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The article present the results of retrospectively analyzed children (4424 boys) with mental and psychomotor retardation, congenital malformations and/or developmental micro anomalies. 23 children had various forms of Y chromosome dysomy syndrome. The frequency of this syndrome in the studied cohort was 0.52%; and in this connection the authors discussed the role of Y-chromosome in the origin of mental retardation. Besides, the chromosome instability in sex and somatic cells is supposed to be a common mechanism of different chromosomal anomalies. The authors discussed the possibility of cytogenetic and molecular cytogenetic diagnosis, and also clinical polymorphism of the syndrome. The authors established the necessity of molecular cytogenetic technologies in the diagnosis of different forms of the syndrome, including mosaic forms and isodicentric chromosomes-connected forms. The severity of clinical symptoms doesn’t depend on presence of regular or mosaic forms of the syndrome. The study assumes a possible connection of clinical polymorphism with mosaisism, associated with the presence of abnormal cells (cell lines) in different tissues, together with the role of Y chromosome in the origin of mental retardation in children with Y- chromosome disomy syndrome and other chromosomal anomalies. The authors underline the necessity of molecular cytogenetic diagnosis of different forms of the syndrome for correct medical and genetic consultation.

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Thu-Ta, Flora, Dalvir Singh Bajwa, Suzanne Leech, Anna Dubois et Brian Wilson. « PA33 Mosaic KRAS mutation associated with epidermal naevus and somatic limb overgrowth ». British Journal of Dermatology 191, Supplement_1 (28 juin 2024) : i137. http://dx.doi.org/10.1093/bjd/ljae090.288.

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Abstract Mosaic KRAS variants are recognized to cause a range of features including somatic overgrowth, lymphatic and vascular malformations and other anomalies. We present a child with a mosaic variant in this gene and discuss the phenotype of this condition. A 2-year-old boy was noted at birth to have an extensive keratinocytic epidermal naevus and swelling of the left lower limb. The child was born after an uncomplicated pregnancy to unrelated parents. No anomalies had been detected prenatally. The naevus was large, affecting the left side of the body with a central demarcation down the midline of his chest to the left groin. The naevus continued down the volar aspect of the left arm onto the palm of the hand. The left lower limb was hypertrophic throughout, with nonpitting oedema. The perfusion and movement of the limb appeared normal. An infantile haemangioma was noted on the lower back, and later a deeper haemangioma of the anterior neck; neither required treatment. The left testis was undescended initially, with subsequent overgrowth of the skin of the penis and scrotum. Investigations soon after birth revealed a cystic dysplastic left kidney. A magnetic resonance imaging scan of the brain was normal. Initial genetic analysis was performed on blood. Diagnostic testing for a panel of genes associated with segmental overgrowth (R110) detected no pathogenic variant. The mosaic skin disorders deep sequencing panel (R327) showed no pathogenic variant using DNA extracted from blood. This panel was subsequently repeated on DNA extracted from skin, and a mosaic pathogenic KRAS variant c.35G>A, p.Gly12Asp was identified in 30% of next-generation sequencing reads. Mosaic RASopathies affect genes involved in the RAS–mitogen-activated protein kinase signalling pathway. Phenotypes of mosaic RASopathies are often distinct from their germline counterparts. The c.35G>A variant seen in our patient is widely reported, and leads to constitutive overactivation and increased signal transduction in downstream pathways. Epidermal naevi, both keratinocytic and sebaceous, are a common finding resulting from mosaic RAS mutations. Good developmental progress was made; milestones were generally met and although the leg remained enlarged due to lymphatic overgrowth, he was able to walk. No neurological symptoms have been noted, and the eyes have been checked with no anomalies found. The kidneys will be kept under review, as renal tumours have been reported in patients with mosaic KRAS variants. Our patient highlights aspects of the phenotype of a mosaic KRAS variant and adds to the growing knowledge of these conditions.

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Leroij, Olivier, Lennart Van der Veeken, Bettina Blaumeiser et Katrien Janssens. « Pushing the Limits of Prenatal Ultrasound : A Case of Dorsal Dermal Sinus Associated with an Overt Arnold–Chiari Malformation and a 3q Duplication ». Reproductive Medicine 2, n^o 3 (9 juillet 2021) : 118–24. http://dx.doi.org/10.3390/reprodmed2030012.

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We present a case of a fetus with cranial abnormalities typical of open spina bifida but with an intact spine shown on both ultrasound and fetal MRI. Expert ultrasound examination revealed a very small tract between the spine and the skin, and a postmortem examination confirmed the diagnosis of a dorsal dermal sinus. Genetic analysis found a mosaic 3q23q27 duplication in the form of a marker chromosome. This case emphasizes that meticulous prenatal ultrasound examination has the potential to diagnose even closed subtypes of neural tube defects. Furthermore, with cerebral anomalies suggesting a spina bifida, other imaging techniques together with genetic tests and measurement of alpha-fetoprotein in the amniotic fluid should be performed.

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Tidrenczel, Zsolt, Erika P. Tardy, Edina Sarkadi, Judit Simon, Artúr Beke et János Demeter. « Praenatalisan diagnosztizált Pallister–Killian-szindróma esete ». Orvosi Hetilap 159, n^o 21 (mai 2018) : 847–52. http://dx.doi.org/10.1556/650.2018.31015.

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Abstract: Pallister–Killian syndrome (PKS) is a rare, sporadic genetic disorder that is caused by the mosaic presence of a supernumerary marker chromosome, isochromosome 12p. The syndrome is a polydysmorphic condition characterized by mental retardation, craniofacial dysmorphism, hypotonia, seizures, epilepsy and certain organic malformations (diaphragmatic hernia, congenital heart disease). Prenatal diagnosis is challenging due to the mosaic tissue-specific distribution of the chromosomal disorder and highly variable phenotype. Prenatal diagnosis is often accidental, however, appropriate laboratory techniques based on the second trimester ultrasound anomalies provide accurate prenatal diagnosis. We report a case of a 36-year-old primipara with second trimester ultrasound markers (polyhydramnion, ventriculomegaly, rhizomelic micromelia, abnormal facial profile). The patient underwent amniocentesis, the conventional karyotyping revealed a supernumerary chromosome in nearly 50 percent of amniocytes. FISH and targeted multicolour FISH probes verified mosaic tetrasomy of the short arm of chromosome 12 of the fetus. Fetopathological examinations and analysis of fetal tissues and blood confirmed the prenatal diagnosis. To our knowledge, this is the first reported case of prenatally diagnosed Pallister–Killian syndrome in Hungary. Orv Hetil. 2018; 159(21): 847–852.

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Stephens, Carol M., Andreea M. Pavel, Sean R. Mathieson, Niamh McSweeney, Brian McNamara, Michael Moore et Geraldine B. Boylan. « Case Report : Early Neonatal EEG in Two Infants with Pallister Killian Syndrome (PKS) ». HRB Open Research 5 (18 février 2022) : 14. http://dx.doi.org/10.12688/hrbopenres.13493.1.

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Pallister Killian Syndrome (PKS) is a rare genetic disorder caused by a mosaic tetrasomy of the short arm of chromosome 12. The syndrome is characterised by typical craniofacial dysmorphism, congenital anomalies and intellectual disability. Epilepsy is a known complication, with onset usually occurring in early childhood and characterised most commonly by spasms and myoclonic seizures. To the best of our knowledge, there have been no cases describing the early neonatal EEG in PKS and electrographic seizures, to date. Here, we report two cases of PKS presenting in the neonatal period with distinctive EEG features and seizures.

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Schneeweiss, Michelle Robyn, Breanne Dale et Resham Ejaz. « Diagnosis and clinical presentation of two individuals with a rareTCF20pathogenic variant ». BMJ Case Reports 15, n^o 12 (décembre 2022) : e248995. http://dx.doi.org/10.1136/bcr-2022-248995.

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TCF20-associated neurodevelopmental disorder (TAND) is a rare and phenotypically variable genetic condition. Common features include intellectual disability, neurobehavioural concerns, postnatal tall stature and hypotonia.Two unrelated early adolescent males were referred to genetics for assessment of developmental delay. The first male of Caucasian descent had a history of autism spectrum disorder (ASD), mitral valve prolapse and subtle craniofacial dysmorphisms. The second male of Somali descent had a history of intellectual disability, thick corpus callosum and ASD. Whole-exome sequencing revealed a pathogenic variant inTCF20in both individuals. Further testing revealed that the former individual’s mother was mosaic for theTCF20 pathogenic variant.We report two individuals withTCF20pathogenic variants presenting with unique findings, including thick corpus callosum, family history of mosaicism and cardiac anomalies. These examples expand the TAND phenotype, describe associated dysmorphism in a minority group and highlight the importance of rare disease research.

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Eid, Maha M., Ola M. Eid, Sawsan Abdel-Hadi, Nehal Hassib, Abdelrahman Madian, Hanan H. Afifi et Ghada M. H. Abdel-Salam. « Clinical Variability of Pallister–Killian Syndrome in Two Egyptian Patients ». Journal of Pediatric Genetics 09, n^o 03 (21 novembre 2019) : 207–10. http://dx.doi.org/10.1055/s-0039-3400489.

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AbstractPallister–Killian syndrome (PKS) is a rare sporadic genetic disorder caused by a mosaic tetrasomy of chromosome 12p, which mainly manifests with craniofacial dysmorphism, intellectual disability (ID), auditory disturbance, epilepsy, and a variety of congenital malformations. The diagnosis of PKS can be complicated due to the phenotypic variation, and an overlap with other syndromes makes the molecular cytogenetic test necessary for a correct diagnosis. We identified two unrelated patients with typical facial features of PKS, including bitemporal alopecia, hypertelorism, and abnormal ears. Furthermore, the two patients had pigmentary skin anomalies, broad and short hands and fingers, and hypotonia. However, they differed in the degree of ID and ophthalmological findings. Patient 1 showed profound ID and poor macular function, whereas patient 2 had moderate ID and normal fundus. Mosaic tetrasomy of chromosome 12p was found in 40 and 25% of the cells of patients 1 and 2, respectively, by fluorescent in situ hybridization of cultured skin fibroblasts. The higher percentage of mosaic cells with tetrasomy 12p found in patient 1 may explain the severe phenotype. This report expands the clinical manifestations of PKS and highlights the variable expressivity of clinical features in relation to the cytogenetics findings.

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Brăila, Anca Daniela, Constantin Marian Damian, Cristina-Crenguţa Albu, Oana Botoacă, Laurențiu Mihai Dȋră, Ştefan-Dimitrie Albu, Matei Georgian Brăila, Andreea-Mariana Bănățeanu, Cristian-Viorel Poalelungi et Claudia Florina Bogdan-Andreescu. « Prenatal Diagnosis of Cleft Lip and Palate : A Retrospective Study ». Journal of Clinical Medicine 13, n^o 16 (15 août 2024) : 4804. http://dx.doi.org/10.3390/jcm13164804.

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Cleft lip and/or palate are prevalent congenital anomalies. Early and accurate diagnosis allows proper case management. The Objective: This retrospective cohort study aimed to investigate the association between cleft lip and palate and other congenital anomalies. Methods: This study analyzed 17 pregnancies prenatally diagnosed with cleft lip and palate. The investigations consisted of ultrasound examination, fetal karyotyping through amniocentesis, and family tree analysis. In the presence of an abnormal fetal karyotype, the parental karyotype was also indicated. Results: Of the 17 cases identified, 9 (52.94%) were syndromic and 8 (47.06%) were non-syndromic. The genetic syndromes identified in association with cleft lip and palate in this study included translocation syndrome (one case), Patau syndrome, trisomy 13 (seven cases), and Edwards syndrome, mosaic trisomy 18 (one case). Conclusions: A comprehensive approach ensures a thorough assessment and accurate diagnosis. Early detection and a multidisciplinary approach allow appropriate case management.

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Juric-Sekhar, Gordana, et Robert F. Hevner. « Malformations of Cerebral Cortex Development : Molecules and Mechanisms ». Annual Review of Pathology : Mechanisms of Disease 14, n^o 1 (24 janvier 2019) : 293–318. http://dx.doi.org/10.1146/annurev-pathmechdis-012418-012927.

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Malformations of cortical development encompass heterogeneous groups of structural brain anomalies associated with complex neurodevelopmental disorders and diverse genetic and nongenetic etiologies. Recent progress in understanding the genetic basis of brain malformations has been driven by extraordinary advances in DNA sequencing technologies. For example, somatic mosaic mutations that activate mammalian target of rapamycin signaling in cortical progenitor cells during development are now recognized as the cause of hemimegalencephaly and some types of focal cortical dysplasia. In addition, research on brain development has begun to reveal the cellular and molecular bases of cortical gyrification and axon pathway formation, providing better understanding of disorders involving these processes. New neuroimaging techniques with improved resolution have enhanced our ability to characterize subtle malformations, such as those associated with intellectual disability and autism. In this review, we broadly discuss cortical malformations and focus on several for which genetic etiologies have elucidated pathogenesis.

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Laurie, Cathy C., Cecelia A. Laurie, Brooke Fridley, Erin Carlson, Stephanie A. Smoley, Ian W. Flinn, Martin S. Tallman et al. « Clonal Chromosomal Anomalies Similar to CLL and Other Hematologic Malignancies Can Be Found in “Normal” Individuals ». Blood 120, n^o 21 (16 novembre 2012) : 873. http://dx.doi.org/10.1182/blood.v120.21.873.873.

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Abstract Abstract 873 Introduction: Clonal chromosomal anomalies have been well-characterized in the blood cells of patients with Chronic Lymphocytic Leukemia (CLL) and other hematological malignancies. However, the frequencies and types of chromosomal anomalies found in “normal” people (i.e. no history of hematological cancer) are much less well known. Here we compare chromosomal anomalies in untreated CLL patients with those found in a large sample of people (n>50,000) recruited for genome-wide association studies in the Gene Environment Association Studies (GENEVA) consortium. This comparison provides information about the extent to which people without a prior history of hematological cancer have chromosomal anomalies that are characteristic of CLL. Methods and Results: The anomaly detection method focused on acquired, rather than inherited, chromosomal anomalies identified in whole blood samples. The method and results for the GENEVA subjects were published recently (Laurie et al. 2012, Nat. Gen. 44:642–650). The same method was applied to pre-treatment samples from 220 CLL patients from US Intergroup Trial E2997 of the Eastern Cooperative Oncology Group (ECOG). Acquired anomalies were detected as mosaic mixtures of normal disomic cells along with cells containing autosomal anomalies consisting of large (generally > 1 Mb) deletions, duplications and/or acquired uniparental disomy (UPD). Detection requires a large fraction of cells with the same abnormal karyotype (>5–10%), which is presumably of clonal origin. The subjects (of all ages) came from 12 different GENEVA studies, which addressed a variety of health conditions not directly related to hematological cancer (e.g. addiction and glaucoma). DNA was extracted mainly from blood samples (or, in 8% of subjects, from buccal/saliva samples) and genotyped on Illumina SNP mircroarrays. Clonal mosaic anomalies were detected from change points in intensity and genotype data (B Allele Frequency and Log R Ratio). We found 514 anomalies in 404 GENEVA subjects out of 50,222 examined (0.8% of subjects), although the prevalence increased with age. Clinical data from about 75% of subjects with a clonal chromosomal abnormality revealed that only a small fraction (2.8%, 95% CI=1.0 – 4.7%) had a record of prior hematological cancer. In the ECOG study, blood samples from 220 CLL patients enrolled in protocol E2997 were genotyped on the Illumina HumanOmni1-Quad_v1 array and clonal mosaic chromosome anomalies were detected using the GENEVA method. Chromosomal anomalies typical of CLL also were identified using interphase FISH (i.e. 6q23.3-, 11q22-, 12q15+, 13q14-, 17p13-) as previously reported (Grever, JCO 25:799-804). We found 489 anomalies in 148 patients of the 220 examined (67% of patients). The anomalies detected by FISH and SNP microarray were highly concordant (>98%). Although, the most common recurrent anomalies occurred on chromosomes 6, 11, 12, 13 and 17 in regions that span the FISH probes (except for chromosome 6), a majority of the anomalies detected by SNP data (74% of 489) were not detected by the CLL FISH panel. The frequency of large chromosomal anomalies was much higher in CLL patients than in GENEVA (67% versus 0.8% of subjects) and the overall composition of anomaly types found was also different. The fraction of anomalies consisting of acquired UPD was substantially higher in GENEVA subjects than in ECOG (34.0% versus 10.6%), while deletions were less common in GENEVA (50.1% versus 72.4%) and duplications were similar (15.6% versus 17.0%) (Chi-squared test p-value=3 × 10−18). We compared the most commonly deleted regions (CDR) on each chromosome across studies. In the ECOG CLL patients, four chromosomes each had 10 or more overlapping deletions in their top CDR (6, 11, 13 and 17), which span the FISH probes (except for chromosome 6). The GENEVA subjects also had CDR on chromosomes 11, 13 and 17, which overlap those in ECOG. In addition, GENEVA had CDR spanning genes or regions implicated in myeloid malignancies, including DNMT3a on 2p, TET2 on 4q, PRAME on 22q, and a region on 20q13. Conclusions: These genotyping results of >50,000 subjects suggest clonal chromosomal anomalies may represent precursor states, or perhaps undiagnosed or unrecorded cases, of a variety of hematological malignancies. Further studies to validate these findings and explore the natural history of these genetic defects in individuals without hematologic malignancy are warranted. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding.

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Dsouza, Nikita R., Catherine E. Cottrell, Olivia M. T. Davies, Megha M. Tollefson, Ilona J. Frieden, Donald Basel, Raul Urrutia, Beth A. Drolet et Michael T. Zimmermann. « Structural and Dynamic Analyses of Pathogenic Variants in PIK3R1 Reveal a Shared Mechanism Associated among Cancer, Undergrowth, and Overgrowth Syndromes ». Life 14, n^o 3 (23 février 2024) : 297. http://dx.doi.org/10.3390/life14030297.

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The PI3K enzymes modify phospholipids to regulate cell growth and differentiation. Somatic variants in PI3K are recurrent in cancer and drive a proliferative phenotype. Somatic mosaicism of PIK3R1 and PIK3CA are associated with vascular anomalies and overgrowth syndromes. Germline PIK3R1 variants are associated with varying phenotypes, including immunodeficiency or facial dysmorphism with growth delay, lipoatrophy, and insulin resistance associated with SHORT syndrome. There has been limited study of the molecular mechanism to unify our understanding of how variants in PIK3R1 drive both undergrowth and overgrowth phenotypes. Thus, we compiled genomic variants from cancer and rare vascular anomalies and sought to interpret their effects using an unbiased physics-based simulation approach for the protein complex. We applied molecular dynamics simulations to mechanistically understand how genetic variants affect PIK3R1 and its interactions with PIK3CA. Notably, iSH2 genetic variants associated with undergrowth destabilize molecular interactions with the PIK3CA receptor binding domain in simulations, which is expected to decrease activity. On the other hand, overgrowth and cancer variants lead to loss of inhibitory interactions in simulations, which is expected to increase activity. We find that all disease variants display dysfunctions on either structural characteristics or intermolecular interaction energy. Thus, this comprehensive characterization of novel mosaic somatic variants associated with two opposing phenotypes has mechanistic importance and biomedical relevance and may aid in future therapeutic developments.

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Ramwani, Miteshkumar, Claire O’Neill, Lea Solman, Alex Barnacle, Mary Glover et Satyamaanasa Polubothu. « PA09 Clinical characterization of a cohort of KRAS-associated low-flow vascular anomalies ». British Journal of Dermatology 191, Supplement_1 (28 juin 2024) : i126—i127. http://dx.doi.org/10.1093/bjd/ljae090.264.

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Abstract Low-flow vascular malformations with associated overgrowth are most often caused by somatic activating variants in the gene PIK3CA. Discovering the genetic basis in this cohort has transformed treatment prospects and enabled targeted medical therapy with inhibitors of the phosphoinositide 3-kinase–AKT–mammalian target of rapamycin pathway. However, a small number of patients are negative for PIK3CA mutations, and identification of such individuals is important to enable stratification for appropriate targeted medical therapies. We report here three patients with low-flow vascular anomalies secondary to somatic activating KRAS variants, highlighting key clinical features and the clinical course in this cohort. Case 1 is an 18-year-old man with a left-leg low-flow vascular malformation associated with overgrowth and notably prominent distended tortuous superficial veins and hyperpigmentation. He previously underwent epiphysiodesis and is currently being treated conservatively with a shoe raise and compression garments. Next-generation sequencing of DNA extracted directly from affected skin demonstrated a mosaic KRAS c.35G>A, p.Gly12Asp variant in 6% of reads. Case 2 is a 13-year-old girl with a capillary malformation of the left leg with overlying hyperpigmentation, and prominent distended veins associated with prominent leg length discrepancy (left longer than right). She is currently pending epiphysiodesis and reports frequent left-knee pain. Next-generation sequencing of DNA extracted directly from affected skin demonstrated a KRAS c.64C>A, p.Gln22Lys variant in 3% of reads. Case 3 is a 17-year-old girl with a capillary malformation of the left leg with associated with overgrowth, hyperpigmentation and distended superficial veins. She required epiphysiodesis to correct leg length discrepancy and reports significant pain in her left knee. She also has left-sided visual impairment and previous focal seizures. Next-generation sequencing of DNA extracted directly from affected skin demonstrated a mosaic KRAS c.35G>T, p.Gly12Val variant in 2% of reads. We describe a cohort of three patients with low-flow vascular malformations secondary to somatic variants in KRAS. Clinical features common to our three patients and potential clues to the underlying genetic diagnosis were associated hyperpigmentation, the progressive development of superficial dilated veins, and progressive overgrowth of the affected limb requiring surgical intervention. Targeted therapy in this cohort could potentially be achieved with the use of mitogen-activated protein kinase kinase inhibitors, which have been shown to be effective in the treatment of KRAS-driven arteriovenous and lymphatic malformations. This series highlights the importance of early genotyping in patients with segmental overgrowth syndromes and vascular anomalies to inform prognosis and to stratify patients for targeted medical therapies.

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Mussa, Alessandro, Diana Carli, Simona Cardaropoli, Giovanni Battista Ferrero et Nicoletta Resta. « Lateralized and Segmental Overgrowth in Children ». Cancers 13, n^o 24 (7 décembre 2021) : 6166. http://dx.doi.org/10.3390/cancers13246166.

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Congenital disorders of lateralized or segmental overgrowth (LO) are heterogeneous conditions with increased tissue growth in a body region. LO can affect every region, be localized or extensive, involve one or several embryonic tissues, showing variable severity, from mild forms with minor body asymmetry to severe ones with progressive tissue growth and related relevant complications. Recently, next-generation sequencing approaches have increased the knowledge on the molecular defects in LO, allowing classifying them based on the deranged cellular signaling pathway. LO is caused by either genetic or epigenetic somatic anomalies affecting cell proliferation. Most LOs are classifiable in the Beckwith–Wiedemann spectrum (BWSp), PI3KCA/AKT-related overgrowth spectrum (PROS/AROS), mosaic RASopathies, PTEN Hamartoma Tumor Syndrome, mosaic activating variants in angiogenesis pathways, and isolated LO (ILO). These disorders overlap over common phenotypes, making their appraisal and distinction challenging. The latter is crucial, as specific management strategies are key: some LO is associated with increased cancer risk making imperative tumor screening since childhood. Interestingly, some LO shares molecular mechanisms with cancer: recent advances in tumor biological pathway druggability and growth downregulation offer new avenues for the treatment of the most severe and complicated LO.

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Lara-Corrales, Irene, Mitra Moazzami, Maria Teresa García-Romero, Elena Pope, Patricia Parkin, Andrea Shugar et Peter Kannu. « Mosaic Neurofibromatosis Type 1 in Children : A Single-Institution Experience ». Journal of Cutaneous Medicine and Surgery 21, n^o 5 (27 avril 2017) : 379–82. http://dx.doi.org/10.1177/1203475417708163.

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Background: Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder caused by loss-of-function mutation in the NF1 gene. Segmental or mosaic NF1 (MNF) is an uncommon presentation of the NF1 result of postzygotic mutations that present with subtle localised clinical findings. Objectives: Our study’s objectives were to describe the clinical characteristics of children with MNF. Methods: We conducted a cross-sectional study of children diagnosed with MNF at the Hospital for Sick Children in Toronto, Canada, from January 1992 to September 2012. Data were abstracted from health records and analysed using a standardised data collection form approved by our hospital Research Ethics Board. Results: We identified 60 patients with MNF; 32 of 60 (53.3%) were female. Mean ± SD age at first assessment was 10.6 ± 4.6 years. The most common initial physical manifestation in 39 of 60 (65.0%) patients was localised pigmentary changes only, followed by plexiform neurofibromas only in 10 of 60 (16.7%) and neurofibromas only in 9 of 60 (15.0%). Unilateral findings were seen in 46 of 60 (76.7%) patients. Most common associations identified included learning disabilities (7/60; 12%) and bony abnormalities (6/60; 10.0%). Conclusions: MNF is an underrecognised condition with potential implications for patients. Children mostly present with pigmentary anomalies only. Most patients do not develop associated findings or complications before adulthood, but long-term follow-up will help determine outcomes and possible associations. Recognition and confirmation of the diagnosis is important to provide follow-up and genetic counselling to patients.

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Strano, Serena, Agata Polizzi, Martino Ruggieri, Maria Garozzo, Flavia Mendola, Simona Marino, Concetta Pirrone et al. « Phacomatosis Pigmentokeratotica ». Journal of Pediatric Neurology 16, n^o 05 (20 août 2018) : 313–18. http://dx.doi.org/10.1055/s-0038-1667132.

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AbstractIn the group of the epidermal nevus syndromes, Happle defined in 1996 a separate entity characterized by the presence of an organoid epidermal nevus, sometimes showing sebaceous differentiation, and a speckled lentiginous nevus of the papular type, occasionally associated with extracutaneous anomalies including neurological, ophthalmological, and skeletal abnormalities. In particular, the syndrome is associated with mental retardation, epilepsy, deafness, hemiatrophy, dysesthesia, and hyperhidrosis, strabismus, lipodermoid of conjunctiva, coloboma and ptosis, and kyphosis, scoliosis, limb asymmetry, and hypertrophy. Rarely, hypertension, vascular abnormalities, atrioventricular block, hypophosphatemic rickets, and pheochromocytoma may occur. The organoid nevus follows the lines of Blaschko whereas the speckled lentiginous nevus is arranged in a checkerboard pattern. For this syndrome, the term “Phacomatosis Pigmentokeratotica” has been coined and, at the present, it is considered a very rare clinical entity, with less than 20 cases reported in the literature. Recent genetic findings have included this syndrome in the group of the mosaic RASopathies, after the discovery of mutations in the HRAS gene occurring in both sebaceous and vascular nevi, but not in nonaffected tissues.

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Khan, Atif Ahmad, Fazal Mabood, Muhammad Jamil Awan, Zarak Khan, Qaisar Ali et Sunaina Riaz. « Conventional Cytogenetic Analysis of Females with Primary Amenorrhea ». BMC Journal of Medical Sciences 5, n^o 1 (3 juillet 2024) : 48–51. https://doi.org/10.70905/bmcj.05.01.0267.

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Abstract Background: Primary amenorrhea, characterized by the absence of menstrual periods in females of reproductive age, presents a multifaceted challenge in clinical practice. Cytogenetic analysis stands as a foundational pillar in unraveling the genetic landscape governing primary amenorrhea. Objective: The study was designed to determine the chromosomal abnormalities of females with primary amenorrhea. Materials and Methods: In the current cross-sectional study, two hundred patients with a history of primary amenorrhea were processed by the standard KAROTYPING technique. The study was carried out at the Molecular genetics/cytogenetic department, chughtai institute of pathology, Lahore, Pakistan for a period of one year from July-2020 – July-2021. Result: In the present study, a total of 200 female patients were included. Among these 200 patients, 80 exhibited chromosomal abnormalities. Specifically, there were 50 (62.5%) cases with 46, XY, 10 (12.5) cases with 45, X, 10 (12.5) cases with iso, Xq, 7 (8.7%) cases with XY del, and 3 (3.7) cases with mosaic Turner syndrome. Notably, the predominant clinical features included the development of breast in 51% of cases, hirsutism in 61% of cases, and pubic hair development in 7% of cases. Ultrasound reports revealed that 19.3% of patients had a normal uterus, 51.4% had a small uterus, and 20.2% were devoid of a uterus, as indicated in Table 1, along with other hormonal values. Conclusion: The present study provides a nuanced understanding of chromosomal abnormalities in females with primary amenorrhea. The identification of diverse anomalies, along with their associated clinical features and uterine morphology, contributes valuable information to the existing literature. The comparison with previous studies underscores both consistencies and novel findings, emphasizing the evolving landscape of knowledge in the field of reproductive genetics. Further research is warranted to explore the implications of these chromosomal variations for clinical management and genetic counseling in females with primary amenorrhea.

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An, Na, Yang Yu, Qi Xi, Fagui Yue, Ruizhi Liu, Shibo Li et Ruixue Wang. « Molecular Characterization of Mosaicism for a Small Supernumerary Marker Chromosome Derived from Chromosome Y in an Infertile Male with Apparently Normal Phenotype : A Case Report and Literature Review ». BioMed Research International 2019 (19 novembre 2019) : 1–8. http://dx.doi.org/10.1155/2019/9398275.

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Small supernumerary marker chromosomes (sSMCs), equal in size or smaller than chromosome 20 of the same metaphase, can hardly be identified through traditional banding technique. They are usually associated with intelligent disability, growth retardation, and infertility, but the genotype-phenotype correlations are still complicated for their complex origins and constitutions. Herein, we identified a 26-year-old Chinese infertile male who carried a mosaic sSMC and was diagnosed as severe oligospermia. The G-banding analysis initially described his karyotype as mos 47, XY, +mar[32]/46, XY[18]. The chromosomal microarray analysis results showed a 25.5 Mb gain in Yp11.31q11.23 and a 0.15 Mb loss in Yq12. Two SRY signals were discovered in the “seemingly” normal chromosome Y in both cell lines using SRY probe: one normal SRY was located on the distal tip of the short arm of chromosome Y while the other SRY was located on the terminal of long arm in the same chromosome Y. The sSMC(Y) was finally identified as der(Y) (pter ⟶ q11.23) (SRY-). To our knowledge, the chromosomal Y anomalies, SRY gene translocated from der(Y) (pter ⟶ q11.23) to qter of normal chromosome Y, were not reported before. Our findings indicated that the mosaic presence of sSMC(Y) may be the main cause of severe oligospermia although no other apparent abnormalities were observed in the proband. Further research on association between sSMC(Y) and spermatogenesis impairment should be investigated. It is recommended measures of traditional and molecular cytogenetic analysis should be taken to determine the origins and constitutions of sSMC so as to offer more appropriate genetic counseling for the infertile sSMC carriers.

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Eren Keskin, Seda, Buket Doğruoğlu, Zeynep İlkay, Deniz Sünnetçi Akkoyunlu, Naci Çine, Hakan Savlı, Yasemin Doğan et Gülseren Yücesoy. « Cytogenetic evaluation of 661 prenatal samples ». Cukurova Medical Journal 49, n^o 2 (6 avril 2024) : 248–59. http://dx.doi.org/10.17826/cumj.1380467.

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Purpose: Fetal karyotyping is commonly used to detect chromosomal abnormalities in high-risk pregnancies. Our study is intended to evaluate the results of fetal karyotyping performed in our laboratory for six years and to determine the frequency of chromosomal abnormalities, thus revealing their clinical significance. Materials and Methods: The cytogenetic results of 661 prenatal samples with an indication for invasive prenatal procedures (amniocentesis, cordocentesis) who had a chromosome analysis and FISH testing between February 2013 and March 2019 were analyzed in our study. Results: A total of 72 (10.8%) abnormal fetal karyotypes were observed in the study group. Trisomy 21 was the most common numerical aberration (29%, n = 23), followed by trisomy 18 (16%, n = 13), trisomy 13 (2.6%, n = 2), triploid (2.6%, n = 2), sex chromosome aneuploidies (5.2%, n = 4), and rare mosaic autosomal aneuploidies (2.6%, n = 2). Inversions (16%, n = 13), inherited translocations (7.8%, n = 6), unbalanced/de novo translocations (6.5%, n = 5), deletions (5.2%, n = 4), additional chromosomes (1.3%, n = 1), isochromosomes (1.3%, n = 1), and derivative chromosomes (1.3%, n = 1) were identified as structural abnormalities. Of the 18 cases that underwent FISH testing, trisomy 18 was detected in 1 case and tetrasomy 12p was detected in 1 case. Conclusion: Fetal karyotyping is still an effective and valuable method in the diagnosis of fetal anomalies and provision of effective genetic counseling. In addition, fetal karyotyping should be supported by complementary methods and advanced technologies for accurate and rapid prenatal genetic diagnosis.

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Khincha, Payal, Lisa Mirabello, Steven R. Ellis, Neelam Giri, Seth Brodie, Settara Chandrasekharappa, Frank Donovan et al. « Novel and Known Ribosomal Causes of Diamond-Blackfan Anemia Identified through Comprehensive Genomic Characterization ». Blood 128, n^o 22 (2 décembre 2016) : 1495. http://dx.doi.org/10.1182/blood.v128.22.1495.1495.

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Abstract Introduction: Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome (IBMFS) characterized by erythroid hypoplasia. It is associated with a number of congenital anomalies and a high risk of developing specific cancers. DBA is caused by germline mutations or deletions in genes affecting ribosomal biogenesis and function, with autosomal dominant or X-linked recessive patterns of inheritance. The most commonly mutated gene is RPS19, seen in approximately 25% of patients. About 45% of DBA families have no known disease-causing pathogenic variant. Methods: Affected and unaffected individuals from families with DBA were ascertained through the IRB-approved NCI IBMFS retrospective/prospective cohort study (ClinicalTrials.gov Identifier: NCT00027274). Study participants completed detailed family and medical history questionnaires, medical records were reviewed, and a subset of families underwent clinical evaluations at the NIH Clinical Center. DBA patients enrolled prior to 2014 underwent routine clinical mutation testing for the established DBA genes; beginning in 2014, DBA patient samples (buccal and blood DNA) were evaluated by whole exome sequencing (WES) for mutation identification. We incorporated WES with deletion analyses and copy number variant (CNV) assessment to uncover the genetic changes causative of DBA. Deletion analyses performed included SNP genotyping and array comparative genomic hybridization. Functional effects of the genetic variants were proven by pre-rRNA processing defect analysis by Northern blot. Controls for functional studies were healthy mutation-negative individuals from the IBMFS study. Results: Genetic testing information was available in 61 of the 87 families with DBA enrolled in the IBMFS study. Thirty-five of the 61 families did not have a known genetic cause at enrollment. Our combined approach of WES, deletion and CNV analyses identified the causative pathogenic variant in 18 of the 35 (51%) uncharacterized DBA families. We discovered pathogenic variants in two previously undescribed genes in two DBA families. One family had a nonsynonymous variant (p.K77N) in RPL35; the second family had a nonsynonymous variant (p. L51S) in RPL18. Both of these variants result in characteristic pre-rRNA processing defects. Our analyses also uncovered germline mosaic deletions in known DBA genes in both buccal and blood cells of two patients from two different families. One was a 1.8 Mb mosaic deletion in chromosome 15 including RPS17; the other was a large 2.5 Mb mosaic deletion on chromosome 3 including RPL35A. In addition to these findings, we found variants in previously known DBA-associated ribosomal genes in 14 of the 35 families. We further evaluated the genomic characteristics of the entire DBA cohort. Pathogenic variants in ribosomal DBA genes were found in a total of 44 of the 61 families (72%) on whom genetic testing information and/or biospecimens were available. RPS19 was the most frequently mutated gene and accounted for 36% of families, followed by RPL35A and RPS26, accounting for 14% and 11% each, respectively. Notably, 30% of the variation in disease-causing genes in our cohort was due to a single copy or mosaic gene deletion. We had complete parental testing and inheritance information on 23 (52%) of the 44 families whose gene was identified. Ten of the 23 (43%) had an inherited mutation and 13 (57%) had a de novo change in the causative gene (both parents were negative for the affected child's disease-associated mutation). At this time, 17 of 61 families tested (28%) do not have a characterized disease-associated mutation. Conclusion: This efficient comprehensive genomic approach was the basis for our discovery of two novel causes of DBA, characterization of ribosomal gene deletions not previously described to be disease-associated, and of DBA-associated germline mosaicism. We identified the disease-associated mutations in 51% (18 of 35) of our families without a known genetic cause of DBA. A total of 74% (44 of 61) of our families are now genetically characterized. Our comprehensive approach appears to provide more genomic information than other methods since pathogenic variants of DBA genes have been reported previously in about 55% of DBA patients. Disclosures No relevant conflicts of interest to declare.

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Gou, Lingshan, Yuan Fang, Na Wang, Man Zhang, Tianya Liu, Yi Wang, Shunan Hu et al. « Clinical management of pregnancies with positive screening results for rare autosomal aneuploidies at a single center ». Journal of International Medical Research 48, n^o 11 (novembre 2020) : 030006052096687. http://dx.doi.org/10.1177/0300060520966877.

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Objective To review our experiences on clinical management of pregnancies with positive noninvasive prenatal testing (NIPT) results for rare autosomal aneuploidies (RAAs) at a single center. Methods We performed a retrospective study and reviewed data from 18,016 pregnancies undergoing NIPT at a single center in China from March 2017 to February 2020. Depending on the patient’s choice, women with positive screening results for RAAs underwent chromosomal microarray analysis for invasive prenatal diagnosis. Results Thirty-three positive cases for RAAs were identified, with a positive screening rate of 0.18%. The most common RAA was trisomy 7 (33.3%), while trisomies for other chromosomes were less frequent. Monosomies involving chromosomes 16, 14, and 22 were observed. Twenty-eight cases of RAAs underwent invasive diagnosis. Abnormal pregnancy outcomes were observed in four cases, including true fetal mosaicism (n=1), partial uniparental disomy (n=1), miscarriage (n=1), and structural anomalies on ultrasound (n=1). Conclusions RAAs at NIPT might be associated with fetal uniparental disomy, mosaic aneuploidy, and poor pregnancy outcomes, but most positive cases have normal pregnancy outcomes. For RAAs, genetic counseling on the potential risks of abnormal NIPT results, as well as on benefits and limitations of invasive prenatal diagnosis, might help guide clinical management.

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Kryzhanovska, M. A., O. Yu Maiorova et N. Ia Holub. « АНАЛІЗ ДИНАМІКИ НАРОДЖЕННЯ ДІТЕЙ З АУТОСОМНИМИ ТРИСОМІЯМИ ПО ХМЕЛЬНИЦЬКІЙ ОБЛАСТІ ». Scientific Issue Ternopil Volodymyr Hnatiuk National Pedagogical University. Series : Biology 83, n^o 1-2 (13 octobre 2023) : 37–43. http://dx.doi.org/10.25128/2078-2357.23.1-2.6.

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In the face of challenging modern demographic conditions, the imperative of preserving human life is becoming increasingly urgent. Environmental pollution, a deteriorating ecological landscape, imbalanced nutrition, unhealthy lifestyles, the accumulation of hereditary defects, and a rising genetic burden collectively exert adverse effects on Ukraine's gene pool. This unfortunate scenario contributes to the increased rate of early child mortality and the birth of children with disabilities [7]. The objective of this study was to analyze the trends in child births with Down, Edwards, and Patau syndromes while investigating the influence of maternal age on the incidence of these genetic anomalies in the Khmelnytskyi region from 2017 to 2021. We conducted an analysis of statistical data pertaining to newborns, utilizing information from the Main Statistical Office in the Khmelnytskyi region. This investigation was undertaken in collaboration with the medical and genetic consultation department of the KP "Khmelnytskyi City Perinatal Center." It involved a comprehensive review of outpatient records for patients born with Down, Edwards, and Patau syndromes, aimed at understanding the clinical condition of the infants and the course of pregnancy in their mothers. The analysis revealed that a total of 50,475 babies were born in the region over the course of five years. However, an annual decrease in the birth rate was observed, with an average reduction of 705 children per year. The incidence rate of newborns with Down syndrome, Edwards syndrome, and Patau syndrome ranged from 0.10% to 0.13%. During the research period, 45 children with Down syndrome were born in the Khmelnytskyi region. Cytogenetic analysis indicated that 39 of these children (87 %) had a complete trisomy, 4 had a mosaic form (9 %), and 2 (4 %) had a translocation form. Children with complete trisomy exhibited four or more phenotypic features simultaneously. In the region, 12 children were born with Edwards syndrome, including 9 with complete trisomy and 3 with a mosaic form. No newborns were identified with partial trisomy. Cases included both full-term and premature births, as well as instances of infant mortality. Two children with Patau syndrome were born (1 boy in 2017 and 1 girl in 2019), both with complete trisomy. They were born full-term but with low birth weight and multiple developmental disabilities, with one child surviving for 12 hours and the other for 31 hours. Upon analyzing the age of the parents of the probands, it was discovered that the majority (38 mothers, 64 %) were not within the age risk group for having a child with trisomy. This suggests that women of any age can be at risk of having a child with trisomy. Thus, there is a clear need for medical-genetic counseling and prenatal screening for every pregnant woman during the first trimester of pregnancy.

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Khan, Mansura, Mohammad Moniruzzaman, Zarina Akhter, Md Azmal Hossain et Ashesh Kumar Chowdhury. « An Analysis of Cytogenetic and Clinical Phenotype of Klinefelter Syndrome Over 17 Years ». BIRDEM Medical Journal 8, n^o 2 (16 mai 2018) : 126–31. http://dx.doi.org/10.3329/birdem.v8i2.36642.

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Background: Clinical phenotype in Klinefelter syndrome (KS) shows utmost contrariety according to the genetic presentation. The karyotype 47, XXY is one of the commonest types of sex chromosomal abnormality in males presenting with infertility, hypogonadism, small penis, gynaecomastia and tall stature. Cytogenetic study is the only way to differentiate between chromosomal abnormality and other androgen deficiency disorders. The aim of this study was to investigate cytogenetic and phenotypic profile of Klinefelter syndrome in a group of referred patients with suspected genetic disorders.Methods: This observational study was carried out at the Cytogenetic Laboratory of the Department of Immunology BIRDEM General Hospital for a period of seventeen years from 2000 to 2016. A total of 9,216 patients suspected for different chromosomal abnormalities (e.g. numerical chromosomal disorders, primary amenorrhoea, ambiguous genitalia etc.) were included in this study referred by physicians of various discipline from different areas of Bangladesh. From the patients referred for cytogenetic study, detailed family history and physical findings were noted. Complete genetic examination and pedigree construction was done to exclude non-chromosomal causes of anomalies. For cytogenetic analysis, peripheral lymphocyte culture by the standard method using the G-banding technique was employed.Results: In this study 1.67% (154) of referred patients were diagnosed as Klinefelter syndrome in cytogenetic study and most of them were diagnosed in their adulthood between 20-29 years of age. Classical cytogenetic form of KS-47, XXY (87%) were most common followed by other mosaic and supernumerary X chromosome aneuploidy. Most of the patients presented with tall stature (61.7%) followed by other features such as gynaecomastia (45.5%), eunuchoid skeleton (29.8%), sexual dysfunction (34.41%), small penis (22.7%), and delayed development of secondary sex characteristics (22.7%).Conclusion: Diagnosis of Klinefelter syndrome in early age before puberty is needed to be differentiated from other related disorders and thereby improving the quality of life by providing appropriate and timely treatment. Therefore, we have to focus to improve our overall capacity to diagnose genetic disorders for proper interventionBirdem Med J 2018; 8(2): 126-131

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Cobanogullari, H., N. Akcan et M. C. Ergoren. « Non-Invasive Screening Test Paradox in a Case Born with Mixed Gonadal Dysgenesis (45,X/46,Xy) ». Balkan Journal of Medical Genetics 26, n^o 1 (1 juillet 2023) : 57–62. http://dx.doi.org/10.2478/bjmg-2023-0007.

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Abstract Noninvasive prenatal testing (NIPT) is commonly used to screen for fetal trisomy 13, 18, and 21 and often for sex chromosomal aneuploidies (SCAs). Although the testing is also used for sex chromosomal aneuploidies, it is not as efficient as it is for common trisomies. In this particular study, we present a case for whom the NIPT diagnosis was originally 45,X and who was diagnosed with mixed gonadal dysgenesis 45,X/46,XY after birth. A 38-year-old [G3P3] pregnant woman underwent NIPT at 15 weeks’ gestation and was found to be at probable risk for 45,X. Because cordocentesis is an invasive procedure, the pregnant woman did not want to undergo cordocentesis. Consequently, postnatal cytogenetic analysis was performed and the baby’s karyotype was shown to be 45,X/46,X,+mar?. No numerical and/or structural anomalies were observed in the karyotypes of parents and siblings. Based on the microarray analysis of the analyzed sample, one copy of the X chromosome was detected in all cells and the presence of one copy of the Y chromosome was detected in a ~40% mosaic state: arr(X) x1,(Y)x1[0.4]. SRY gene duplication on Y chromosome was confirmed by fluorescence in situ hybridization (FISH) and microarray analysis. The patient’s clinical examination showed ambiguous genitalia (clitoromegaly) and dysmorphic facial features. The baby underwent surgery for aortic coarctation. The results were consistent with a genetic diagnosis of 45,X/46,XY mixed gonadal dysgenesis. Genetic counselling was offered to the family. In conclusion, NIPT still has potential limitations in correctly identifying sex chromosomes and mosaicism that may mislead clinicians and families.

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Law, Jennifer, Judith Ross, Chijioke Ikomi, Julie Blatt, Alyssa Truxon et Corinne Lawler. « PMON190 Characterization Of Lymphedema With Respect To Phenotype and Karyotype in Patients With Turner Syndrome ». Journal of the Endocrine Society 6, Supplement_1 (1 novembre 2022) : A620—A621. http://dx.doi.org/10.1210/jendso/bvac150.1286.

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Abstract We characterize karyotypic and phenotypic features of a cohort of patients with Turner syndrome (TS) and lymphedema (LD). Medical records from two large TS specialized pediatric clinics were reviewed retrospectively. Seventy-one patients with TS and history of LD were identified, mean age 15.9 ± 7.71 years. Reported LD onset was in infancy in 72% of patients, with 56% (40/71) reporting LD present at birth. LD affected hands in 29% of patients, feet in 57%, and both hands and feet in 25%. 46% reported LD was a current problem, with 11% stating it was present but not a problem. 73% (52/71) of children in this cohort had the 45,X karyotype. The remainder had mosaic/complex karyotypes. 55% of children had congenital heart disease and 10% had renal anomalies. 76% were on growth hormone treatment, 52% had a history of estrogen replacement. Lymphedema is a frequently under-documented comorbidity in Turner syndrome, with limited data currently available. Analysis of a larger cohort comparing patients with TS with and without LD is underway including the role of growth hormone and estrogen replacement in LD. Given that new therapies are being developed for LD in other genetic conditions, a better understanding of LD in Turner syndrome is important for management considerations. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

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Kulbachuk, N. V., S. V. Matviiuk, S. V. Bilokon et O. L. Sechnyak. « The kariotype variability in children with Down syndrome from the Odesa region ». Zaporozhye Medical Journal 23, n^o 1 (7 avril 2021) : 77–82. http://dx.doi.org/10.14739/2310-1210.2021.1.224888.

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The aim of the work is to analyze the frequency of cytogenetic variants of Down syndrome among patients in Odesa and the region, as well as to identify combined karyotype anomalies. Materials and methods. Studies were conducted between 2013–2018 years in Odesa Specialized Medical Genetic Center. The experimental group was formed of patients with cytogenetically confirmed Down syndrome. Chromosomes were painted according to GTG method and identified according to ISCN 2013. Results. Among patients with Down syndrome, in 93.9 % of cases complete trisomy 21 was observed, the translocation form was in 3.7 %, and the mosaic form was in 2.4 %. Similar results were revealed in the analysis of populations belonging to different ethnic and racial groups. Complete trisomy 21 was accompanied by chromosome rearrangements of other chromosomes or additional modifications of chromosome 21. Changes in the heterochromatin in chromosome 9 were more frequently observed. In total, 5.5 % of examined karyotypes were found with additional heterochromatin in both arms of chromosome 1 and in the long arm of chromosome 21. An increase in the size of satellites in chromosomes 14, 15 and more often 21, as well as the appearance of additional satellites in chromosome 2 represented 3.6 % of the total examined karyotypes. A deletion on chromosome 6 involved in translocation with chromosome 13 also was found. Translocation forms included Robertsonian translocations involving chromosomes 21 and 21, 14 and 21, as well as translocations involving chromosomes 21 and 21, 21 and 22. Patients with a mosaic form of the disease had two cell lines: with a normal karyotype 3 (15–67 % of the studied cells) and with complete trisomy 21 without additional chromosomal abnormalities (33–85 % of the studied cells). Conclusions. Among patients with cytogenetically confirmed diagnosis of Down syndrome, the ratio of the main variants was similar to many populations studied. At the same time, additional changes in the karyotype were identified which can either be a variant of the norm or aggravate the course of the disease. This requires further studies of the disease course in such patients.

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Пожитнова, В. О., В. В. Свиридова, А. В. Кислова, Ф. С. Свиридов, Д. Г. Жегло et Е. С. Воронина. « Karyotype abnormalities in induced pluripotent stem cells derived from Russian donors ». Nauchno-prakticheskii zhurnal «Medicinskaia genetika 22, n^o 12 (21 décembre 2023) : 59–66. http://dx.doi.org/10.25557/2073-7998.2023.12.59-66.

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Введение. Кариотипирование индуцированных плюрипотентных стволовых клеток (иПСК) − общепринятый этап характеристики генетической стабильности клеточных линий, необходимый при их регистрации и дальнейшем научном и медицинском использовании. Для текущего мониторинга возникновения рекуррентных аномалий кариотипа допустимо применение таргетных методов анализа (FISH, количественная ПЦР), однако спектр возникающих хромосомных аберраций может зависеть от особенностей протоколов культивирования клеток, принятых в конкретных лабораториях. Цель: выявление аномалий кариотипа в выборке линий иПСК, полученных от российских доноров, методом стандартного цитогенетического анализа и сравнение их с известными из литературных данных рекуррентными аберрациями. Методы. Кариотипирование культур иПСК проводили на 7-28 пассаже. Для уточнения частоты трисомии, выявленной при анализе кариотипа, в отдельных случаях применяли FISH с центромерными зондами. Проанализированы кариотипы 34 линий иПСК, полученных от 19 доноров. Результаты. Выявлены две линии с численными хромосомными аномалиями (+8 и +20), три линии с крупными структурными хромосомными перестройками (дупликация в 2q и две дупликации в 1q) и одна линия со спонтанными неклональными хроматидными разрывами. Дополнительный FISH-анализ с центромерными зондами линии с мозаичной трисомией 8 и аутологичной ей линии с нормальным кариотипом выявил присутствие низкопредставленного аномального клона в обеих линиях. Таким образом, частота возникновения хромосомной нестабильности в проанализированной выборке линий иПСК соответствует литературным данным. Хромосомные аберрации в двух из семи аномальных линиях не описаны как частые рекуррентные генетические аномалии в иПСК, используемые для таргетных методов контроля генетической стабильности клеток. Заключение. Наше исследование дает представление о частоте и структуре аномалий кариотипа в иПСК, полученных от российских доноров, и обосновывает рациональность комбинирования полногеномных и таргетных методов оценки генетической стабильности этих клеток. Представленные данные могут быть использованы для разработки рекомендаций по оценке качества культур иПСК. Background. Karyotyping of induced pluripotent stem cells (iPSCs) is a generally accepted stage of characterization of the genetic stability of cell lines, necessary for their registration and further scientific and medical use. Recurrent karyotype anomalies can be also detected by targeted methods (FISH, qPCR), however, the laboratory-specific peculiarities of cell handling protocols can influence the pattern of aberrations. Aim. Identification of karyotype abnormalities in iPSC lines obtained from Russian donors and their comparison with recurrent aberrations known from literature data. Methods. Karyotyping of iPSC cultures was carried out on passage 7-28, FISH with centromeric probes was used in specific cases to clarify the frequency of trisomy detected during karyotype analysis. Results. We analyzed karyotypes of 34 iPSC lines obtained from 19 donors. Two lines with numerical chromosomal abnormalities (+8 and +20), three lines with large structural chromosomal rearrangements (duplication in 2q and two duplications in 1q) and one line with spontaneous non-clonal chromatid breaks were revealed. Additional FISH analysis with centromeric probes of a line with mosaic trisomy 8 and an autologous line with a normal karyotype revealed the presence of an abnormal clone in both lines. Thus, the frequency of karyotype abnormalities in the analyzed iPSC lines corresponds to the literature data. Chromosomal aberrations in two of the seven abnormal lines are not described as frequent recurrent genetic anomalies in iPSCs used for targeted methods for monitoring the genetic stability of cells. Conclusions. Our study clarifies the frequency and structure of karyotype anomalies in iPSCs obtained from Russian donors and substantiates the rationality of combining genome-wide and targeted methods for assessing the genetic stability of these cells. The presented data can be used to develop recommendations for assessing the quality of iPSC.

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Vahidi, Parisa, Seyed Ali Rahmani et Nahid Hadige Rezvan. « Study of pregnant women with high risk of fetus abnormalities by routine cytogenetics method (karyotyping) and molecular method (FISH) by using X and Y probs and comparing the advantages and disadvantages of these methods in the northwest of Iran's patients ». Medical Journal of Tabriz University of Medical Sciences and Health Services 43, n^o 1 (17 avril 2021) : 108–15. http://dx.doi.org/10.34172/mj.2021.035.

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Background: The health of the fetus during the 9 months of pregnancy is very important for every pregnant couple. Identifying carriers of the genetic diseases and their diagnosis before birth, controls the disease's prevalence and does not impose huge costs on the patient's family and community. This study aimed to evaluate the rapid prenatal diagnosis importance in the chromosomal abnormalities identification. Methods: 50 amniotic fluid samples were studied by karyotyping and fluorescence in situ hybridization (FISH). Karyotyping was performed on me taphase chromosomes to identify all the chromosomal abnormalities and FISH detected chromosomal abnormalities by using X and Y probs, as the rapid method. Results: We identified one cases of Down syndrome (2%), three cases of extension in the polymorphism region of P arms of chromosome 15(15p+) (6%), one cases of extension in the polymorphism region of chromosome 9 (9 qh+) (2%), one case of peristaltic inversion in chromosome Y (2%), one case of XYY mosaic embryo, 46, XY /47, XYY variant (2%) and one case with the extra unknown segment on P arms of chromosome 15 (2%). Conclusion: FISH is a useful method with high sensitivity to provide rapid results for couples who don't have enough time to end their pregnancy legally. In cases of X-linked diseases, it is a reliable method to learn the sex of the fetus. FISH is not able to detect structural anomalies, therefore karyotyping is required for absolute right outcomes of chromosome abnormalities.

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Hsiao, Ching-Hua, Jia-Shing Chen, Yu-Ming Shiao, Yann-Jang Chen, Ching-Hsuan Chen, Woei-Chyn Chu et Yi-Cheng Wu. « Prenatal Diagnosis Using Chromosomal Microarray Analysis in High-Risk Pregnancies ». Journal of Clinical Medicine 11, n^o 13 (23 juin 2022) : 3624. http://dx.doi.org/10.3390/jcm11133624.

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Background: To assess the value of chromosomal microarray analysis (CMA) during the prenatal diagnosis of high-risk pregnancies. Methods: Between January 2016 and November 2021, we included 178 chorionic villi and 859 amniocentesis samples from consecutive cases at a multiple tertiary hospital. Each of these high-risk singleton pregnancies had at least one of the following indications: (1) advanced maternal age (AMA; ≥35 years; 546, 52.7%); (2) fetal structural abnormality on ultrasound (197, 19.0%); (3) high-risk first- or second-trimester Down syndrome screen (189, 18.2%), including increased nuchal translucency (≥3.5 mm; 90, 8.7%); or (4) previous pregnancy, child, or family history (105, 10.1%) affected by chromosomal abnormality or genetic disorder. Both G-banding karyotype analysis and CMA were performed. DNA was extracted directly and examined with oligonucleotide array-based comparative genomic hybridization. Results: Aneuploidies were detected by both G-banding karyotyping and CMA in 42/1037 (4.05%) cases. Among the 979 cases with normal karyotypes, 110 (10.6%) cases had copy number variants (CNVs) in CMA, including 30 (2.9%) cases with reported pathogenic and likely pathogenic CNVs ≥ 400 kb, 37 (3.6%) with nonreported VOUS, benign, or likely benign CNVs ≥ 400 kb, and 43 (4.1%) with nonreported CNVs < 400 kb. Of the 58 (5.6%) cases with aneuploidy rearrangements, 42 (4.1%) were diagnosed by both G-banding karyotyping and CMA; four inversions, six balanced translocations, and six low mosaic rates were not detected with CMA. Conclusions: CMA is an effective first step for the prenatal diagnosis of high-risk pregnancies with fetal structural anomalies found in ultrasonography or upon positive findings.

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Diociaiuti, Andrea, Roberta Rotunno, Elisa Pisaneschi, Claudia Cesario, Claudia Carnevale, Angelo Giuseppe Condorelli, Massimo Rollo et al. « Clinical and Molecular Spectrum of Sporadic Vascular Malformations : A Single-Center Study ». Biomedicines 10, n^o 6 (20 juin 2022) : 1460. http://dx.doi.org/10.3390/biomedicines10061460.

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Sporadic vascular malformations (VMs) are a large group of disorders of the blood and lymphatic vessels caused by somatic mutations in several genes—mainly regulating the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways. We performed a cross-sectional study of 43 patients affected with sporadic VMs, who had received molecular diagnosis by high-depth targeted next-generation sequencing in our center. Clinical and imaging features were correlated with the sequence variants identified in lesional tissues. Six of nine patients with capillary malformation and overgrowth (CMO) carried the recurrent GNAQ somatic mutation p.Arg183Gln, while two had PIK3CA mutations. Unexpectedly, 8 of 11 cases of diffuse CM with overgrowth (DCMO) carried known PIK3CA mutations, and the remaining 3 had pathogenic GNA11 variants. Recurrent PIK3CA mutations were identified in the patients with megalencephaly–CM–polymicrogyria (MCAP), CLOVES, and Klippel–Trenaunay syndrome. Interestingly, PIK3CA somatic mutations were associated with hand/foot anomalies not only in MCAP and CLOVES, but also in CMO and DCMO. Two patients with blue rubber bleb nevus syndrome carried double somatic TEK mutations, two of which were previously undescribed. In addition, a novel sporadic case of Parkes Weber syndrome (PWS) due to an RASA1 mosaic pathogenic variant was described. Finally, a girl with a mild PWS and another diagnosed with CMO carried pathogenic KRAS somatic variants, showing the variability of phenotypic features associated with KRAS mutations. Overall, our findings expand the clinical and molecular spectrum of sporadic VMs, and show the relevance of genetic testing for accurate diagnosis and emerging targeted therapies.

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Маркова, Ж. Г., М. Е. Миньженкова, Ф. М. Бостанова et Н. В. Шилова. « Clinical and molecular cytogenetic characteristics of the unique pseudotricentric X chromosome ». Nauchno-prakticheskii zhurnal «Medicinskaia genetika 22, n^o 8 (18 septembre 2023) : 44–51. http://dx.doi.org/10.25557/2073-7998.2023.08.44-51.

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Структурные и числовые перестройки половых хромосом являются наиболее распространенными хромосомными аномалиями, совместимыми с живорождением. Гоносомные аномалии, как правило, имеют менее выраженные клинические последствия по сравнению с числовыми или структурными аутосомными перестройками. Структурные аномалии хромосомы Х в мозаичном варианте часто обнаруживают в кариотипе у женщин с фенотипическими проявлениями синдрома Шерешевского-Тернера. Однако у пациенток со структурно перестроенной половой хромосомой аномалии развития могут отсутствовать. Это связанно с отсутствием клона 45,X и селективной инактивацией перестроенной хромосомы Х. Широкая фенотипическая изменчивость и недостаточное количество данных о наблюдении пациентов со структурными аномалиями хромосомы Х значительно осложняют медико-генетическое консультирование таких пациентов. Мы сообщаем об уникальном случае псевдотрицентрической хромосомы Х с дупликацией короткого плеча, четырьмя копиями района Xq11.1q22 и делецией терминального района длинного плеча Xq22. Целью исследования стало установление структуры и механизма формирования аномальной хромосомы Х у пациентки с задержкой психомоторного и полового развития. Проведены стандартное цитогенетическое исследование, FISH, хромосомный микроматричный анализ. Псевдотрицентрическая хромосома X с дуплицированным коротким плечом, частичной тетрапликацией и делецией длинного плеча является уникальной структурной гоносомной перестройкой. Комплексный молекулярно-цитогенетический подход позволил определить структуру дериватной хромосомы Х и установить генотип-фенотип взаимодействие при присутствии в геноме псевдотрицентрической хромосомы Х. Structural and numerical rearrangements of the sex chromosomes represent the most commonly observed chromosomal abnormalities that are compatible with live birth. Compared to numerical or structural autosomal rearrangements abnormalities of sex chromosomes tend to have less pronounced clinical consequences. In women with phenotypic manifestations of Turner syndrome, structural anomalies of the X chromosome, particularly in the mosaic form, are frequently observed in the karyotype. However, in individuals with a structurally rearranged sex chromosome, developmental anomalies may be absent. This can be attributed to the absence of cell clone 45,X and selective inactivation of the rearranged X chromosome. The wide phenotypic variability and limited data available on patients with structural anomalies of the X chromosome significantly complicate the process of medical genetic counseling for such patients. In this report, we present a unique case of a pseudotricentric X chromosome featuring a short arm duplication, four copies of the Xq11.1q22 region, and a deletion of the Xq22 long arm terminal region. The aim of the study was to establish the structure and mechanism of the formation of an abnormal X chromosome in a patient with delayed psychomotor and sexual development. A standard cytogenetic study, FISH, chromosomal microarray analysis was carried out. The pseudotricentric X chromosome with a duplicated short arm, partial tetraplication, and a long arm deletion is a unique structural gonosomal rearrangement. An integrated molecular cytogenetic approach made it possible to determine the structure of the derivative X chromosome and establish the genotype-phenotype interaction in the presence of a pseudotricentric X chromosome in the genome.

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Tvrdik, Tatiana, Kristian T. Schafernak, Jeffrey R. Jacobsen, Reha Toydemir, Alexandra M. Walsh et Bo Hong. « Clinical and Cytogenomic Features of Lymphoblastic Leukemia with Intrachromosomal Amplification of Chromosome 21 (iAMP21) in the Context of Constitutional Ring Chromosome 21 ». Blood 134, Supplement_1 (13 novembre 2019) : 5208. http://dx.doi.org/10.1182/blood-2019-123766.

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Constitutional ring chromosome 21, r(21)c, is a rare chromosome abnormality associated with variable clinical features that range from mild dysmorphism to severe congenital anomalies and intellectual disability. Recently, r(21)c has been reported to predispose to B-cell acute lymphoblastic leukemia (B-ALL) with intrachromosomal amplification of chromosome 21 (iAMP21), a distinct subgroup of high-risk pediatric B-ALL. Only a few iAMP21-B-ALL cases with r(21)c have been reported to date. The mechanism of leukemogenesis of r(21)c has not been entirely elucidated. Here we report an 11-year-old boy with iAMP21-B-ALL carrying an atypical r(21)c. The patient has a history of attention-deficit/hyperactivity disorder, sensorineural hearing loss s/p cochlear implant, intellectual disability and scoliosis. Three months before admission he developed a soft tissue nodule on the occipital scalp deemed to possibly represent an enlarged lymph node. Subsequently, he presented with spontaneous bruising followed by severe epistaxis. The initial CBC showed a white blood cell count of 4.3K/uL with circulating blasts, absolute neutropenia, profound normocytic normochromic anemia (hemoglobin of 5.2 g/dL), and marked thrombocytopenia (platelets, 12K/uL ). Peripheral blood flow cytometry showed 17.9% phenotypically abnormal B lymphoblasts which were negative for CD45, and positive for CD34, nuclear TdT, CD19, CD22, CD79a, CD10, HLA-DR , as well as CD20 (21% positive). The bone marrow aspirate contained 98% blasts. CNS status was 2a (RBC 0, WBC 0, 8% blasts) and clear after the second lumbar puncture. Fine-needle aspiration of the scalp mass demonstrated B-lymphoblastic leukemia/lymphoma. The patient was treated per COG protocol AALL1131 and was assigned to the very high-risk arm when bone marrow interphase FISH showed iAMP21. The chromosome analysis failed to yield metaphase cells on the diagnostic bone marrow sample. A concurrent genomic microarray showed chromothripsis with multiple non-contiguous losses and high copy gains on 21q involving the RUNX1 gene, as well as mosaic deletions within 7q22.3q36.3, 9p24.3p24.1 (including JAK2), 12q12 (several exons of ARID2), 13q14.2q21.2 (RB1, DLEU1/2/7, miR-15a/miR-16-1 cluster), 14q32.33 (IGH locus), 19p13.2 (several exons of the SMARCA4), and mosaic gains within 3q22.3q29 and Xp22.33p11.3. Day 29 end of induction bone marrow examination was positive for minimal residual disease (MRD) at 0.13% of nucleated mononuclear cells, but FISH was negative for iAMP21. On day 57 of consolidation, the bone marrow was negative for both MRD and iAMP21. However, chromosome analysis on both of these follow-up studies showed an abnormal chromosome 21. Chromosome analysis on peripheral blood lymphocytes confirmed the presence of a constitutional r(21). A subsequent genomic microarray analysis on peripheral blood sample did not show chromothripsis observed in the diagnostic bone marrow sample, but showed a 4.7 Mb terminal deletion and two interstitial deletions (3.0 Mb and 5.5 Mb) on the long arm of chromosome 21. These findings are consistent with a r(21) with interstitial deletions, which is likely responsible for the congenital anomalies reported in this patient. iAMP21 is associated with a poor outcome in B-ALL. Accurate detection of iAMP21 is critical for risk stratification and treatment in B-ALL. The strong association between iAMP21 and r(21)c has been proposed based on previous studies on r(21)c carriers with iAMP21-ALL. Our data further support an increased risk of developing iAMP21-ALL in carriers of constitutional r(21) and demonstrate the value of intensive treatment on iAMP21-B-ALL. The r(21) observed in this patient contains a relatively larger (4.7 Mb) terminal deletion along with two additional interstitial deletions. Due to the scarcity of r(21)c, the pathogenetic mechanisms of this leukemic process is not fully understood, and the clinical significance of loss of additional genetic content is unknown. More case reports are needed to generate more comprehensive clinical and genetic profile for this high risk ALL. Figure 1. Genomic microarray findings on diagnostic bone marrow sample (top) and the follow up peripheral blood sample (bottom). Chromothripsis and amplification were observed only in the diagnostic bone marrow specimen, whereas the peripheral blood sample in remission showed two interstitial and a terminal deletion. Figure 1 Disclosures No relevant conflicts of interest to declare.

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Steidl, Christian, Rainer Schabla, Ulrich Germing, Barbara Hildebrandt, Thomas Noesslinger, Michael Pfeilstoecker, Aristoteles Giagounidis et al. « Sequential Cytogenetic Analyses of 577 Patients with Myelodysplastic Syndromes : Correlations between Initial Karyotype, Cytogenetic Dynamics, and Clinical Course. » Blood 106, n^o 11 (16 novembre 2005) : 2531. http://dx.doi.org/10.1182/blood.v106.11.2531.2531.

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Abstract Myelodysplastic syndromes are dynamic diseases presenting with different clinical courses ranging from almost stable courses to rapid progression to acute myeloid leukemias. Karyotype is one of the most important prognostic factors and defines subgroups of favorable, intermediate and adverse prognosis. So far, comparably low attention has been payed on karyotypic changes occuring in sequential cytogentic examinations during the course of the disease. We retrospectively examined karyotypes of 577 patients with MDS or AML with previous history of MDS and at least two successfully performed metaphase analyses. The cytogenetic and clinical data was collected from 5 different centres of the “Kompetenznetz Akute und Chronische Leukaemien” (Duesseldorf, Duisburg, Freiburg, Goettingen, Vienna). Compared to the inital karyotype, karyotype evolution was defined as acquisition of additional aberrations, expansion of an aberrant clone by more than 20% or development of a completely aberrant karyotype after a former mosaic karyotype. According to these criteria, we found karyotype evolution in 155 cases (27%). 2–8 cytogenetic examinations have been performed per case. In 121 cases additional aberrations occured and in 34 cases the aberrant clone expanded in a subsequent analysis. In the group of patients with expansion of the aberrant clone the most frequent karyotypes were 5q- (9x) and +8 (7x). The most frequent aberrant karyotypes later acquiring additional aberrations were complex (22x) and karyotypes with two aberrations (11x), but in the vast majority of cases additional aberrations occurred on basis of a normal karyotype (70x). The most frequent additional aberrations were −7/7q- (23x), 5q- (11x) and +8 (11x). In the group of initially normal karyotypes patients with karyotype evolution had a shorter survivial (p<0.05). In summary, partial or complete momosomy 7 is the most frequent additional aberration in sequential cytogenetic analyses, indicating progression of disease. Due to their genetic instability complex karyotypes or karyotypes with 2 aberrations typically acquire additional anomalies in the course, whereas karyotypes with 5q- and +8 tend to have comparably stable courses. Furthermore, we show that also cases with a normal karyotype can harbour genetic instability as in 12% of all cases a normal karyotype evolved into an aberrant karyotype which was associated with a worse prognosis compared to stable normal karyotypes. Subgroup analyses are necessary to address correlations with therapy, time to AML progression, and the dependency on examination intervals.

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Massara, Lucía S., Marisol Delea, Lucía Espeche, Carlos D. Bruque, Jaen Oliveri, Paloma Brun, Lilian Furforo, Liliana Dain et Sandra Rozental. « Double Autosomal/Gonosomal Mosaic Trisomy 47,XXX/47,XX,+14 in a Newborn with Multiple Congenital Anomalies ». Cytogenetic and Genome Research 159, n^o 3 (2019) : 137–42. http://dx.doi.org/10.1159/000504238.

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Chromosomal trisomies are the most frequent major chromosomal anomalies in humans and can be present in a mosaic or a non-mosaic constitution. We report the first case of a newborn girl presenting with multiple congenital anomalies and a double mosaic trisomy involving chromosome 14 and the X chromosome detected by array CGH. Karyotype analysis revealed a double mosaic with 2 independent abnormal cell lines and the absence of 46,XX and 48,XXX,+14 cell lineages. The patient showed most of the clinical characteristics of mosaic trisomy 14. Analysis of autosomal DNA markers in the proband's blood sample did not support the presence of chimerism. Further analysis of chromosome X DNA markers suggests that the extra X chromosome most probably arose as a consequence of nondisjunction in meiosis II in the maternal lineage.

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Eggenhuizen, Geerke M., Attie Go, Maria P. H. Koster, Esther B. Baart et Robert Jan Galjaard. « Confined placental mosaicism and the association with pregnancy outcome and fetal growth : a review of the literature ». Human Reproduction Update 27, n^o 5 (13 mai 2021) : 885–903. http://dx.doi.org/10.1093/humupd/dmab009.

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Abstract BACKGROUND Chromosomal mosaicism can be detected in different stages of early life: in cleavage stage embryos, in blastocysts and biopsied cells from blastocysts during preimplantation genetic testing for aneuploidies (PGT-A) and later during prenatal testing, as well as after birth in cord blood. Mosaicism at all different stages can be associated with adverse pregnancy outcomes. There is an onward discussion about whether blastocysts diagnosed as chromosomally mosaic by PGT-A should be considered safe for transfer. An accurate diagnosis of mosaicism remains technically challenging and the fate of abnormal cells within an embryo remains largely unknown. However, if aneuploid cells persist in the extraembryonic tissues, they can give rise to confined placental mosaicism (CPM). Non-invasive prenatal testing (NIPT) uses cell-free (cf) DNA released from the placenta in maternal blood, facilitating the detection of CPM. In literature, conflicting evidence is found about whether CPM is associated with fetal growth restriction (FGR) and/or other pregnancy outcomes. This makes counselling for patients by clinicians challenging and more knowledge is needed for clinical decision and policy making. OBJECTIVE AND RATIONALE The objective of this review is to evaluate the association between CPM and prenatal growth and adverse pregnancy outcomes. All relevant literature has been reviewed in order to achieve an overview on merged results exploring the relation between CPM and FGR and other adverse pregnancy outcomes. SEARCH METHODS The following Medical Subject Headings (MESH) terms and all their synonyms were used: placental, trophoblast, cytotrophoblast, mosaicism, trisomy, fetal growth, birth weight, small for gestational age and fetal development. A search in Embase, PubMed, Medline Ovid, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL) and Google Scholar databases was conducted. Relevant articles published until 16 July 2020 were critically analyzed and discussed. OUTCOMES There were 823 articles found and screened based on their title/abstract. From these, 213 articles were selected and full text versions were obtained for a second selection, after which 70 publications were included and 328 cases (fetuses) were analyzed. For CPM in eight different chromosomes (of the total 14 analyzed), there was sufficient evidence that birth weight was often below the 5th percentile of fetal growth standards. FGR was reported in 71.7% of CPM cases and preterm birth (<37 weeks of delivery) was reported in 31.0% of cases. A high rate of structural fetal anomalies, 24.2%, in cases with CPM was also identified. High levels of mosaicism in CVS and presence of uniparental disomy (UPD) were significantly associated with adverse pregnancy outcomes. WIDER IMPLICATIONS Based on the literature, the advice to clinicians is to monitor fetal growth intensively from first trimester onwards in case of CPM, especially when chromosome 2, 3, 7, 13, 15, 16 and 22 are involved. In addition to this, it is advised to examine the fetuses thoroughly for structural fetal anomalies and raise awareness of a higher chance of (possibly extreme) premature birth. Despite prematurity in nearly a fifth of cases, the long-term follow-up of CPM life borns seems to be positive. More understanding of the biological mechanisms behind CPM will help in prioritizing embryos for transfer after the detection of mosaicism in embryos through PGT-A.

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Berti, Emilio, Daniele Fanoni, Francesco Onida, Valentina Girgenti, Francesca Novara, Laura Corti, Luigia Venegoni et al. « Molecular Analysis of Primary Cutaneous Aggressive T-Cell Lymphomas : the Epidermotropic CD8+, the Pleomorphic CD8+ and the Gamma Delta Subsets. » Blood 120, n^o 21 (16 novembre 2012) : 2713. http://dx.doi.org/10.1182/blood.v120.21.2713.2713.

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Abstract Abstract 2713 Primary cutaneous T-cell lymphomas (CTCL) are usually characterized by a T-helper CD4+ immunophenotype and show an indolent clinical course; on the contrary, cases harbouring a CD8+ cytotoxic immunophenotype exhibiting epidermotropism (AECTCL) or pleomorphic morphology (PTL-NOS), as well as cases with gamma-delta + (CGDL) immunophenotype, display a very different course. Clinically, these tumours are very aggressive, with poor outcome in adults. Chemotherapy, preferably based on intensive CHOP-like regimens, represents the mainstay of treatment, when possible followed by stem cell transplantation. Histologically, tumour cells constitute a population of pleomorphic medium-large size elements. In these rare CTCL subtypes few reports have been published dealing with oncogenomic investigations. With this study, by array-based comparative genomic hybridization (a-CGH) and gene expression profiling (a-GEP), we aimed to explore genomic alterations possibly involved in tumorigenesis of aggressive CTCL referred to our department. We focused on 9 cases of CD8+ AECTCL, 3 cases of CD8+ PTL-NOS and 4 cases of CGDL, who were extensively investigated by a-CGH; a-GEP was applied in 5 cases of AECTCL to further expose genomic profile of neoplastic cells. Among AECTCL patients, immunophenotype was always typical and EBV was demonstrated only in one case. Results were assessed by statistical analysis to reveal more significant common chromosomal aberrations. By a-CGH investigations, we found the presence of extensive gains and losses of both large and small chromosomal regions; copy number gains were more frequent than losses. In CD8+ cases, we observed gains of 3p21.33-p21.2 in 10 out of 12 cases, 6p21.2-p21.1 in 8/12, 7q11.23 in 9/12, 7q21.2-q22.1 in 10/12, 7q36.1-q36.3 in 7/12, 8q24.3 in 8/12, 11pter in 11/12, 11q12.3-q13.2 in 10/12, 16p13.3 in 10/12, 17q in 10/12, trisomy 19 (as a mosaic aberration) in 12/12, and trisomy 22 in 8/12; losses involved 4q12-q22.2 in 8/12, 9p21.3 in 10/12 (homozygous in 7) and 14q11.2 in 9/12. In CGDL, recurrent copy number alterations (observed in 50% to 75% of cases) were gains of 2q13-qter, 17q21.3, 19 (trisomy, as mosaic) and 22q11.21, along with losses of 4q12-q22, 6q23.3 and 9p21.3. Summarizing, most of our genomic results have been previously described in other cutaneous lymphomas: gains of 3p21 in diffuse large B-cell lymphomas (DLBCL), of 7q21 in mycosis fungoides (MF), of 8q24 in PTL-NOS and in Sézary syndrome (SS), of 11q22-q13 in DLBCL, of 16p in DLBCL and in angioimmunoblastic T-cell lymphoma (AITL), of 19p in AITL and natural killer lymphomas, trisomy 22 in AITL, PTL-NOS and SS, gain of 17q in SS and in ALCL, MF and PTL-NOS. However, we underline the loss of p21.3, determining CDKN2A deletion, as a common alteration in these three CTCL entities. We also found other common anomalies in AECTCL and PTL-NOS, with particular interest with regard to gain of 17q, 19p13 and 19q13.11-q32, which associate with the JAK/STAT signaling pathway activation. Other alterations in AECTCL cases involve c-MYC (8q24), CCND1/CDK4–6 (11q13) and IL21R (16p13.3). Worth mentioning, GEP analysis in AECTCL confirmed altered expression of CDKN2A, JAK3 and STAT6 genes. Although most genetic aberrations detected in our study have already been described in other lymphoproliferative disorders, we conclude that the combination of aberrations appears characteristic in these aggressive disorders. Disclosures: No relevant conflicts of interest to declare.

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Boulanger, L., P. Chavatte-Palmer, D. Lebouhris, N. Daniel, Y. Heyman, L. Gall, N. Borenstein et C. Cotinot. « 325 GENERATION OF A CLONED GREEN FLUORESCENT PROTEIN (GFP) EXPRESSING TRANSGENIC SHEEP FOR MUSCLE STEM CELL GRAFT EXPERIMENTS ». Reproduction, Fertility and Development 23, n^o 1 (2011) : 259. http://dx.doi.org/10.1071/rdv23n1ab325.

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Sheep are a good model for cardiopathy and surgery training in medical studies because organ volumes are similar to humans. Grafting of stem cells collected from skeletal muscles is a major area of research into treatments for heart failure. To establish an efficient protocol it is first necessary to follow the fate of grafted cells in an animal model. The aim of the project was to obtain 2 cloned sheep of the same genetic background, 1 conventional and 1 expressing green fluorescent protein (GFP), to be used for graft experiments. First, chimeric transgenic fetuses were generated by transduction of 8-cell stage embryos with a lentivirus expressing GFP under the EF1a human ubiquitous promoter. A large dilution of the lentivirus solution was used so that only some cells were transduced. Chimeric transgenic embryos were examined for GFP expression and transferred to recipients at the blastocyst stage. At 50 days of pregnancy, 8 fetuses were obtained. Three showed stable but mosaic expression of GFP in some tissues, as expected. The proportion of green cells ranged from 20 to 80% between fetuses. To make sure that low-level expression was not overlooked in GFP-negative fetuses, skin cells from each of the 8 fetuses were cultured for 10 days to isolate green from white cell colonies. This step confirmed the negative signal in 5 fetuses, but also led to the elimination of 1 positive fetus whose cells tended to switch off the GFP signal. Only 1 fetus yielded a good enough ratio of white to green cell colonies to enable the freezing of cells, which were subsequently used in 4 NT experiments. In total, 42 blastocysts were transferred to 20 recipients, of which 4 reached late pregnancy. A GFP-positive cloned fetus was delivered by C-section 4 days before term and required no intensive care. This animal is now over 6 months old and clinically normal. Expression of GFP in skin is stable and readily visualised with specialised GFP glasses. Global expression of GFP in all tissues will be followed in an F1 generation to avoid risk of contamination after biopsies in this first precious animal. Weekly ultrasound examination revealed the onset of fetal suffering (abdominal fluid accumulation, reduced heart rate, and fetal movements) in the last week before term in 3 other fetuses. These did not survive despite emergency C-section and intensive neonatal care. Fetal anomalies were similar to those observed in bovine NT. Gross placental abnormalities, however, were not present. None of the postmortem observations could be attributed to lentivirus integration as they were similar to those seen in nontransgenic cloned animals. Experiments are now proceeding to generate a normal white cloned sheep by NT using frozen nontransgenic cells from the same fetus. This will allow generation of sheep with the same genetic background that can be used to develop muscle stem cell grafting protocols. The authors thank M. Bonneau, CRII, for help in C-section, and J. P. Albert, J. Massoneau, and S. Rotg for animal care.

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KROISEL, P. M. « Skin pigmentary anomalies in a mosaic form of partial tetrasomy 3q ». Journal of Medical Genetics 37, n^o 9 (1 septembre 2000) : 723–25. http://dx.doi.org/10.1136/jmg.37.9.723.

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Van den Enden, A., M. R. Verschraegen-Spae, N. Van Roy, W. Decaluwe, C. De Praeter et F. Speleman. « Mosaic tetrasomy 15q25→qter in a newborn infant with multiple anomalies ». American Journal of Medical Genetics 63, n^o 3 (14 juin 1996) : 482–85. http://dx.doi.org/10.1002/(sici)1096-8628(19960614)63:3<482 ::aid-ajmg13>3.0.co;2-i.

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Tidrenczel, Zsolt, Erika P. Tardy, Ildikó Böjtös, Edina Sarkadi, Judit Simon, Henriett Pikó, Gábor Vermes, János Demeter et Artúr Beke. « A ritka kromoszóma-rendellenességek és a fetoplacentaris mozaikosság jelentősége a praenatalis diagnosztikában a nem invazív szűrővizsgálatok tükrében ». Orvosi Hetilap 162, n^o 29 (18 juillet 2021) : 1156–65. http://dx.doi.org/10.1556/650.2021.32098.

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Összefoglaló. Bevezetés és célkitűzés: A gyakori autoszomális trisomiák és a nemi kromoszómaeltérések a mikroszkóppal észlelhető kromoszóma-rendellenességek kb. 80–85%-át képviselik. A ritka kromoszóma-rendellenességek klinikai következménye jelentős, kimutatásukat a jelenlegi szűrővizsgálatok ugyan nem célozzák, de a teljes kromoszómaszerelvényt vizsgáló, nem invazív praenatalis tesztelés új lehetőséget nyitott a korai felismerésükre. Módszer: Retrospektív analízis (2014–2019) a mikroszkóppal kimutatható kromoszóma-rendellenességek eloszlására, a fetoplacentaris mozaikosság előfordulására, klinikai összefüggéseire a praenatalis vizsgálatok tükrében egy hazai tercier centrumban. Eredmények: 2504 invazív beavatkozást végeztünk és 200 kromoszómaeltérést mutattunk ki (8%), melyek közül újonnan kialakult, ritka rendellenesség 27 volt (13,5%). Ritka autoszomális trisomia 14, poliploidia 6, de novo szerkezeti kromoszómaeltérés 5, marker kromoszóma 2 esetben igazolódott. A fetoplacentaris mozaikosság aránya a gyakori/ritka kromoszómaeltérésekben 12,4%/77,8% volt (p = 0,001), 17/40 esetben lepényre korlátozódott. A gyakori trisomiákkal kóros tarkóredő-vastagság 58%-ban, major ultrahangeltérés 35%-ban társult, melyek jelentősen különböztek a ritka kromoszómaeltérésekben (11%, p = 0,006; 67%, p = 0,047). A ritka kromoszómaeltérések jellemző praenatalis major ultrahangeltérése a facialis dysmorphismus volt. A teljes kromoszómaszerelvényt vizsgáló praenatalis tesztelés a ritka kromoszómaeltérések 12 lepényi mozaikos esetében (44%) feltételezhetően álpozitív, 1 esetben (3,7%) álnegatív eredményt generált volna, miközben a ritka autoszomális trisomiák 2 esetében ultrahangeltérés nélkül is korán detektálta volna a ritka magzati kromoszómaeltérést (7,4%). Következtetés: A normális tarkóredő-vastagság esetén észlelt major ultrahangeltérések felhívhatják a figyelmet a döntően mozaikos ritka kromoszóma-rendellenességekre. A teljes kromoszómaszerelvényt vizsgáló, nem invazív szűrőteszt a korai diagnosztika alternatívája lehet, a mozaikosságból adódó álpozitív eredményekre azonban számítani kell. A fetoplacentaris mozaikosság ismerete fontos klinikai információt biztosít, mely befolyásolhatja a terhesség kimenetelét, a terhesség követésének módját. A pontos citogenetikai karakterizálás elengedhetetlen. Orv Hetil. 2021; 162(29): 1156–1165. Summary. Introduction and objective: To determine the prevalence of microscopically visible de novo atypical chromosomal aberrations and fetoplacental mosaicism in a prenatal tertial referral center, and to investigate the maternal and fetal characteristics in connection with genomewide non-invasive prenatal screening. Method: Retrospective cohort study from 2014 to 2019 of pregnancies with invasive genetic analysis. Results: In the cohort of 2504 cases, the proportion of CVS was 53.3%. We diagnosed 200 chromosomal aberrations (8%), including 13.5% of de novo rare chromosomal aberrations (14 rare autosomal trisomies, 6 polyploidies, 5 structural aberrations and 2 small supernumerary marker chromosomes). The rate of fetoplacental mosaicism was 12.4%/77.8% in common/atypical chromosomal aberrations (p = 0.001) and confined to placenta in 17/40 cases. Associated ultrasound abnormalities were abnormal nuchal translucency and major malformations in 58% and 35% with common trisomies and 11% (p = 0.006) and 67% (p = 0.047) with true mosaic cases of rare abnormalities, respectively. Major ultrasound malformation was facial dysmorphism with rare aberrations. Potential application of genomewide non-invasive prenatal test in atypical chromosomal aberrations presumably would have been false-positive in 12 cases (44%), false-negative in 1 case (3.7%), and would have early detected 2 cases of rare autosomal trisomies (7.4%) without ultrasound anomalies. Conclusion: Structural ultrasound malformations with normal nuchal translucency thickness may be indicative of rare chromosomal aberrations. Application of genomewide non-invasive prenatal test is an alternative of early diagnostic methods with a potential of discordant results due to mosaicism. Knowledge about the presence of fetoplacental mosaicism influences risk estimation and genetic counseling, detailed cytogenetic characterization is of utmost importance. Orv Hetil. 2021; 162(29): 1156–1165.

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Dewar, Janine, Debra Lomas, Claire O’Neill, Mary Glover, Veronica Kinsler et Satyamaanasa Polubothu. « PA04 Germline activating variants in PIK3CA result in a diffuse overgrowth phenotype characterized by macrocephaly, cardiovascular and renal anomalies : recommendations for screening and monitoring ». British Journal of Dermatology 191, Supplement_1 (28 juin 2024) : i124. http://dx.doi.org/10.1093/bjd/ljae090.259.

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Abstract Somatic activating mutations in PIK3CA cause a wide spectrum of clinical phenotypes characterized by mosaic pattern overgrowth of tissues. These are grouped under the umbrella term ‘PIK3CA-related overgrowth syndrome’ (PROS). Mosaic PROS has a reported prevalence of 1 in 28 000 live births. However, germline heterozygous PIK3CA variants leading to an overgrowth phenotype are extremely rare, reported in fewer than 20 cases to date. Here we report three new patients with germline PI3KCA variants and present this in the context of the existing literature, highlighting key clinical findings with recommendations for baseline evaluation and monitoring. Patient 1, an 11-year-old girl, was diagnosed antenatally with a single umbilical artery and presented with multiple congenital cardiac anomalies: dysplastic pulmonary valve, multiple apical muscular ventricular septal defects, patent ductus arteriosus, and secundum atrial septal defects. Other features noted include marked hypotonia, developmental delay, digit abnormalities, cutaneous capillary malformations, and bilateral duplex kidneys. Macrocephaly has been prominent throughout childhood, but with normal cranial imaging. Patient 2, a 6-year-old boy, presented with macrosomia, macrocephaly (normal cranial imaging) and subtle left-sided overgrowth with one small area of capillary malformation. He has mild developmental delay. Patient 3, a 20-month-old girl, presented with macrocephaly, left-sided capillary malformations and mild gross motor developmental delay with hypermobility. Magnetic resonance imaging findings include macrocephaly with polymicrogyria, thick corpus callosum and large cerebellum. Including our three patients, 21 patients with germline PIK3CA variants have been reported to date. Macrocephaly was a predominant feature in 95% (20 of 21), as was developmental delay 100% (9 of 9), where data were available. Importantly, of those with available data, 33% of patients had renal anomalies (3 of 9) and 71% had cardiac or vascular anomalies (10 of 14), neither of which are frequently observed in mosaic PROS. Germline heterozygous activating PIK3CA variants cause diffuse overgrowth, forming a rare but distinct part of PROS. We characterize here a cohort of patients, adding three new cases to the existing literature. Macrocephaly and developmental delay are observed almost universally in this cohort, and in contrast to mosaic PROS there is a high proportion of renal and cardiovascular anomalies. Clinicians should be alerted to these salient features and perform baseline neurological, cardiac and renal imaging at diagnosis, and ensure close neurodevelopmental monitoring. Unlike mosaic PROS, where the risk of passing the variant to offspring is small, in rare cases of gonadal mosaicism, inheritance of germline PIK3CA variants will follow an autosomal dominant pattern, thus referral to clinical genetics for counselling is critical for this cohort.

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Venditti, Charles P., Piper Hunt, Alan Donnenfeld, Elaine Zackai et Nancy B. Spinner. « Mosaic paternal uniparental (iso)disomy for chromosome 20 associated with multiple anomalies ». American Journal of Medical Genetics 124A, n^o 3 (2003) : 274–79. http://dx.doi.org/10.1002/ajmg.a.20430.

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Wyss, Danielle, Celia D. DeLozier, James Daniell et Eric Engel. « Structural anomalies of the X chromosome : personal observation and review of non-mosaic cases ». Clinical Genetics 21, n^o 2 (23 avril 2008) : 145–59. http://dx.doi.org/10.1111/j.1399-0004.1982.tb00752.x.

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Myers, T. L., et L. A. Prouty. « Non-mosaic trisomy 20 in amniotic fluid cultures with minor anomalies in the fetus ». Clinical Genetics 35, n^o 4 (28 juin 2008) : 233–36. http://dx.doi.org/10.1111/j.1399-0004.1989.tb02936.x.

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Bower, K. L., N. R. Dennis, D. Wellesley, C. P. R. Williams, P. Hodgkins, C. Tyreman, C. E. Browne et J. C. K. Barber. « New case of “Apple-Peel” intestinal atresia and ocular anomalies with mosaic variegated aneuploidy ». American Journal of Medical Genetics Part A 117A, n^o 2 (12 octobre 2001) : 200–201. http://dx.doi.org/10.1002/ajmg.a.10035.

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Mešanović, Semir, Milan Perić et Aneta Vareškić. « Prenatal Screening of Cytogenetic Anomalies -A Ten Year Retrospective Study on 1510 Cases ». European Journal of Medical and Health Sciences 5, n^o 3 (24 juin 2023) : 70–73. http://dx.doi.org/10.24018/ejmed.2023.5.3.1804.

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Introduction: Prenatal diagnostic is a diagnostic method which is used to prove the presence of chromosome changes, a large number of metabolic disorders and other morphological fetus abnormalities. Prenatal genetic testing mostly refers to the molecular genetic and cytogenetic methods used during pregnancy to diagnose genetic fetal conditions. Aim: To investigate the existence and incidence of cytogenetics abnormalities in fetuses. Material and Methods: The retrospective research is based on cytogenetic analysis of the 1510 amniotic fluid samples collected from pregnant women sent to the cytogenetic laboratory from January, 2012 to December, 2022. Results: The karyotype without visible structural and numerical changes was detected in 96.8% (1462/1510) cases. The fetal karyotype was abnormal in 3.2 % (48/1510) of the cases. Trisomy 21 was the most frequent chromosome aberration detected in 1.12% (17/1510) cases followed by pericentric inversion 9 (10/1510; 0.66%) and trisomy 18 (4/1510; 0.26%). Mosaics were detected in five cases (5/1510; 0.33%). Comparing the prevalence of chromosome abnormalities according to maternal age, we come to know the prevalence of chromosome aberrations in the group of females above age 35 (26/790; 17.2/1000) is higher than in the group of females under age 25 (7/95; 4.63/1000), but not significantly different (P= 0.09). Conclusion: Conventional cytogenetics maintains its role as a powerful diagnostic tool in detecting chromosomal changes during prenatal screening.

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Mokhtar, M. M., A. M. Abdel Aziz, N. A. Nazmy et H. S. Mahrous. « Cytogenetic profile of Down syndrome in Alexandria, Egypt ». Eastern Mediterranean Health Journal 9, n^o 1-2 (2 avril 2003) : 37–44. http://dx.doi.org/10.26719/2003.9.1-2.37.

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During 1992-2001, 673 Down syndrome patients were referred to the Department of Human Genetics in Alexandria. Regular [free] trisomy 21 constituted 95.4% of cases; Robertsonian translocation 2.7%; and mosaicism 0.7%. In 8 cases, regular trisomy 21 was associated with structural or numerical chromosome anomalies. Translocation was parentally inherited for 33.3% of cases and maternal transmission was twice as common as paternal. Two translocated Down syndrome fetuses were diagnosed prenatally in at [14; 21] carrier mother. Mean maternal age was high in regular trisomy 21 [38.2 years] but not in translocation [25.3 years]. There was an excess of males in all groups except the mosaic group where the male: female ratio was 0.67. Cytogenetic investigations assist in patient management and family counselling

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Isik, Sevgi, Gulcin Gunden, Eren Gunduz, Olga Meltem Akay, Abdulvahap Aslan, Hulya Ozen, Oguz Cilingir et al. « An Anomaly with Potential as a New Prognostic Marker in CLL with del(13q) : Gain of 16p13.3 ». Cytogenetic and Genome Research 161, n^o 10-11 (2021) : 479–87. http://dx.doi.org/10.1159/000520242.

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Deletion 13q [del(13q)] is a favorable prognostic marker if it is detected as a sole abnormality in chronic lymphocytic leukemia (CLL). However the clinical courses of cases with isolated del(13q) are quite heterogeneous. In our study, we investigated copy number variations (CNVs), loss of heterozygosity (LOH), and the size of del(13q) in 30 CLL patients with isolated del(13q). We used CGH+SNP microarrays in order to understand the cause of this clinical heterogeneity. We detected del(13q) in 28/30 CLL cases. The size of the deletion varied from 0.34 to 28.81 Mb, and there was no clinical effect of the deletion size. We found new prognostic markers, especially the gain of 16p13.3. These markers have statistically significant associations with short time to first treatment and advanced disease stage. Detecting both CNVs and LOH at the same time is an advantageous feature of aCGH+SNP. However, it is very challenging for the array analysis to detect mosaic anomalies. Therefore, it is very important to confirm the results by FISH. In our study, we detected approximately 9% mosaic del(13q) by microarray. In addition, the gain of 16p13.3 may affect the disease prognosis in CLL. However, additional studies with more patients are needed to confirm these results.

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