Articles de revues : « Probandho »

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Cotter, Philip D., Alison May, Liping Li, A. I. Al-Sabah, Edward J. Fitzsimons, Mario Cazzola et David F. Bishop. « Four New Mutations in the Erythroid-Specific 5-Aminolevulinate Synthase (ALAS2) Gene Causing X-Linked Sideroblastic Anemia : Increased Pyridoxine Responsiveness After Removal of Iron Overload by Phlebotomy and Coinheritance of Hereditary Hemochromatosis ». Blood 93, n^o 5 (1 mars 1999) : 1757–69. http://dx.doi.org/10.1182/blood.v93.5.1757.

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Abstract X-linked sideroblastic anemia (XLSA) in four unrelated male probands was caused by missense mutations in the erythroid-specific 5-aminolevulinate synthase gene (ALAS2). All were new mutations: T647C, C1283T, G1395A, and C1406T predicting amino acid substitutions Y199H, R411C, R448Q, and R452C. All probands were clinically pyridoxine-responsive. The mutation Y199H was shown to be the first de novo XLSA mutation and occurred in a gamete of the proband’s maternal grandfather. There was a significantly higher frequency of coinheritance of the hereditary hemochromatosis (HH)HFE mutant allele C282Y in 18 unrelated XLSA hemizygotes than found in the normal population, indicating a role for coinheritance ofHFE alleles in the expression of this disorder. One proband (Y199H) with severe and early iron loading coinherited HH as a C282Y homozygote. The clinical and hematologic histories of two XLSA probands suggest that iron overload suppresses pyridoxine responsiveness. Notably, reversal of the iron overload in the Y199H proband by phlebotomy resulted in higher hemoglobin concentrations during pyridoxine supplementation. The proband with the R452C mutation was symptom-free on occasional phlebotomy and daily pyridoxine. These studies indicate the value of combined phlebotomy and pyridoxine supplementation in the management of XLSA probands in order to prevent a downward spiral of iron toxicity and refractory anemia.

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Cotter, Philip D., Alison May, Liping Li, A. I. Al-Sabah, Edward J. Fitzsimons, Mario Cazzola et David F. Bishop. « Four New Mutations in the Erythroid-Specific 5-Aminolevulinate Synthase (ALAS2) Gene Causing X-Linked Sideroblastic Anemia : Increased Pyridoxine Responsiveness After Removal of Iron Overload by Phlebotomy and Coinheritance of Hereditary Hemochromatosis ». Blood 93, n^o 5 (1 mars 1999) : 1757–69. http://dx.doi.org/10.1182/blood.v93.5.1757.405a12_1757_1769.

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X-linked sideroblastic anemia (XLSA) in four unrelated male probands was caused by missense mutations in the erythroid-specific 5-aminolevulinate synthase gene (ALAS2). All were new mutations: T647C, C1283T, G1395A, and C1406T predicting amino acid substitutions Y199H, R411C, R448Q, and R452C. All probands were clinically pyridoxine-responsive. The mutation Y199H was shown to be the first de novo XLSA mutation and occurred in a gamete of the proband’s maternal grandfather. There was a significantly higher frequency of coinheritance of the hereditary hemochromatosis (HH)HFE mutant allele C282Y in 18 unrelated XLSA hemizygotes than found in the normal population, indicating a role for coinheritance ofHFE alleles in the expression of this disorder. One proband (Y199H) with severe and early iron loading coinherited HH as a C282Y homozygote. The clinical and hematologic histories of two XLSA probands suggest that iron overload suppresses pyridoxine responsiveness. Notably, reversal of the iron overload in the Y199H proband by phlebotomy resulted in higher hemoglobin concentrations during pyridoxine supplementation. The proband with the R452C mutation was symptom-free on occasional phlebotomy and daily pyridoxine. These studies indicate the value of combined phlebotomy and pyridoxine supplementation in the management of XLSA probands in order to prevent a downward spiral of iron toxicity and refractory anemia.

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Pujol, Pascal, Nathalie Alegre, Pierre vande Perre, Yves-Jean Bignon, Jean Chiesa, Marie Christine Picot, Virginie Galibert, Helena Bertet et Carole Corsini. « Psychosocial and clinical factors of probands impacting intrafamilial disclosure and uptake of genetic testing in families with BRCA1/2 or MMR gene mutations. » Journal of Clinical Oncology 37, n^o 15_suppl (20 mai 2019) : e13151-e13151. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e13151.

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e13151 Background: Intrafamilial disclosure of hereditary cancer predisposition in BRCA1/2 and mismatch repair gene (MMR) syndromes allows appropriate prevention strategies in at-risk relatives. We previously showed in a nationwide study that the uptake of genetic targeted testing (GTT) in these families by relatives was only 30%. We aimed to identify the medical and psychosocial factors affecting the proband’s intrafamilial disclosure and relatives’ uptake of GTT in BRCA1/2 or MMR syndromes. Methods: We assessed clinical variables, family history and several psychological variables of probands (depression, anxiety, alexithymia, optimism, coping, family relationship, perception of cancer risks and of hereditary transmission risks), together with disclosure and verified uptake of GTT in BRCA1/2 or MMR families. Results: Among relatives eligible for GTT, 68% were informed of the predisposition and 37% underwent GTT, according to proband reports. Intrafamilial disclosure was inversely associated with the degree of kinship (P < 0.01). In multivariable analysis, disclosure increased with time since proband’s genetic diagnosis (P < 0.01) and proband’s feeling of family cohesion (P = 0.01). GTT uptake increased with proband’s depression score (P = 0.02) and decreased with proband’s perception of cancer risks (P = 0.03). BRCA1/2 and MMR groups did not differ in findings concerning family information and GTT uptake. Conclusions: This study identified factors affecting disclosure to relatives and GTT uptake in BRCA1/2 and MMR syndromes and gives new insights to improve probands’ follow-up and intrafamilial sharing of genetic information.

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Fisher, S. G., P. Mumby et S. Kohli. « Effect of familial breast cancer outcomes on health behaviors of relatives ». Journal of Clinical Oncology 25, n^o 18_suppl (20 juin 2007) : 1521. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.1521.

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1521 Background: While the disease outcomes of breast cancer probands do not affect the objective risk of first degree relatives (FDR), the morbidity and mortality experience may impact their subsequent perceptions and health behaviors. This study examines the influence of a proband’s disease course on screening behaviors, perceived risk, self-efficacy, traumatic stress and related mood disturbances of FDR. Methods: A cross-sectional sample of 149 FDR was recruited (79% of respondents) by invitations distributed by 545 probands. Respondents were categorized into a ‘high impact’ group whose familial proband had expired, relapsed or undergone intensive chemotherapy (n=55), and a ‘low impact’ group whose proband was disease-free after surgery ± radiation (n=94). This sample provided a power of 84% for detection of a 1.5 unit difference in screening indices and a 10% difference in perceived risk between groups with a two-sided alpha level of 0.05. Parameters were measured by self-administered, mailed surveys of newly-developed and established instruments. Objective risk assessments were completed by a genetic counselor. Statistical analyses included parametric and non-parametric methods, as appropriate. Results: While the high impact group reported perceptions of greater familial proband suffering (8.6 vs.5.8) and greater anxiety and doubt regarding mammography benefits (11% vs. 1%) (p<0.01), there was no statistically significant difference between groups in screening behaviors or perceived risk. The high impact group experienced sleep disturbances (28%), emotional stress (52%), and mood swings (61%) more often than the comparison group (p<0.001). FDR with the highest objective risk had significantly higher scores on screening indices and perceived risk (p<0.01) but significantly lower knowledge regarding breast cancer (p=0.04). Conclusions: This study suggests that while morbidity and mortality of familial probands is not associated with screening practices of FDR, it does have a negative impact on their psychological well-being. Enhanced strategies to educate and support FDR regarding familial breast cancer risk and potential psychological repercussions of the proband’s experience are warranted. No significant financial relationships to disclose.

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De Paiva, Isaias Soares, Gleyson da Cruz Pinto, Fellipe Carlos Correa Batista et Caroline Graça De Paiva. « Mucopolissacaridose IIIB – relato de três casos e estimativa da incidência no município de Teresópolis - RJ ». Brazilian Journal of Health Review 6, n^o 4 (29 août 2023) : 19091–106. http://dx.doi.org/10.34119/bjhrv6n4-399.

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As mucopolissacaridoses (MPSs), são doenças metabólicas hereditárias raras, causadas pela deficiência de uma enzima lisossomal, necessária para degradar os glicosaminoglicanos (GAGs). Atualmente 11 deficiências enzimáticas estão envolvidas em MPS, produzindo sete fenótipos clínicos, classificadas em tipo I, II, III, IV, VI, VII e IX, de acordo com a deficiência enzimática específica. A MPS III ou Síndrome de Sanfilippo é subdividida em quatro subtipos: IIIA, IIIB, IIIC e IIID, de acordo com a deficiência enzimática. A incidência global da MPS é 1:25.000 a 1:45.000. A incidência da MPS III varia de 0,004:100.000 a 2,40:100.000, sendo mais frequente em países do sul da Europa. No Brasil, a incidência é muito inferior, estimando-se 0,09:100.000. Relatar três pacientes com diagnóstico de MPS III e estimar sua incidência no município de Teresópolis/RJ. estudo descritivo constando de relato de caso e estimativa da incidência da MPS III em Teresópolis/RJ. Probanda 1 – GCB, 13 anos, feminino, branca. Mãe Gesta III, Para III. Nasceu de parto cesáreo no termo; pesou 3.300 gramas e mediu 51 cm. Sintomas neurológicos proeminentes após sete anos idade. Ensaio enzimático NAGLU diminuído. Probando 2 – PFC, 22 meses, masculino, branco. Referido por fenótipo MPS. Quinto filho de pais consanguíneos. Nasceu parto cesáreo, termo; pesou 2.700 gramas, mediu 47 cm. Ensaio enzimático para NAGLU indetectável. Probanda 3 - MECO, 31 meses, feminino. Primeira filha de pais consanguíneos. Nasceu parto cesáreo, termo; pesou 4.200 gramas, mediu 51 cm. Os três probandos são naturais de Teresópolis/RJ, filhos de pais consanguíneos, evoluiram com atraso do DNPM e apresentavam fenótipo típico MPS e hepatoesplenomegalia. A incidência estimada de MPS III na cidade Teresópolis é superior à incidência global e brasileira. A probanda 1 apresentava sintomas neurológicos predominantes, enquanto os probandos 2 e 3 tinham sintomas somáticos predominantes e precoces, o que não é habitual na MPS III. Todos os pacientes eram filhos de pais consanguíneos e apresentavam o fenótipo típico de MPS. A incidência de MPS III de 1,81:100.000 é muito alta em relação à incidência global e brasileira.

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Pedrazzani, Carla, Monica Aceti, Reka Schweighoffer, Andrea Kaiser-Grolimund, Nicole Bürki, Pierre O. Chappuis, Rossella Graffeo et al. « The Communication Chain of Genetic Risk : Analyses of Narrative Data Exploring Proband–Provider and Proband–Family Communication in Hereditary Breast and Ovarian Cancer ». Journal of Personalized Medicine 12, n^o 8 (29 juillet 2022) : 1249. http://dx.doi.org/10.3390/jpm12081249.

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Low uptake of genetic services among members of families with hereditary breast and ovarian cancer (HBOC) suggests limitations of proband-mediated communication of genetic risk. This study explored how genetic information proceeds from healthcare providers to probands and from probands to relatives, from the probands’ perspectives. Using a grounded-theory approach, we analyzed narrative data collected with individual interviews and focus groups from a sample of 48 women identified as carriers of HBOC-associated pathogenic variants from three linguistic regions of Switzerland. The findings describe the “communication chain”, confirming the difficulties of proband-mediated communication. Provider–proband communication is impacted by a three-level complexity in the way information about family communication is approached by providers, received by probands, and followed-up by the healthcare system. Probands’ decisions regarding disclosure of genetic risk are governed by dynamic and often contradictory logics of action, interconnected with individual and family characteristics, eventually compelling probands to engage in an arbitrating process. The findings highlight the relevance of probands’ involvement in the communication of genetic risk to relatives, suggesting the need to support them in navigating the complexity of family communication rather than replacing them in this process. Concrete actions at the clinical and health system levels are needed to improve proband-mediated communication.

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Miller, Jessica E., Kim W. Carter, Nicholas de Klerk et David P. Burgner. « The familial risk of infection-related hospitalization in children : A population-based sibling study ». PLOS ONE 16, n^o 4 (28 avril 2021) : e0250181. http://dx.doi.org/10.1371/journal.pone.0250181.

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Objective To assess the risk of severe childhood infections within families, we conducted a sibling analysis in a population-based cohort study with genealogical linkage. We investigated the sibling risk of hospitalization with common infections, a marker of severity. We hypothesized that having siblings hospitalized for infection would increase the proband’s risk of admission with infection. Study design We used population data on Western Australian live-born singletons and their siblings between 1980 and 2014. Measures of infection were infection-related hospitalizations from discharge diagnostic codes. Exposure was having a sibling who had an infection-related hospitalization. Outcomes were infection-related hospitalizations in the child/proband. Probands were followed until an infection-related hospitalization admission (up to the first three), death, 18th birthday, or end of 2014, whichever occurred first. Infection risks were estimated by adjusted Cox proportional hazard models for multiple events. Results Of 512,279 probands, 142,915 (27.9%) had infection-related hospitalizations; 133,322 (26.0%) had a sibling with a previous infection-related hospitalization (i.e. exposed). Median interval between sibling and proband infection-related hospitalizations was 1.4 years (inter-quartile range 0.5–3.7). Probands had a dose-dependent increase in risk if sibling/s had 1, 2, or 3+ infection-related hospitalizations (adjusted hazard ratio, aHR 1.41, 95% CI 1.39–1.43; aHR 1.65, 1.61–1.69; aHR 1.83, 1.77–1.90, respectively). Among siblings with the same clinical infection type, highest sibling risks were for genitourinary (aHR 2.06, 1.68–2.53), gastrointestinal (aHR 2.07, 1.94–2.19), and skin/soft tissue infections (aHR 2.34, 2.15–2.54). Overall risk of infection-related hospitalization was higher in children with more siblings and with older siblings. Conclusion In this population-based study, we observed an increased risk of infection-related hospitalization in children whose siblings were previously hospitalized for infection. Public health interventions may be particularly relevant in families of children hospitalized with infection.

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Scheftner, William A., Michael A. Young, Jean Endicott, William Coryell, Louis Fogg, David C. Clark et Jan Fawcett. « Family History and Five-year Suicide Risk ». British Journal of Psychiatry 153, n^o 6 (décembre 1988) : 805–9. http://dx.doi.org/10.1192/bjp.153.6.805.

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Family history was examined to determine whether suicide in index patients is associated with suicidal behaviour or mental disorder in their first-degree relatives. Twenty-seven suicides occurred within 5½ years among 955 affectively disordered probands. Among 5042 proband relatives aged 18 years and older, 44 had committed suicide prior to proband entry to the study; however, only one was the relative of a proband suicide. Only two of the relatives who committed suicide were themselves related. As to attempted suicide of relatives, neither the number of attempts nor the severity of attempt was predictive of suicide in probands. Comparison of diagnosis between groups of relatives showed more drug abuse among relatives of proband suicides; this appears to be related to drug abuse among the proband suicides themselves. In contrast to the clustering of suicides within biological families found in other research, these data do not support the use of family history as a clinically useful indicator of suicidal potential in affectively disordered probands.

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Rice, Mabel L., Karla R. Haney et Kenneth Wexler. « Family Histories of Children With SLI Who Show Extended Optional Infinitives ». Journal of Speech, Language, and Hearing Research 41, n^o 2 (avril 1998) : 419–32. http://dx.doi.org/10.1044/jslhr.4102.419.

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Previous family history studies have demonstrated that there are elevated rates of language and language-related impairments in families identified through probands with language impairments. This study examines family histories of children with specific language impairment (SLI) known to have particular grammatical limitations in a core feature of grammatical acquisition, a stage known as Extended Optional Infinitives (EOI). Family affectedness rates are reported for 31 families identified through preschool probands with this clearly defined language impairment and 67 control families, identified through nonaffected preschool children developmentally similar to the probands. It was found that significantly more speech and language difficulties, as well as language-related difficulties, such as reading, were reported for proband families than control families. The elevated rates were obtained for nuclear family members and extended family members as well. Fathers of probands were more often reported as having difficulties (29% for speech/language impairments) than were mothers of probands (7%), but there was no difference between brothers (26%) and sisters (29%). No differences were evident between proband families based on proband gender. The findings are relevant for theoretical models of sources of unexplained variations in grammatical competence in young children. In addition, the findings contribute new information about expected rates of affectedness, means of identification of affected family members, and comorbidity of symptomatology.

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Zhuang, Jianlong, Yu Zheng, Yuanbai Wang, Qianmei Zhuang, Yuying Jiang, Qingyue Xie, Shuhong Zeng et Jianxing Zeng. « Identification of a new β-thalassaemia variant Term CD+32(HBB : c.32A>C) in two Chinese families ». Journal of Clinical Pathology 73, n^o 9 (27 février 2020) : 593–96. http://dx.doi.org/10.1136/jclinpath-2020-206426.

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Aimsβ-Thalassaemia is an inherited blood disorder caused by mutations in the β-globin gene cluster. Molecular characterisation of β-thalassaemia is essential for its diagnosis and management. More and more rare and novel mutations have been reported.MethodsTwo Chinese families with β-thalassaemia from Fujian Province were recruited in this study. The phenotypes of the probands were confirmed through haematological analysis. Routine molecular analysis of thalassaemia was employed to identify the common mutations of thalassaemia. The rare and novel mutations were detected by direct DNA sequencing.ResultsIn family 1, the proband, a Chinese woman aged 31 years, showed elevated level of haemoglobin A2 (HbA2). No common mutations associated with β-thalassaemia were detected, whereas a rare mutation Term CD+32(HBB: c.32A>C) was identified through DNA sequencing. Subsequent investigation of the β-thalassaemia mutation in her family showed that her mother, her brother as well as her nephew also carried this mutation. In addition, both the proband’s husband and her son carrying the rare --THAI mutation exhibited decreased levels of MCH, MCH and HbA2. In family 2, the proband, a child aged 1 year, showed elevated level of HbA2, but had no common mutations of β-thalassaemia. The proband was identified carrying the mutation Term CD+32(HBB: c.32A>C), which was inherited from his mother.ConclusionsIn this study, we first report a rare β-thalassaemia mutation in Fujian Province, Southeast China. Moreover, our study also identified this rare mutation in humans. This finding has helped broaden the spectrum of β-thalassaemia mutations in our region and suggested that this rare mutation may be more prevalent in the Chinese population.

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Meschia, James F., Robert D. Brown, Thomas G. Brott, John Hardy, Elizabeth J. Atkinson et Peter C. O’Brien. « Ischemic Stroke Mechanism and Likelihood of Having a Positive Family History of Stroke ». Stroke 32, suppl_1 (janvier 2001) : 361. http://dx.doi.org/10.1161/str.32.suppl_1.361-b.

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P122 Introduction: It is not known whether the magnitude of the inherited component to ischemic stroke risk varies according to presumed mechanism. Differences in familial aggregation of stroke might imply differences in the magnitude of inherited stroke risk. Methods: Probands were eligible for entry into a two-center prospective consecutive patient registry if they presented with an ischemic stroke within 180 days of onset of symptoms. Stroke was defined using WHO criteria. A stroke was considered ischemic if CT or MR imaging done within 7 days of onset of symptoms failed to reveal an alternative diagnosis. Probands were excluded if they had onset of symptoms within 48 hours of a cerebrovascular or cardiovascular proceedure or within 60 days of a nontraumatic subarachnoid hemorhage. Probands were also excluded if they were known to have: CADASIL, Fabry’s disease, homocysteinuria, MELAS, sickle cell disease, mechanical aortic or mitral valve, or biopsy-proven CNS vasculitis. Proband family history was obtained by systematic interview of the proband or next-of-kin. Proband past medical history was obtained by proband interview, record review, or both. A neurologist confirmed the diagnosis of and assigned a TOAST subtype to all index ischemic strokes. A positive family history was defined as a history of stroke in at least one parent or full sibling. Results: We enrolled 283 probands (median age, 75 yrs; male, 52%). Frequencies of TOAST subtypes were: cardioembolic, 17.0% (n=48); large-vessel, 24.7% (n=70); small-vessel, 23.0% (n=65); other, 2.5% (n=7); and unknown, 32.9% (n=93). Frequencies of positive family history by proband ischemic stroke subtype were: cardioembolic, 43.8% (95%CI, 29.5–58.8); large-vessel, 40.0% (95%CI, 28.5–52.4); small-vessel, 47.7% (95%CI, 35.1–60.5); other, 42.9% (95%CI, 9.9–81.6%); and unknown 48.8% (95%CI, 37.9–59.0). Frequencies were not significantly different among subtypes (P=0.718, chi square). Conclusions: The magnitude of inherited risk may not differ dramatically for various clinical subtypes of ischemic stroke. Qualitative differences in inherited stroke risk may exist at the molecular level.

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Susanti, Reka, Bhakti Karyadi, Deni Parlindungan et Aceng Ruyani. « Pengaruh Minuman Segar Buah Etlingera hemisphaerica (MSBE) terhadap Kadar Asam Urat dan Kolesterol Warga Kabupaten Lebong dan Kepahiang ». Bioscientist : Jurnal Ilmiah Biologi 11, n^o 1 (30 juin 2023) : 279. http://dx.doi.org/10.33394/bioscientist.v11i1.7303.

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Fresh fruit drink Etlingera hemisphaerica (forest honje; MSBE) has been produced, and has obtained a distribution permit in the community. It is deemed necessary to study the benefits of MSBE. This limited clinical study aims to determine the effect of MSBE administration on uric acid and cholesterol levels in residents of Lebong and Kepahiang Regencies, Bengkulu Province. Five (5) men from Lebong and five (5) men from Kepahiang who were involved as probands in limited clinical research. Initial levels of uric acid and cholesterol for each probandus were measured by Auto Check. Each probandus was asked to consume MSBE once a day for seven (7) days. On the 8th day, the probandus uric acid and cholesterol levels were measured again by Auto Check. The levels of uric acid and cholesterol before and after the probandus consumed MSBE were then compared. Uric acid levels in 10 probands before (5.95 ± 1.48 mg/dL) and after (6.56 ± 1.64 mg/dL) MSBE consumption tended to increase but were not significantly different. Uric acid levels in Lebong residents before (6.40 ± 1.78 mg/dL) and after (6.60 ± 1.42 mg/dL) tended to increase but were not significantly different, while uric acid levels in Lebong residents before (5.50 ± 1.10 mg/dL) and after (6.52 ± 2.01 mg/dL) tended to increase but not significantly different. Cholesterol levels in 10 probands before (144.30 ± 17.38 mg/dL) and after (147.60 ± 29.53 mg/dL) MSBE consumption tended to increase but were not significantly different. Cholesterol levels in Lebong residents before (134.00 ± 17.99 mg/dL) and after (166.40 ± 18.73 mg/dL) tended to increase but were not significantly different, while cholesterol levels in Lebong residents before (154.60 ± 9.53 mg/dL) and after (128.80 ± 26.97 mg/dL) tended to decrease but not significantly different. MSBE consumption for one week had no significant effect on probandus uric acid and cholesterol levels. Cholesterol levels in Kepahiang residents tend to decrease after consuming MSBE.

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Grigoroiu-Serbanescu, M., et R. C. Elston. « Incongruent psychosis in bipolar i disorder : heritability and importance for genetic association studies ». European Psychiatry 26, S2 (mars 2011) : 213. http://dx.doi.org/10.1016/s0924-9338(11)71923-x.

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IntroductionPhenotype homogeneity and heritability are important conditions for identifying the genetic basis of bipolar I disorder (BPI) in association studies. Our objective was to study the heritability of mood-incongruent psychosis (MIP) in BPI in a sample of 504 families ascertained through BPI probands (294 females; 210 males) recruited from consecutive hospital admissions.MethodThere were 402 families with a psychotic proband and 275 families with a proband with MIP. All probands were directly interviewed as well as 79.55% first-degree and 22.59% second-degree relatives. The narrow and the broad sense heritability (h2) of MIP and the effect of sex and age were estimated using S.A.G.E.v.6.01-software (2009).ResultsThere was no sex difference for the psychosis prevalence in probands but MIP was two times more frequent in females than in males. In families with MIP probands the narrow-sense h2 for MIP was 0.14 (SE = 0.02, P = 0.002) and the broad-sense h2 was 0.20 (SE = 0.014, P = 0.0000). Significant but lower heritabilities were found in families with a psychotic proband (narrow-sense h2 = 0.12; broad-sense h2 = 0.13). In the total sample the narrow-sense h2 was 0.06 (P < 0.005) and the broad-sense h2 was 0.10 (P < 0.00001). The female sex was more prone to incongruency (χ2 = 33.32, P = 0.0000).ConclusionThe heritability of MIP was significant but not high in families ascertained through BPI probands regardless of familial psychopathology. These finding is in line with GWAS-studies showing that the polygenic score fails to differentiate psychotic BPI from non-psychotic BPI. Is therefore incongruent psychosis a useful dimension for association studies?

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Hlavatá, Lucia, Ľubica Ďuďáková, Jana Moravíková, Anna Zobanová, Bohdan Kousal et Petra Lišková. « Molecular Genetic Cause of Achromatopsia in Two Patients of Czech Origin ». Czech and Slovak Ophthalmology 75, n^o 5 (21 octobre 2019) : 272–76. http://dx.doi.org/10.31348/2019/5/5.

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Introduction: Achromatopsia is an autosomal recessive retinal disorder with an estimated prevalence ranging from 1 in 30.000 to 50.000. The disease is caused by mutations in six different genes. The aim of the study was to perform molecular genetic analysis in 11 unrelated probands with a clinical diagnosis of achromatopsia and to describe clinical findings in those that were found to carry biallelic pathogenic mutations. Methods: All probands and their parents underwent ophthalmic examination. Mutation detection was performed using Sanger sequencing of CNGB3 exons 6, 7, 9-13, which have been found to harbour most diseasecausing mutations in patients with achromatopsia of European origin. Results: Three known pathogenic variants in CNGB3 were identified in 2 probands. Proband 1 was a compound heterozygote for the c.819_826del; p.(Arg274Valfs*13) and c.1006G>T; p.(Glu336*). Proband 2 carried the c.1148del; p.(Thr383Ilefs*13) in a homozygous state. The best corrected visual acuity in proband 1 (aged 19 years) was 0.1 in both eyes, in proband 2 (aged 8 years) 0.05 in the right eye and 0.1 in the left eye. Both individuals had nystagmus, photophobia, and absence of colour discrimination. Fundus examination appeared normal however spectral-domain optical coherence tomography revealed subtle bilaterally symmetrical structural changes in the fovea. Conclusion: Molecular genetic analysis of Czech patients with achromatopsia was performed for the first time. Identification of diseasecausing mutations in achromatopsia is important for establishing an early diagnosis, participation in clinical trials assessing gene therapies and may be also used for preimplantation genetic diagnosis.

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Fontaine, Robert, Ping Wang et Charles Glueck. « Interaction of Heritable and Estrogen-induced Thrombophilia : Possible Etiologies for Ischemic Optic Neuropathy and Ischemic Stroke ». Thrombosis and Haemostasis 85, n^o 02 (2001) : 256–59. http://dx.doi.org/10.1055/s-0037-1615698.

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SummaryOur specific aim was to assess how thrombophilic exogenous estrogens interacted with heritable thrombophilias leading to nonarteritic ischemic optic neuropathy (NAION) and ischemic stroke. Coagulation measures were performed in a 74 year old patient and her immediate family. The proband had a 47 year history of 9 previous thrombotic episodes, and developed unilateral NAION 4 years after starting estrogen replacement therapy (ERT). The proband was heterozygous for two thrombophilic gene mutations (G20210A prothrombin gene, platelet glycoprotein IIIa PlA1/A2 polymorphism), and homozygous for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. Of 238 normal controls, none had these 3 gene mutations together. The proband’s mother and brother had deep venous thrombosis (DVT). The proband’s brother, sister, nephew, daughter, and two granddaughters were homozygous for the C677T MTHFR mutation. The proband’s brother was heterozygous for the G20210A prothrombin gene mutation. The proband’s niece was heterozygous for the G20210A prothrombin gene mutation, homozygous for the C677T MTHFR mutation, homozygous for the hypofibrinolytic 4G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene, and heterozygous for the platelet glycoprotein IIIa PlA1/A2 polymorphism. Of 238 normal controls, none had the niece’s combination of 4 gene mutations. When ERT-mediated thrombophilia was superimposed on the proband’s heritable thrombophilias, unilateral ischemic optic neuropathy developed, her tenth thrombotic event over a 5 decade period. When estrogenprogestin oral contraceptives were given to the proband’s niece, she had an ischemic stroke at age 22. Exogenous estrogen-mediated thrombophilia superimposed on heritable thrombophilia and hypofibrinolysis is associated with arterial and venous thrombi, and appears to be a preventable, and potentially reversible etiology for ischemic optic neuropathy and ischemic stroke.

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Xian, Xiaoying, Lin Liao, Wei Shu, Hongtao Li, Yuanyuan Qin, Jie Yan, Jianming Luo et Fa-Quan Lin. « A Novel Mutation of SLC19A2 in a Chinese Zhuang Ethnic Family with Thiamine-Responsive Megaloblastic Anemia ». Cellular Physiology and Biochemistry 47, n^o 5 (2018) : 1989–97. http://dx.doi.org/10.1159/000491467.

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Background/Aims: Thiamine-responsive megaloblastic anemia syndrome is a rare autosomal recessive disorder resulting from mutations in SLC19A2, and is mainly characterized by megaloblastic anemia, diabetes, and progressive sensorineural hearing loss. Methods: We study a Chinese Zhuang ethnicity family with thiamine-responsive megaloblastic anemia. The proband of the study presented with anemia and diabetes, similar to his late brother, as well as visual impairment. All clinical manifestations were corrected with thiamine (30 mg/d) supplementation for 1–3 months, except for visual impairment, which was irreversible. The presence of mutations in all exons and the flanking sequences of the SLC19A2 gene were analyzed in this family based on the proband’s and his brother’s clinical data. Computer analysis and prediction of the protein conformation of mutant THTR-1. The relative concentration of thiamine pyrophosphate in the proband’s whole blood before and after initiation of thiamine supplement was measured by high performance liquid chromatography (HPLC). Results: Gene sequencing showed a homozygous mutation in exon 6 of the SLC19A2 gene (c.1409insT) in the proband. His parents and sister were diagnosed as heterozygous carriers of the c.1409insT mutation. Computer simulation showed that the mutations caused a change in protein conformation. HPLC results suggested that the relative concentration of thiamine pyrophosphate in the proband’s whole blood after thiamine supplement was significantly different (P=0.016) from that at baseline. Conclusions: This novel homozygous mutation (c.1409insT) caused the onset of thiamine-responsive megaloblastic anemia in the proband.

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Vaillant, George E., George E. Vaillant, Maren Batalden, John Orav, Diane Roston et James E. Barrett. « Evidence for a Possibly X-Linked Trait Related to Affective Illness ». Australian & ; New Zealand Journal of Psychiatry 39, n^o 8 (août 2005) : 730–35. http://dx.doi.org/10.1080/j.1440-1614.2005.01658.x.

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Objective: The present report attempts to replicate on the probands' brothers, a previously reported (1992) negative relationship between maternal grandfather longevity (MGFL) and affective illness in grandsons. Hitherto this finding had not been replicated. To provide further evidence that the association may be recessive and X-linked, we also examined the association between MGFL and affective illness in the probands' mothers. Finally, in order to examine why MGFL might be a predictor of affective illness, the report examines the association of the probands' affective illness and their own mortality. Method: A 60-year prospective study of men selected in 1940 and followed until the present day provided good information on depressive illness in relatives and longevity of ancestors. To overcome the uncertainty of depressive diagnoses, we assessed affective illness in the probands categorically, dimensionally, operationally and with the Lazare Personality Inventory. Results: Presence of affective illness in brothers was negatively associated with MGFL (p=0.003) but maternal affective illness was independent of MGFL. Test items suggesting emotional lability in the probands were significantly and negatively associated with MGFL. Consistent with the association of increased MGFL with low affective distress in the probands, the 70 probands showing the least evidence of affective distress before age 50 had twofold (p<0.001) lower mortality at 80 than the rest of the sample. The 31 probands manifesting the greatest affective distress manifested twofold higher mortality before age 65 (p<0.001) than the rest of the sample. Conclusion: The strong negative association of proband affective distress – and equally important – the positive association of proband mental health with MGFL and the lack of association of maternal longevity and depression with MGFL points to the possibility of a recessive X-gene or genes playing a role in depressive illness.

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Smith, Maria, Kristina Hwang, Julia Anne Smith et Bhavana Pothuri. « Evaluation of proband adherence and satisfaction with a prospective cascade testing protocol. » Journal of Clinical Oncology 39, n^o 15_suppl (20 mai 2021) : 10593. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.10593.

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10593 Background: We sought to evaluate the feasibility of a Cascade Testing (CT) protocol for family members of probands with actionable germline mutations associated with endometrial or ovarian cancer. Here, we characterize proband compliance with contacting family members for CT and proband satisfaction/regret. Methods: In this prospective study, consenting patients with pathogenic germline mutations associated ovarian or endometrial cancer completed a demographic survey and were asked to contact first- and second-degree relatives with genetic testing results. After a 1–3-month period, probands completed a survey indicating how many relatives had been contacted. At 3 months following consent, probands were asked to complete the validated Impact of Event Scale (IES) and Decision Regret Scales (DRS). Characteristics of probands who contacted relatives and those who did not were compared. Results: The study has accrued 57 probands since opening in March 2019. Germline mutations identified in the 57 probands include 27 BRCA1 (47.4%); 21 BRCA2 (36.8%); 3 BRIP1 (5.3%); 2 MLH1 (3.5%); 2 MSH2 (3.5%); 3 MSH6 (5.3%); 3 PMS2 (5.3%); 1 EPCAM (1.8%); 1 RAD50 (1.8%). Twenty-four (42.1%) probands had a history of cancer (breast 12; ovarian 8; uterine 2; other 5). Of the probands, 32 (56.1%) completed follow-up questionnaires and 29 (50.9%) had contacted relatives about participating in CT. In total, 67 relatives were contacted. Probands contacted an average of 1 relative, ranging from 1-20. Of the 29 probands who contacted relatives, 13 (44.8%) completed IES and DRS questionnaires. The median IES score was 0 out of 75 (IQR 0.0-4.5) and the median DRS score was 0 out of 100 (IQR 0.0-11.3). When comparing characteristics of probands who contacted relatives with those who did not, those with annual household incomes <$75,000 were more likely to contact relatives vs those with incomes ≥$75,000 (77.8% vs 39.5%; p=0.01). There was no association between contacting relatives and personal cancer history, race/ethnicity, education status, or age (Table). Conclusions: Half of probands enrolled in this study contacted relatives about CT, and those with household incomes <$75,000 were more likely to contact relatives than those with higher incomes. Overall, probands reported little/no regret or distress after contacting relatives about genetic testing results.[Table: see text]

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FYER, ABBY J., JOSHUA D. LIPSITZ, SALVATORE MANNUZZA, BONNIE ARONOWITZ et TIMOTHY F. CHAPMAN. « A direct interview family study of obsessive–compulsive disorder. I ». Psychological Medicine 35, n^o 11 (28 juillet 2005) : 1611–21. http://dx.doi.org/10.1017/s0033291705005441.

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Background. This and the companion paper present two sequential family studies of obsessive–compulsive disorder (OCD) conducted by the same research group, but with different sampling and best-estimate procedures. In addition to providing further data on familial transmission of OCD, we used comparison of disparate findings (moderate, specific familial aggregation in this first study versus a stronger effect for other anxiety disorders than for OCD alone in the second) to examine possible effects of proband characteristics and informant data on outcome.Method. In this initial study we interviewed 179 first-degree relatives of 72 OCD probands and 112 relatives of 32 never mentally ill (NMI) controls. Informant data were obtained on an additional 126 relatives (total ‘combined’ samples of 263 and 154 respectively). Analyses used best-estimate diagnoses made by consensus of two ‘blinded’ senior clinicians who reviewed all diagnostic materials including proband informant data about relatives.Results. Significantly higher risk for OCD but not other anxiety disorders was found in relatives of OCD probands compared to relatives of controls in both the directly interviewed and combined samples. There was no relationship between proband age at onset of OCD and strength of familial aggregation.Conclusions. These data indicate moderate familial aggregation of OCD, but do not support increased transmission by early onset probands, or a familial relationship between OCD and other anxiety disorders with the possible exception of generalized anxiety disorder.

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Kendler, Kenneth S. « Is seeking treatment for depression predicted by a history of depression in relatives ? Implications for family studies of affective disorder ». Psychological Medicine 25, n^o 4 (juillet 1995) : 807–14. http://dx.doi.org/10.1017/s0033291700035054.

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SYNOPSISMost family studies of psychiatric illness ascertain probands through treatment facilities. If psychiatric illness in relatives influences the probability of treatment seeking, then the risk of illness in the relatives of treated probands will not be representative of the risk of illness in all probands. We have investigated this question in a population-based sample of female twins with lifetime history of DSM-III-R defined major depression (MD) (N = 753), 36% of whom reported seeking professional help for their depression. Logistic and Cox regression methods were used. Treatment seeking for MD was significantly associated with age, education, comorbidity with anxiety disorders, degree of impairment and number of symptoms. Controlling for these predictors, treatment seeking was significantly predicted by the presence of one or more relatives with a lifetime diagnosis of MD (OR = 1·62). The probability of treatment seeking for MD in the proband was significantly increased if the affected relative: (i) had an onset of their MD prior that of the proband and; (ii) themselves sought treatment for their depression. Seeking treatment in this epidemiological sample of depressed women was associated with a 32% increase in risk of MD in relatives. Selecting probands for family studies from treated populations may select for families with an increased rate of illness. For MD, this artefact can explain only a modest proportion of the familial aggregation observed in prior family studies that utilized treated probands.

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Sham, Pak Chung, Peter Jones, Ailsa Russell, Karyna Gilvarry, Paul Bebbington, Shôn Lewis, Brian Toone et Robin Murray. « Age at Onset, Sex, and Familial Psychiatric Morbidity in Schizophrenia ». British Journal of Psychiatry 165, n^o 4 (octobre 1994) : 466–73. http://dx.doi.org/10.1192/bjp.165.4.466.

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BackgroundAlthough a genetic component in schizophrenia is well established, it is likely that the contribution of genetic factors is not constant for all cases. Several recent studies have found that the relatives of female or early onset schizophrenic patients have an increased risk of schizophrenia, compared to relatives of male or late onset cases. These hypotheses are tested in the current study.MethodA family study design was employed; the probands were 195 patients with functional psychosis admitted to three south London hospitals, diagnosed using Research Diagnostic Criteria (RDC), and assessed using the Present State Examination (PSE). Information on their relatives was obtained by personal interview of the mother of the proband, and from medical records. Psychiatric diagnoses were made using Family History – Research Diagnostic Criteria (FH-RDC), blind to proband information.ResultsThere was a tendency for homotypia in the form of psychosis within families. The lifetime risk of schizophrenia in the first degree relatives of schizophrenic probands, and the risk of bipolar disorder in the first degree relatives of bipolar probands, were 5–10 times higher than reported population risks. Relatives of female and early onset (<22 years) schizophrenic probands had higher risk of schizophrenia than relatives of male and late onset schizophrenic probands. However, this effect was compensated in part by an excess of non-schizophrenic psychoses in the relatives of male probands.ConclusionsThese results suggest a high familial, possibly genetic, loading in female and early onset schizophrenia, but do not resolve the question of heterogeneity within schizophrenia.

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Pulver, Ann E., Kung-Yee Liang, C. Hendricks Brown, Paula Wolyniec, John McGrath, Lawrence Adler, Doreen Tam, William T. Carpenter et Barton Childs. « Risk Factors in Schizophrenia ». British Journal of Psychiatry 160, n^o 1 (janvier 1992) : 65–71. http://dx.doi.org/10.1192/bjp.160.1.65.

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The risk for schizophrenia among first-degree relatives of schizophrenic probands obtained from an epidemiological sample using family history methods was examined to determine whether month of birth of the proband was associated with familial risk. The results of this study of the first-degree relatives of 106 female schizophrenics and 275 male schizophrenics suggested that the relatives of probands born in the months February to May had the highest risk, although the association between month of birth and familial risk among the male probands was present only for those relatives who had onset of schizophrenia before the age of 30.

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Zhang, Jian-hui, Dan-dan Ruan, Ya-nan Hu, Xing-lin Ruan, Yao-bin Zhu, Xiao Yang, Jia-bin Wu, Xin-fu Lin, Jie-wei Luo et Fa-qiang Tang. « Review and Analysis of Two Gitelman Syndrome Pedigrees Complicated with Proteinuria or Hashimoto’s Thyroiditis Caused by Compound Heterozygous SLC12A3 Mutations ». BioMed Research International 2021 (10 mai 2021) : 1–12. http://dx.doi.org/10.1155/2021/9973161.

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Gitelman syndrome (GS) is an autosomal recessive inherited salt-losing renal tubular disease, which is caused by a pathogenic mutation of SLC12A3 encoding thiazide-sensitive Na-Cl cotransporter, which leads to disturbance of sodium and chlorine reabsorption in renal distal convoluted tubules, resulting in phenotypes such as hypovolemia, renin angiotensin aldosterone system (RAAS) activation, hypokalemia, and metabolic alkalosis. In this study, two GS families with proteinuria or Hashimoto’s thyroiditis were analyzed for genetic-phenotypic association. Sanger sequencing revealed that two probands carried SLC12A3 compound heterozygous mutations, and proband A carried two pathogenic mutations: missense mutation Arg83Gln, splicing mutation, or frameshift mutation NC_000016.10:g.56872655_56872667 (gcggacatttttg>accgaaaatttt) in exon 8. Proband B carries two missense mutations: novel Asp839Val and Arg904Gln. Both probands manifested hypokalemia, hypomagnesemia, hypocalcinuria, metabolic alkalosis, and RAAS activation; in addition, the proband A exhibited decreased urinary chloride, phosphorus, and increased magnesium ions excretion, complicated with Hashimoto’s Thyroiditis, while the proband B exhibited enhanced urine sodium excretion and proteinuria. The older sister of proband B with GS also had Hashimoto’s thyroiditis. Electron microscopy revealed swelling and vacuolar degeneration of glomerular epithelial cells, diffuse proliferation of mesangial cells and matrix, accompanied by a small amount of low-density electron-dense deposition, and segmental fusion of epithelial cell foot processes in proband B. Light microscopy showed mild mesangial hyperplasia in the focal segment of the glomerulus, hyperplasia, and hypertrophy of juxtaglomerular apparatus cells, mild renal tubulointerstitial lesions, and one glomerular sclerosis. So, long-term hypokalemia of GS can cause kidney damage and may also be susceptible to thyroid disease.

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Norero, Enrique, M. Alejandra Alarcon, Christopher Hakkaart, Tomas de Mayo, Cecilia Mellado, Marcelo Garrido, Gloria Aguayo et al. « Identification of c.1531C>T Pathogenic Variant in the CDH1 Gene as a Novel Germline Mutation of Hereditary Diffuse Gastric Cancer ». International Journal of Molecular Sciences 20, n^o 20 (9 octobre 2019) : 4980. http://dx.doi.org/10.3390/ijms20204980.

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Germline pathogenic variants in the CDH1 gene are a well-established cause of hereditary diffuse gastric cancer (HDGC) syndrome. The aim of this study was to characterize CDH1 mutations associated with HDGC from Chile, a country with one of the highest incidence and mortality rates in the world for gastric cancer (GC). Here, we prospectively include probands with family history/early onset of diffuse-type of GC. The whole coding sequence of the CDH1 gene was sequenced from genomic DNA in all patients, and a multidisciplinary team managed each family member with a pathogenic sequence variant. Thirty-six cases were included (median age 44 years/male 50%). Twenty-seven (75%) patients had diffuse-type GC at ≤50 years of age and 19 (53%) had first or second-degree family members with a history of HDGC. Two cases (5.5%) carried a non-synonymous germline sequence variant in the CDH1 gene: (a) The c.88C>A missense variant was found in a family with three diffuse-type GC cases; and (b) c.1531C>T a nonsense pathogenic variant was identified in a 22-year-old proband with no previous family history of HDGC. Of note, six family members carry the same nonsense pathogenic variant. Prophylactic gastrectomy in the proband’s sister revealed stage I signet-ring cell carcinoma. The finding of 1531C>T pathogenic variant in the CDH1 in proband with no previous family history of HDGC warrants further study to uncover familial clustering of disease in CDH1 negative patients. This finding may be particularly relevant in high incidence countries, such as the case in this report.

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Kinnamon, Daniel D., Elizabeth Jordan, Garrie J. Haas, Mark Hofmeyer, Evan Kransdorf, Gregory A. Ewald, Alanna A. Morris et al. « Effectiveness of the Family Heart Talk Communication Tool in Improving Family Member Screening for Dilated Cardiomyopathy : Results of a Randomized Trial ». Circulation 147, n^o 17 (25 avril 2023) : 1281–90. http://dx.doi.org/10.1161/circulationaha.122.062507.

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Background: Managing disease risk among first-degree relatives of probands diagnosed with a heritable disease is central to precision medicine. A critical component is often clinical screening, which is particularly important for conditions like dilated cardiomyopathy (DCM) that remain asymptomatic until severe disease develops. Nonetheless, probands are frequently ill-equipped to disseminate genetic risk information that motivates at-risk relatives to complete recommended clinical screening. An easily implemented remedy for this key issue has been elusive. Methods: The DCM Precision Medicine Study developed Family Heart Talk , a booklet designed to help probands with DCM communicate genetic risk and the need for cardiovascular screening to their relatives. The effectiveness of the Family Heart Talk booklet in increasing cardiovascular clinical screening uptake among first-degree relatives was assessed in a multicenter, open-label, cluster-randomized, controlled trial. The primary outcome measured in eligible first-degree relatives was completion of screening initiated within 12 months after proband enrollment. Because probands randomized to the intervention received the booklet at the enrollment visit, eligible first-degree relatives were limited to those who were alive the day after proband enrollment and not enrolled on the same day as the proband. Results: Between June 2016 and March 2020, 1241 probands were randomized (1:1) to receive Family Heart Talk (n=621) or not (n=620) within strata defined by site and self-identified race/ethnicity (non-Hispanic Black, non-Hispanic White, or Hispanic). Final analyses included 550 families (n=2230 eligible first-degree relatives) in the Family Heart Talk arm and 561 (n=2416) in the control arm. A higher percentage of eligible first-degree relatives completed screening in the Family Heart Talk arm (19.5% versus 16.0%), and the odds of screening completion among these first-degree relatives were higher in the Family Heart Talk arm after adjustment for proband randomization stratum, sex, and age quartile (odds ratio, 1.30 [1-sided 95% CI, 1.08–∞]). A prespecified subgroup analysis did not find evidence of heterogeneity in the adjusted intervention odds ratio across race/ethnicity strata ( P =0.90). Conclusions: Family Heart Talk , a booklet that can be provided to patients with DCM by clinicians with minimal additional time investment, was effective in increasing cardiovascular clinical screening among first-degree relatives of these patients. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03037632.

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Ananth, Cande, Kathleen Jablonski, Leslie Myatt, James Roberts, Alan Tita, Kenneth Leveno, Uma Reddy et al. « Risk of Ischemic Placental Disease in Relation to Family History of Preeclampsia ». American Journal of Perinatology 36, n^o 06 (3 octobre 2018) : 624–31. http://dx.doi.org/10.1055/s-0038-1672177.

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Objective To assess the risk of ischemic placental disease (IPD) including preeclampsia, small for gestational age (SGA), and abruption, in relation to preeclampsia in maternal grandmother, mother, and sister(s). Study Design We performed a secondary analysis of data from a randomized trial of vitamins C and E for preeclampsia prevention. Data on family history of preeclampsia were based on recall by the proband. The associations between family history of preeclampsia and the odds of IPD were evaluated from alternating logistic regressions. Results Of the 9,686 women who delivered nonmalformed, singleton live births, 17.1% had IPD. Probands provided data on preeclampsia in 55.5% (n = 5,374) on all three family members, 26.5% (n = 2,562) in mother and sister(s) only, and 11.6% (n = 1,125) in sister(s) only. The pairwise odds ratio (pOR) of IPD was 1.16 (95% confidence interval [CI]: 1.00–1.36) if one or more of the female relatives had preeclampsia. The pORs of preeclampsia were 1.54 (95% CI: 1.12–2.13) and 1.35 (95% CI: 1.03–1.77) if the proband's mother or sister(s) had a preeclamptic pregnancy, respectively, but no associations were seen for SGA infant or abruption. Conclusion This study suggests that IPD may share a predisposition with preeclampsia, suggesting a familial inheritance.

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Szulik, Marta W., Miguel Reyes-Múgica, Daniel F. Marker, Ana M. Gomez, Matthew D. Zinn, Leslie K. Walsh, Juan Pablo Ochoa, Sarah Franklin et Lina Ghaloul-Gonzalez. « Identification of Two Homozygous Variants in MYBPC3 and SMYD1 Genes Associated with Severe Infantile Cardiomyopathy ». Genes 14, n^o 3 (6 mars 2023) : 659. http://dx.doi.org/10.3390/genes14030659.

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Mutations in cardiac genes are one of the primary causes of infantile cardiomyopathy. In this study, we report the genetic findings of two siblings carrying variations in the MYBPC3 and SMYD1 genes. The first patient is a female proband exhibiting hypertrophic cardiomyopathy (HCM) and biventricular heart failure carrying a truncating homozygous MYBPC3 variant c.1224-52G>A (IVS13-52G>A) and a novel homozygous variant (c.302A>G; p.Asn101Ser) in the SMYD1 gene. The second patient, the proband’s sibling, is a male infant diagnosed with hypertrophic cardiomyopathy and carries the same homozygous MYBPC3 variant. While this specific MYBPC3 variant (c.1224-52G>A, IVS13-52G>A) has been previously reported to be associated with adult-onset hypertrophic cardiomyopathy, this is the first report linking it to infantile cardiomyopathy. In addition, this work describes, for the first time, a novel SMYD1 variant (c.302A>G; p.Asn101Ser) that has never been reported. We performed a histopathological evaluation of tissues collected from both probands and show that these variants lead to myofibrillar disarray, reduced and irregular mitochondrial cristae and cardiac fibrosis. Together, these results provide critical insight into the molecular functionality of these genes in human cardiac physiology.

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Shi, Xiao, Hao Geng, Hui Yu, Xiaolong Hu, Guanxiong Wang, Jin Yang et Hui Zhao. « Biallelic Variants in CCDC39 Gene Lead to Primary Ciliary Dyskinesia and Kartagener Syndrome ». BioMed Research International 2022 (26 juin 2022) : 1–8. http://dx.doi.org/10.1155/2022/7130555.

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Background. Primary ciliary dyskinesia (PCD) is a clinical syndrome characterized by cilia with an abnormal structure or function. Its main clinical manifestations comprise chronic bronchitis, cough, recurrent respiratory infections, situs inversus, and male infertility. Single-gene variants are widely assumed to be the main cause of this rare disease, and more than 40 genes have been described to be associated with its onset. CCDC39 is essential for assembling the inner dynein arms and dynein regulatory complex and is important in cilia motility. CCDC39 variants were reported as a monogenic etiology of PCD. Methods. This study investigated two unrelated Chinese patients diagnosed as PCD. The chest computed tomography scan was performed to identify PCD phenotypes of the two probands. Considering the effect of PCD on male fertility, routine semen analysis, sperm morphology examination, and scanning electron microscopy were performed to assess the semen characteristics of male proband in family 2 (F2 II-1), who had a history of infertility. Subsequently, the peripheral blood samples of probands were collected to perform whole-exome sequencing (WES) to explore the possible genetic causes of this disease. Results. Whole-exome sequencing revealed a homozygous CCDC39 variant in the female proband of family 1 (F1 II-1: c.286C>T:p.Arg96Ter) and two compound heterozygous CCDC39 variants in the male proband of family 2 (F2 II-1: c.732_733del: p.Ala245PhefsTer18; c.2800_2802dup:p.Val934dup). The two probands showed the typical PCD phenotypes, including chronic bronchitis, recurrent respiratory infections, and situs inversus. The male proband also showed oligoasthenoteratospermia with multiple morphological abnormalities of the sperm flagella. Additionally, CCDC39 protein level was significantly lower in the sperm of male proband than in the sperm from normal controls. Conclusion. We identified a homozygous variant reported previously and two compound heterozygous variants of CCDC39 possibly responsible for PCD pathogenesis, expanding the variant spectrum of Chinese PCD, Kartagener syndrome, and morphological abnormalities of the sperm flagella involving CCDC39.

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Li, Qian, Yongpeng Zhang, Liyun Jia et Xiaoyan Peng. « A novel nonsense mutation in BBS4 gene identified in a Chinese family with Bardet-Biedl syndrome ». Chinese Medical Journal 127, n^o 24 (20 décembre 2014) : 4190–96. http://dx.doi.org/10.3760/cma.j.issn.0366-6999.20141359.

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Background Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disease, and information about BBS in Chinese populations is very limited. The purpose of the present study was to determine the genetic cause of BBS in a Chinese Han family. Methods Clinical data were recorded for the 4-year-old female proband and the available family members. The proband was screened for mutation by Sanger sequencing for a total of 142 exons of the 12 BBS-causing genes (BBS1-BBS12). The variants detected in the proband were further confirmed in the other family members. Results We identified a novel homozygous nonsense mutation (c.70A>T, p.K24X) in the BBS4 gene exon 2 in the proband. Such mutant allele was predicted to cause a premature truncation in the N-terminal of the BBS4 protein, and probably induced the nonsense-mediated decay of BBS4 messenger RNAs. The proband's parents and brother were heterozygous for the nonsense mutant allele. It was absent in 50 Chinese control subjects. An additional rare heterozygous missense single nucleotide polymorphism (SNP) named rs200718870 in BBS10 gene was also detected in the proband, her father and her brother. Some manifestations of the proband including atypical retinitis pigmentosa, choroidal sclerosis, high myopia, and early onset of obesity might be associated with this mutation in BBS4 gene. The proband's father also reported surgical removal of an extra finger during childhood. Conclusions The present study described a novel nonsense mutation in BBS4 gene in a Chinese family. This homozygous mutation was predicted to completely abolish the synthesis of the BBS4 protein. We also detected a rare heterozygous missense SNP in BBS10 gene in the family, but did not find sufficient evidence to support the triallelic inheritance.

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Quee, P. J., B. Z. Alizadeh, A. Aleman et E. R. van den Heuvel. « Cognitive subtypes in non-affected siblings of schizophrenia patients : characteristics and profile congruency with affected family members ». Psychological Medicine 44, n^o 2 (9 mai 2013) : 395–405. http://dx.doi.org/10.1017/s0033291713000809.

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BackgroundAlthough cognitive subtypes have been suggested in schizophrenia patients, similar analyses have not been carried out in their non-affected siblings. Subtype classification may provide more insight into genetically driven variation in cognitive function. We investigated cognitive subtypes in siblings.MethodCluster analyses were performed in 654 non-affected siblings, on a cognitive battery that included tests of attention, intellectual function and episodic memory. Resulting subtypes in the siblings were analyzed for cognitive, demographic and clinical characteristics and compared with those of their probands.ResultsThree sibling subtypes of cognitive function were distinguished: ‘normal’, ‘mixed’ and ‘impaired’. Normal profile siblings (n = 192) were unimpaired on cognitive tests, in contrast to their proband (n = 184). Mixed profile siblings (n = 228) and their probands (n = 222) had a more similar performance pattern. Impaired profile siblings had poorer functional outcomes (n = 234) and their profile was almost identical to that of their proband (n = 223). Probands with cognitively impaired siblings could be distinguished from other schizophrenia patients by their own cognitive performance. They also had poorer clinical characteristics, including achievement of symptomatic remission.ConclusionsUnaffected siblings of patients with schizophrenia are heterogeneous with respect to cognitive function. The poorer the cognitive profile of the sibling, the higher the level of correspondence with the proband. The sibling's cognitive subtype was predictive for disease course in the proband. Distinguishing cognitive subtypes of unaffected siblings may be of relevance for genetic studies.

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Shigekiyo, Toshio, Hidemasa Yoshida, Kazuya Matsumoto, Hiroyuki Azuma, Sadao Wakabayashi, Shiro Saito, Kazuo Fujikawa et Takehiko Koide. « HRG Tokushima : Molecular and Cellular Characterization of Histidine-Rich Glycoprotein (HRG) Deficiency ». Blood 91, n^o 1 (1 janvier 1998) : 128–33. http://dx.doi.org/10.1182/blood.v91.1.128.

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AbstractPreviously, we found the first congenital deficiency of histidine-rich glycoprotein (HRG) in a Japanese woman with thrombosis. To elucidate the genetic basis of this deficiency, we first performed Southern blot analysis and found no gross deletion or insertion in the proband's HRG gene. We then examined the nucleotide sequences of all seven exons of the proband's HRG gene. A single nucleotide substitution, G to A at nucleotide position 429, which mutates Gly85 to Glu in the first cystatin-like domain, was found in exon 3 in 13 of 22 amplified clones. This mutation generates a unique Taq I site. Exon 3 was amplified from the proband, her family members, and 50 unrelated normal Japanese individuals, and Taq I fragmentation was examined. Fragmentation of exon 3 was observed in one allele of the genes from the proband and the family members who also have decreased plasma levels of HRG. Fifty unrelated normal Japanese individuals had a normal HRG gene, indicating that the G to A mutation is not a common polymorphism. To elucidate the identified mutation as a cause for the secretion defect of HRG in the proband's plasma, we constructed and transiently expressed the recombinant Tokushima-type HRG mutant (Gly85 to Glu) in baby hamster kidney (BHK) cells, and examined an intracellular event of the mutant protein. The results showed that only about 20% of the Tokushima-type HRG was secreted into the culture medium, and intracellular degradation of the mutant was observed. Thus, the present study strongly suggests that the HRG deficiency is caused by intracellular degradation of the Gly85 to Glu mutant of HRG in the proband.

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Shigekiyo, Toshio, Hidemasa Yoshida, Kazuya Matsumoto, Hiroyuki Azuma, Sadao Wakabayashi, Shiro Saito, Kazuo Fujikawa et Takehiko Koide. « HRG Tokushima : Molecular and Cellular Characterization of Histidine-Rich Glycoprotein (HRG) Deficiency ». Blood 91, n^o 1 (1 janvier 1998) : 128–33. http://dx.doi.org/10.1182/blood.v91.1.128.128_128_133.

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Previously, we found the first congenital deficiency of histidine-rich glycoprotein (HRG) in a Japanese woman with thrombosis. To elucidate the genetic basis of this deficiency, we first performed Southern blot analysis and found no gross deletion or insertion in the proband's HRG gene. We then examined the nucleotide sequences of all seven exons of the proband's HRG gene. A single nucleotide substitution, G to A at nucleotide position 429, which mutates Gly85 to Glu in the first cystatin-like domain, was found in exon 3 in 13 of 22 amplified clones. This mutation generates a unique Taq I site. Exon 3 was amplified from the proband, her family members, and 50 unrelated normal Japanese individuals, and Taq I fragmentation was examined. Fragmentation of exon 3 was observed in one allele of the genes from the proband and the family members who also have decreased plasma levels of HRG. Fifty unrelated normal Japanese individuals had a normal HRG gene, indicating that the G to A mutation is not a common polymorphism. To elucidate the identified mutation as a cause for the secretion defect of HRG in the proband's plasma, we constructed and transiently expressed the recombinant Tokushima-type HRG mutant (Gly85 to Glu) in baby hamster kidney (BHK) cells, and examined an intracellular event of the mutant protein. The results showed that only about 20% of the Tokushima-type HRG was secreted into the culture medium, and intracellular degradation of the mutant was observed. Thus, the present study strongly suggests that the HRG deficiency is caused by intracellular degradation of the Gly85 to Glu mutant of HRG in the proband.

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Vančová, Dominika, Ľudmila Jančoková, Júlia Palovičová et Pavol Pivovarniček. « Identifikácia chronotypov vysokoškolských študentiek ». Studia sportiva 7, n^o 2 (2 décembre 2013) : 79–84. http://dx.doi.org/10.5817/sts2013-2-9.

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The aim of the study was chronotype´s identification of university´s students who have been practising the activity of aerobics during their free time. The experimental ensemble composed of probands (n = 62, age = 21.2±1.4 years) who attended I. and II. level of university´s studies. The probands attended various study programmes and field of studies on particular faculties of Matej Bel University in Banská Bystrica. We identified chrontypes thanks to the method of standardised questionnaire. The identification was being done by quantification of score points of all questions. The scores were added together and the sum converted into a stated five point scale. The analysis has shown that 48 probands (77.4 %) tend to be the neither chronotype, 8 probands (12.9 %) are represented by moderately morning chronotype. Moderately evening chronotype is dominated for 5 probands (8.1 %). 1 proband (1.6 %) tends to be definitely evening chronotype. Definitely morning chronotype was not identified.

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Russell, MB, S. Østergaard, L. Bendtsen et J. Olesen. « Familial Occurrence of Chronic Tension-Type Headache ». Cephalalgia 19, n^o 4 (mai 1999) : 207–10. http://dx.doi.org/10.1046/j.1468-2982.1999.019004207.x.

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Chronic tension-type headache (CTTH) assessed by proband report was evaluated in a family study of CTTH. A clinical interview of first-degree relatives by a physician was used as index of validity. Familial occurrence of CTTH in first-degree relatives was also investigated. Patterns of familial aggregation of CTTH were assessed by calculating the population relative risk. A neurological resident carried out all the interviews of probands and their first-degree relatives. The operational diagnostic criteria of the International Headache Society were used. The 122 probands had 377 first-degree relatives. Sensitivity, specificity, predictive values, and chance-corrected agreement rate for the diagnosis CTTH were 68%, 86%, 53% (PVpos), 92% (PVneg), and 0.48, respectively. The low sensitivity of CTTH assessed by proband report indicates that a clinical interview by a physician is necessary in family studies of CTTH. Clinically interviewed parents, siblings, and children had a 2.1 to 3.9-fold significantly increased risk of CTTH compared with the general population. The gender of the probands did not influence the risk of CTTH among first-degree relatives. The significantly increased familial risk of CTTH and no increased risk of CTTH in spouses suggest that a genetic factor is involved in CTTH.

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NEWMAN, STEPHEN C., et ROGER C. BLAND. « A population-based family study of DSM-III generalized anxiety disorder ». Psychological Medicine 36, n^o 9 (15 mai 2006) : 1275–81. http://dx.doi.org/10.1017/s0033291706007732.

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Background. A recent meta-analysis provides evidence that generalized anxiety disorder (GAD) is familial. However, two of the key studies relied on subjects who were self-selected or recruited from the clinic setting, thereby limiting generalizability.Method. We conducted a family study of GAD in which probands and controls came from a community sample originally enrolled in a prevalence study in Edmonton, Canada. One hundred and sixty probands, 764 controls and 2386 first-degree relatives (FDRs) were interviewed using the Diagnostic Interview Schedule (DIS); lifetime diagnoses were made according to DSM-III criteria without exclusions. Logistic regression analysis was performed with GAD (in a proband) as the ‘exposure’, and GAD in an FDR as the ‘outcome’. Several analytic strategies were used to control for potential confounding by major depressive disorder (MDD) and several anxiety disorders (panic disorder, phobic disorders, obsessive–compulsive disorder, and post-traumatic stress disorder).Results. The odds ratios for the association between GAD in a proband and GAD in an FDR were in the range 1·4–1·8 when the entire FDR sample was analysed, and in the range 2·1–2·8 when we restricted to FDRs who were children of probands and controls.Conclusion. In the community setting, GAD exhibits mild to moderate familial aggregation.

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Cardot Bauters, Catherine, Emmanuelle Leteurtre, Bruno Carnaille, Christine Do Cao, Stéphanie Espiard, Malo Penven, Evelyne Destailleur et al. « Genetic predisposition to neural crest-derived tumors : revisiting the role of KIF1B ». Endocrine Connections 9, n^o 10 (octobre 2020) : 1042–50. http://dx.doi.org/10.1530/ec-20-0460.

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Objective We previously described a family in which predisposition to pheochromocytoma (PCC) segregates with a germline heterozygous KIF1B nucleotide variant (c.4442G>A, p.Ser1481Asn) in three generations. During the clinical follow-up, one proband’s brother, negative for the KIF1B nucleotide variant, developed a bilateral PCC at 31 years. This prompted us to reconsider the genetic analysis. Design and methods Germline DNA was analyzed by next-generation sequencing (NGS) using a multi-gene panel plus MLPA or by whole exome sequencing (WES). Tumor-derived DNA was analyzed by SnapShot, Sanger sequencing or NGS to identify loss-of-heterozygosity (LOH) or additional somatic mutations. Results A germline heterozygous variant of unknown significance in MAX (c.145T>C, p.Ser49Pro) was identified in the proband’s brother. Loss of the wild-type MAX allele occurred in his PCCs thus demonstrating that this variant was responsible for the bilateral PCC in this patient. The proband and her affected grandfather also carried the MAX variant but no second hit could be found at the somatic level. No other pathogenic mutations were detected in 36 genes predisposing to familial PCC/PGL or familial cancers by WES of the proband germline. Germline variants detected in other genes, TFAP2E and TMEM214, may contribute to the multiple tumors of the proband. Conclusion In this family, the heritability of PCC is linked to the MAX germline variant and not to the KIF1B germline variant which, however, may have contributed to the occurrence of neuroblastoma (NB) in the proband.

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Ireland, H., E. Thompson et D. A. Lane. « Gene Mutations in 21 Unrelated Cases of Phenotypic Heterozygous Protein C Deficiency and Thrombosis ». Thrombosis and Haemostasis 76, n^o 06 (1996) : 0867–73. http://dx.doi.org/10.1055/s-0038-1650677.

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SummaryMutations have been identified in the protein C gene in 21 patients with venous thromboembolism and phenotypic heterozygous protein C deficiency. In 20 probands, single mutations were the only abnormalities identified by sequencing all coding regions, intron exon boundaries and the promoter region back to -1540. In one proband 2 mutations were identified and in another family 2 mutations were identified (but not both in the proband). Of the 23 mutations, 18 resulted in predicted amino acid substitutions, 3 were mutations resulting in stop codons, one was a mutation within a consensus splice sequence and another a 9 base pair insertion within exon 5 (this region within exon 5 is proposed as a deletion/insertion hot spot). A novel polymorphism was also, uniquely, identified in the propeptide region of the molecule (Pro-21 Pro; CCT to CCC) in a kindred from Hong Kong. Cosegregation of the protein C gene mutation with protein C deficiency could be determined in 13 families. In a further family, phenotypic protein C deficiency and the genetic mutation cosegregated in only 4/5 members.The first thrombotic incident occurred in the probands between the ages of 11 and 59 years and 12 individuals suffered recurrent thrombosis. Thrombosis occurred in at least one other family member in 9/21 families, but in 2 of these it was inconsistently associated with protein C deficiency. An independent genetic risk factor, factor V Arg506Gln (FV Leiden) was identified in 2 probands (and 3 family members) and in 4 protein C deficient members of a third family but not in the proband. The results suggest that in the majority of probands with thrombosis and phenotypic protein C deficiency, a single protein C gene mutation is associated with thrombosis. However, it is also possible that additional unknown genetic risk factors contribute to the thrombotic risk. An added, acquired, risk factor leads to thrombosis at an early age (< 25 years).

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Vachon, Celine M., Robert Kyle, Terry Therneau, Dirk R. Larson, Colin Colby, Barbara J. Foreman, Angela Dispenzieri, Shaji Kumar, Jerry Katzmann et S. Vincent Rajkumar. « Increased Risk of Monoclonal Gammopathy in First-Degree Relatives of Patients with Multiple Myeloma or Monoclonal Gammopathy of Undetermined Significance. » Blood 112, n^o 11 (16 novembre 2008) : 1672. http://dx.doi.org/10.1182/blood.v112.11.1672.1672.

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Abstract Background: Monoclonal gammopathy of undetermined significance (MGUS) is a common pre-malignant plasma cell disorder associated with a 1% per year risk of progression to multiple myeloma or related malignancy. Since the risk factors for MGUS are poorly defined, the goal of the present study was to determine if the risk of MGUS is increased in first degree relatives of patients with known multiple myeloma (MM) or MGUS. Methods: MGUS probands (index cases) were recruited from a population-based prevalence study of MGUS in Olmsted County, MN while MM probands were recruited through the Mayo Clinic practice. Consenting probands were asked to provide contact information on all first-degree relatives ages 40 years and older. Serum samples were then collected from first-degree relatives with informed consent and subjected to agaraose-gel electrophoresis and immunofixation. The prevalence of MGUS in first-degree relatives of MM and MGUS probands was compared to population-based rates from Olmsted County using risk ratios (RR). For comparisons to the reference population, only cases detected by protein electrophoresis and confirmed by immunofixation were included so that the diagnostic strategy was identical in the two groups being compared. Results: Serum samples were obtained from 911 relatives of 329 unique families, including 493 siblings, 324 children and 94 parents of patients with MGUS or MM. Using protein electrophoresis, monoclonal protein was detected in the serum of 55 (6%) while immunofixation identified 28 additional relatives (3%), for an age- and sex-adjusted prevalence rate of 8.1% (95%CI: 6.3, 9.8). The age-specific prevalence of MGUS in first-degree relatives increased with age (1.9%, 6.9%, 11.6%, 14.6%, and 21.0% for ages 40–49, 50–59, 60–69, 70–79 and ≥80, respectively; P<0.001). Based on similar MGUS detection methodology as the reference population, there was a significantly higher risk of MGUS in first-degree relatives (age-adjusted RR, 2.6, 95%CI: 1.9, 3.4) compared to the reference population. The increased risk (P<0.001) was seen both in relatives of MM probands (RR, 2.0, 95%CI: 1.4, 2.8), as well as MGUS probands (RR, 3.3, 95%CI: 2.1, 4.8). This association was similar across age of proband, age and gender of relative, and relationship of the first-degree relative. When examining whether the increased risk of MGUS in relatives was specific to probands with a large monoclonal protein concentration or specific monoclonal immunoglobulin isotype (i.e. high-risk MGUS phenotype), there was suggestion of a greater risk for relatives of probands with a high (3 1.5 g/dL) M-protein (RR, 2.8, 95%CI: 2.0,3.8) compared to lower M-protein levels (RR, 1.8, 95%CI: 1.1,2.8) although the difference did not reach statistical significance (P=0.12). The risk of MGUS in relatives did not differ by proband’s isotype (IgG vs. other). Conclusions: First-degree relatives of patients with MM or MGUS have a greater than two-fold risk of MGUS compared to the general population, implying underlying genetic predisposition for these diseases and providing rationale for identifying genetic determinants of MGUS. This study also provides important baseline rates of MGUS in first-degree relatives that impact the clinical care of these patients.

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Pandelache, Alison, David Francis, Ralph Oertel, Rebecca Dickson, Rani Sachdev, Ling Ling, Dinusha Gamage et David E. Godler. « Detection of Cryptic Fragile X Full Mutation Alleles by Southern Blot in a Female and Her Foetal DNA via Chorionic Villus Sampling, Complicated by Mosaicism for 45,X0/46,XX/47,XXX ». Genes 12, n^o 6 (24 mai 2021) : 798. http://dx.doi.org/10.3390/genes12060798.

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We describe a female with a 72 CGG FMR1 premutation (PM) (CGG 55–199) and family history of fragile X syndrome (FXS), referred for prenatal testing. The proband had a high risk of having an affected pregnancy with a full mutation allele (FM) (CGG > 200), that causes FXS through hypermethylation of the FMR1 promoter. The CGG sizing analysis in this study used AmplideX triplet repeat primed polymerase chain reaction (TP-PCR) and long-range methylation sensitive PCR (mPCR). These methods detected a 73 CGG PM allele in the proband’s blood, and a 164 CGG PM allele in her male cultured chorionic villus sample (CVS). In contrast, the Southern blot analysis showed mosaicism for: (i) a PM (71 CGG) and an FM (285–768 CGG) in the proband’s blood, and (ii) a PM (165 CGG) and an FM (408–625 CGG) in the male CVS. The FMR1 methylation analysis, using an EpiTYPER system in the proband, showed levels in the range observed for mosaic Turner syndrome. This was confirmed by molecular and cytogenetic karyotyping, identifying 45,X0/46,XX/47,XXX lines. In conclusion, this case highlights the importance of Southern blot in pre- and postnatal testing for presence of an FM, which was not detected using AmplideX TP-PCR or mPCR in the proband and her CVS.

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Graziani, Ludovico, Stefania Zampatti, Miriam Lucia Carriero, Chiara Minotti, Cristina Peconi, Mario Bengala, Emiliano Giardina et Giuseppe Novelli. « Co-Inheritance of Pathogenic Variants in PKD1 and PKD2 Genes Determined by Parental Segregation and De Novo Origin : A Case Report ». Genes 14, n^o 8 (6 août 2023) : 1589. http://dx.doi.org/10.3390/genes14081589.

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, and it is typically caused by PKD1 and PKD2 heterozygous variants. Nonetheless, the extensive phenotypic variability observed among affected individuals, even within the same family, suggests a more complex pattern of inheritance. We describe an ADPKD family in which the proband presented with an earlier and more severe renal phenotype (clinical diagnosis at the age of 14 and end-stage renal disease aged 24), compared to the other affected family members. Next-generation sequencing (NGS)-based analysis of polycystic kidney disease (PKD)-associated genes in the proband revealed the presence of a pathogenic PKD2 variant and a likely pathogenic variant in PKD1, according to the American College of Medical Genetics and Genomics (ACMG) criteria. The PKD2 nonsense p.Arg872Ter variant was segregated from the proband’s father, with a mild phenotype. A similar mild disease presentation was found in the proband’s aunts and uncle (the father’s siblings). The frameshift p.Asp3832ProfsTer128 novel variant within PKD1 carried by the proband in addition to the pathogenic PKD2 variant was not found in either parent. This report highlights that the co-inheritance of two or more PKD genes or alleles may explain the extensive phenotypic variability among affected family members, thus emphasizing the importance of NGS-based techniques in the definition of the prognostic course.

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Vähäsalo, Paula, Mikael Knip, Jukka Karjalainen, Eva Tuomilehto-Wolf, Raisa Lounamaa, Hans K. Åkerblom et _. _. « Islet cell-specific autoantibodies in children with insulin-dependent diabetes mellitus and their siblings at clinical manifestation of the disease ». European Journal of Endocrinology 135, n^o 6 (décembre 1996) : 689–95. http://dx.doi.org/10.1530/eje.0.1350689.

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Vähäsalo P, Knip M, Karjalainen J, Tuomilehto-Wolf E, Lounamaa R, Åkerblom HK, and the Childhood Diabetes in Finland Study Group. Islet cell-specific autoantibodies in children with insulin-dependent diabetes mellitus and their siblings at clinical manifestation of the disease. Eur J Endocrinol 1996;135:689–95. ISSN 0804–4643 The aim of this work was to characterize both newly diagnosed insulin-dependent diabetic subjects and their siblings with positive tests for islet cell-specific autoantibodies (ICSAA) and to evaluate whether there is an association between the ICSAA levels detected in the diabetic children and siblings. We analysed 781 probands younger than 15 years of age for islet cell antibodies (ICA) and 755 for insulin autoantibodies (IAA) and 610 of their 3–19-year-old non-diabetic siblings for ICA and IAA upon diagnosis of the proband. Islet cell antibodies were observed in 657 of the probands (84.1%) and IAA in 353 (46.8%). The ICA-positive probands were younger in age and had higher IAA levels than the ICA-negative probands, while the IAA-positive probands were younger and had higher levels of ICA than the IAA-negative probands. Islet cell antibodies were detected in 46 (7.5%) and IAA in 16 (2.6%) siblings, and the ICA-positive siblings had higher IAA levels than the ICA-negative siblings. A falling trend was seen in the frequency of ICA [2A7E] 20 Juvenile Diabetes Foundation units in the siblings with decreasing degrees of HLA identity with the index case. Infections during the preceding year, especially respiratory infections, increased the prevalence of both ICA and IAA in the diabetic children at diagnosis and the frequency of IAA in the siblings. There was a significant, although weak, correlation between the IAA levels of the probands and those of their siblings when 594 pairs were tested (rs = 0.15; p < 0.001). No association could be seen between the ICA levels of the probands and those of their siblings, not even when including only HLA-identical proband–sib pairs in the analysis. The lack of any relation between ICA levels in the probands and siblings supports the view that there may be multiple exogenous factors capable of inducing ICA formation or else a common factor but variable responsiveness in the index case and the sibling. Paula Vähäsalo, Department of Pediatrics, University of Oulu, FIN-90220 Oulu, Finland

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Lui, S., L. Yao, Y. Xiao, S. K. Keedy, J. L. Reilly, R. S. Keefe, C. A. Tamminga et al. « Resting-state brain function in schizophrenia and psychotic bipolar probands and their first-degree relatives ». Psychological Medicine 45, n^o 1 (20 mai 2014) : 97–108. http://dx.doi.org/10.1017/s003329171400110x.

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BackgroundSchizophrenia (SCZ) and psychotic bipolar disorder (PBD) share considerable overlap in clinical features, genetic risk factors and co-occurrence among relatives. The common and unique functional cerebral deficits in these disorders, and in unaffected relatives, remain to be identified.MethodA total of 59 healthy controls, 37 SCZ and 57 PBD probands and their unaffected first-degree relatives (38 and 28, respectively) were studied using resting-state functional magnetic resonance imaging (rfMRI). Regional cerebral function was evaluated by measuring the amplitude of low-frequency fluctuations (ALFF). Areas with ALFF alterations were used as seeds in whole-brain functional connectivity analysis. We then tested whether abnormalities identified in probands were present in unaffected relatives.ResultsSCZ and PBD probands both demonstrated regional hypoactivity in the orbital frontal cortex and cingulate gyrus, as well as abnormal connectivity within striatal-thalamo-cortical networks. SCZ probands showed greater and more widely distributed ALFF alterations including the thalamus and bilateral parahippocampal gyri. Increased parahippocampal ALFF was related to positive symptoms and cognitive deficit. PBD patients showed uniquely increased functional connectivity between the thalamus and bilateral insula. Only PBD relatives showed abnormal connectivity within striatal-thalamo-cortical networks seen in both proband groups.ConclusionsThe present findings reveal a common pattern of deficits in frontostriatal circuitry across SCZ and PBD, and unique regional and functional connectivity abnormalities that distinguish them. The abnormal network connectivity in PBD relatives that was present in both proband groups may reflect genetic susceptibility associated with risk for psychosis, but within-family associations of this measure were not high.

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Jacobs, M. J., S. Roesch, S. A. Wonderlich, R. Crosby, L. Thornton, D. E. Wilfley, W. H. Berrettini et al. « Anorexia nervosa trios : behavioral profiles of individuals with anorexia nervosa and their parents ». Psychological Medicine 39, n^o 3 (26 juin 2008) : 451–61. http://dx.doi.org/10.1017/s0033291708003826.

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BackgroundAnorexia nervosa (AN) is associated with behavioral traits that predate the onset of AN and persist after recovery. We identified patterns of behavioral traits in AN trios (proband plus two biological parents).MethodA total of 433 complete trios were collected in the Price Foundation Genetic Study of AN using standardized instruments for eating disorder (ED) symptoms, anxiety, perfectionism, and temperament. We used latent profile analysis and ANOVA to identify and validate patterns of behavioral traits.ResultsWe distinguished three classes with medium to large effect sizes by mothers' and probands' drive for thinness, body dissatisfaction, perfectionism, neuroticism, trait anxiety, and harm avoidance. Fathers did not differ significantly across classes. Classes were distinguished by degree of symptomatology rather than qualitative differences. Class 1 (~33%) comprised low symptom probands and mothers with scores in the healthy range. Class 2 (~43%) included probands with marked elevations in drive for thinness, body dissatisfaction, neuroticism, trait anxiety, and harm avoidance and mothers with mild anxious/perfectionistic traits. Class 3 (~24%) included probands and mothers with elevations on ED and anxious/perfectionistic traits. Mother–daughter symptom severity was related in classes 1 and 3 only. Trio profiles did not differ significantly by proband clinical status or subtype.ConclusionsA key finding is the importance of mother and daughter traits in the identification of temperament and personality patterns in families affected by AN. Mother–daughter pairs with severe ED and anxious/perfectionistic traits may represent a more homogeneous and familial variant of AN that could be of value in genetic studies.

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Capellini, Simone Aparecida, Niura Aparecida de Mouro Ribeiro Padula, Lara Cristina Antunes dos Santos, Maria Dalva Lourenceti, Erika Hasse Carrenho et Lucilene Arilho Ribeiro. « Desempenho em consciência fonológica, memória operacional, leitura e escrita na dislexia familial ». Pró-Fono Revista de Atualização Científica 19, n^o 4 (décembre 2007) : 374–80. http://dx.doi.org/10.1590/s0104-56872007000400009.

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TEMA: dislexia familial. OBJETIVO: caracterizar o desempenho em consciência fonológica, memória operacional, leitura e escrita do probando com dislexia e de seus familiares afetados. MÉTODO: participaram deste estudo 10 núcleos familiais de parentesco natural de indivíduos com queixa específica de problemas de leitura e compreensão. Foram selecionadas famílias de probandos naturais e residentes na região do oeste do estado de São Paulo. Os requisitos de inclusão dos probandos foram: ser falante nativo do Português Brasileiro, ter idade acima de oito anos, apresentar histórico familial positivo para os problemas de aprendizagem, ou seja, apresentar no mínimo um outro parente com dificuldade para aprender em três gerações. Os critérios de exclusão para o grupo de probandos foram: apresentar qualquer distúrbio neurológico-genético tais como distonia, doenças extras piramidais, deficiência mental, epilepsia, transtorno do déficit de atenção e hiperatividade (TDAH); sintomas ou condições psiquiátricas; ou outras condições pertinentes que poderiam gerar erros no diagnóstico. Para o diagnóstico de dislexia do desenvolvimento foram coletados dados de antecedente familial na histórica clínica com os pais das crianças e adolescentes para realização do heredograma. Foram realizadas avaliações neurológica, fonoaudiológica, psicológica e de desempenho escolar nos probandos e em seus parentes. RESULTADOS: os resultados deste estudo sugeriram que os probandos e seus familiares com dislexia apresentaram desempenho inferior ao grupo controle quanto à nomeação rápida, leitura, escrita e consciência fonológica. CONCLUSÃO: alterações em consciência fonológica, memória de trabalho, leitura e escrita tem susceptibilidade genética que possivelmente em interação com o meio ambiente determinam o quadro de dislexia.

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Radecki Breitkopf, Carmen, Susan M. Wolf, Kari G. Chaffee, Marguerite E. Robinson, Noralane M. Lindor, Deborah R. Gordon, Barbara A. Koenig et Gloria M. Petersen. « Attitudes Toward Return of Genetic Research Results to Relatives, Including After Death : Comparison of Cancer Probands, Blood Relatives, and Spouse/Partners ». Journal of Empirical Research on Human Research Ethics 13, n^o 3 (27 avril 2018) : 295–304. http://dx.doi.org/10.1177/1556264618769165.

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Genetic research generates results with implications for relatives. Recommendations addressing relatives’ access to a participant’s genetic research findings include eliciting participant preferences about access and choosing a representative to make decisions about access upon participant incapacity/death. Representatives are likely to be blood relatives or spouse/partners (who may share genetically related children). This raises the question of whether relatives hold similar attitudes about access or divergent attitudes that may yield conflict. We surveyed pancreatic cancer biobank participants (probands) and relatives in a family registry (blood relatives and spouse/partners of probands); 1,903 (>55%) surveys were returned. Results revealed few attitudinal differences between the groups. A slightly higher proportion of blood relatives agreed with statements reflecting proband privacy. In conclusion, probands’ decisions on access are likely to be accepted by relatives; in choosing a representative, probands may not face major differences in attitudes about privacy/sharing between a blood relative and a spouse/partner.

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Goldstein, Jill M., Stephen V. Faraone, Wei J. Chen et Ming T. Tsuang. « The Role of Gender in Understanding the Familial Transmission of Schizoaffective Disorder ». British Journal of Psychiatry 163, n^o 6 (décembre 1993) : 763–68. http://dx.doi.org/10.1192/bjp.163.6.763.

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The purpose of this study was to test the effect of gender on the familial risk for schizophrenia and affective disorders in probands with schizoaffective disorder. The sample consisted of 42 DSM–III schizoaffective probands and 149 first-degree relatives from the retrospective cohort family studies, the Iowa 500 and non-500. Survival analysis estimated differences in morbidity risks, analysed by sex of proband and of relative. Findings showed that, among probands, relatives of females had significantly higher rates of schizophrenia and unipolar disorder than relatives of males. Further, among relatives, males were at significantly higher risk for schizophrenia spectrum disorders than females. Results were similar when probands were subdivided into their primary symptom patterns, that is ‘mainly schizophrenic’ or ‘mainly affective’, as well as by ‘schizoaffective, depressed’ or ‘schizoaffective, manic’. Implications for the taxonomy of schizoaffective disorder suggest a stronger relationship with schizophrenia, although the relationship with affective disorder remains unclear.

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Bonaventure, J., L. Cohen-Solal, P. Ritvaniemi, L. Van Maldergem, N. Kadhom, A. L. Delezoide, P. Maroteaux, D. J. Prockop et L. Ala-Kokko. « Substitution of aspartic acid for glycine at position 310 in type II collagen produces achondrogenesis II, and substitution of serine at position 805 produces hypochondrogenesis : analysis of genotype-phenotype relationships ». Biochemical Journal 307, n^o 3 (1 mai 1995) : 823–30. http://dx.doi.org/10.1042/bj3070823.

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Two different mutations were found in two unrelated probands with lethal chondrodysplasias, one with achondrogenesis type II and the other with the less severe phenotype of hypochondrogenesis. The mutations in the COL2A1 gene were identified by denaturing gradient gel electrophoresis analysis of genomic DNA followed by dideoxynucleotide sequencing and restriction site analysis. The proband with achondrogenesis type II had a heterozygous single-base mutation that substituted aspartate for glycine at position 310 of the alpha 1(II) chain of type II procollagen. The proband with hypochondrogenesis had a heterozygous single-base mutation that substituted serine for glycine at position 805. Type II collagen extracted from cartilage from the probands demonstrated the presence of type I collagen and a delayed electrophoretic mobility, indicating post-translational overmodifications. Analysis of CNBr peptides showed that, in proband 1, the entire peptides were overmodified. Examination of chondrocytes cultured in agarose or alginate indicated that there was a delayed secretion of type II procollagen. In addition, type II collagen synthesized by cartilage fragments from the probands demonstrated a decreased thermal stability. The melting temperature of the type II collagen containing the aspartate-for-glycine substitution was reduced by 4 degrees C, and that of the collagen containing the serine-for-glycine substitution was reduced by 2 degrees C. Electron microscopy of the extracellular matrix from the chondrocyte cultures showed a decreased density of matrix and the presence of unusually short and thin fibrils. Our results indicate that glycine substitutions in the N-terminal region of the type II collagen molecule can produce more severe phenotypes than mutations in the C-terminal region. The aspartate-for-glycine substitution at position 310, which was associated with defective secretion and a probable increased degradation of collagen, is the most destabilizing mutation yet reported in type II procollagen.

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Grant, Robert C., Spring Holter, Ayelet Borgida, Melania Pintile, Mohammad R. Akbari, George Zogopoulos et Steven Gallinger. « Comparison of guidelines, BRCAPRO, and genetic counsellors estimates for the identification of BRCA1 and BRCA2 mutations in pancreatic cancer. » Journal of Clinical Oncology 35, n^o 15_suppl (20 mai 2017) : e15784-e15784. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e15784.

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e15784 Background: Germline BRCA1 and BRCA2 (BRCA) mutation carriers with pancreatic adenocarcinoma (PDAC) are eligible for precision therapy trials and their relatives should undergo genetic testing and tailored cancer prevention. We assessed the performance of strategies to identify BRCA mutation carriers in PDAC. Methods: Incident cases of PDAC were prospectively recruited for BRCA sequencing in a multidisciplinary PDAC clinic. Probands were evaluated according to the National Comprehensive Cancer Network 2017 (NCCN) and the Ontario Ministry of Health and Long-Term Care (MOHLTC) guidelines for BRCA testing. The probability of each proband carrying a BRCA mutation was estimated using BRCAPRO and by surveying genetic counsellors. Guidelines were compared across sensitivity, specificity, and positive and negative predictive values (PPV and NPV). Estimates from BRCAPRO and the genetic counsellors were compared using the area-under-the-curve (AUC) for discrimination and the Hosmer-Lemeshow test for calibration. Results: 22/484 (4.5%) of probands carried a BRCA mutation. The mutation rate was higher in probands with Ashkenazi Jewish ancestry (7/57, p=0.009) or a first-degree relative with breast cancer (8/83, p=0.036). 119 genetic counsellors responded to the survey and each proband was assessed by a mean of 5.9 genetic counsellors. The Table displays the performance of the guidelines. Discrimination was similar for the estimates from genetic counsellors and BRCAPRO (AUC 0.755 and 0.775, respectively, p=0.701). Genetic counsellors generally overestimated (p=0.008), whereas BRCAPRO severely underestimated (p<0.001), the probability that each proband carried a mutation. Conclusions: The NCCN 2017 guidelines and estimates from genetic counsellors accurately identify BRCA mutations in PDAC. The MOHLTC guidelines and BRCAPRO should be updated to account for the association between PDAC and BRCA mutations. [Table: see text]

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Griffin, Tomás P., Caroline M. Joyce, Sumaya Alkanderi, Liam M. Blake, Derek T. O’Keeffe, Delia Bogdanet, Md Nahidul Islam et al. « Biallelic CYP24A1 variants presenting during pregnancy : clinical and biochemical phenotypes ». Endocrine Connections 9, n^o 6 (juin 2020) : 530–41. http://dx.doi.org/10.1530/ec-20-0150.

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Introduction Inactivating mutations in CYP24A1, encoding vitamin D-24-hydroxylase, can lead to an accumulation of active vitamin D metabolites and consequent hypercalcaemia. Patient (infantile and adult) presentation is varied and includes mild-severe hypercalcaemia, hypercalciuria, nephrocalcinosis and nephrolithiasis. This study aimed to characterize the clinical and biochemical phenotypes of a family with two CYP24A1 missense variants. Methods The proband and seven family members underwent detailed clinical and biochemical evaluation. Laboratory measurements included serum calcium, intact parathyroid hormone (iPTH), vitamin D metabolites and urine calcium and creatinine. Results The proband presented during the second trimester of a planned pregnancy with flu-like symptoms. Laboratory tests showed elevated adjusted calcium of 3.27 (upper reference limit (URL: 2.30) mmol/L), suppressed iPTH (<6 ng/L), elevated 25(OH)D (264 (URL: 55) nmol/L) and elevated 1,25(OH)D (293 (URL: <280) pmol/L). Ionized calcium was 1.55 (URL: 1.28) mmol/L. Sanger sequencing revealed two heterozygous missense variants in the CYP24A1: p.(Arg439Cys), R439C and p.(Trp275Arg), W275R. The proband’s brother and sister had the same genotype. The brother had intermittent hypercalcaemia and hypervitaminosis D. Only the sister had a history of nephrolithiasis. The proband’s daughter and two nephews were heterozygous for the R439C variant. The proband and her brother frequently had elevated 25(OH)D:24,25(OH)2D ratios (>50) during follow-up. Conclusions W275R is a new pathogenic CYP24A1 mutation in compound heterozygotic form with R439C in this family.

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Moniruzzaman, Mohammad, Pallab Kumar Das, Mhabuba Akter, Jasmin Nur, Zeenat Farzana Rahman, Md Sohrab Alam, Mansura Khan et M. Sawkat Hasan. « Down’s Syndrome Presented with Transmission of Maternal Translocation of 2 ; 21 Chromosomes. A Case Report ». Bangladesh Medical Research Council Bulletin 49, n^o 2 (1 août 2023) : 143–47. http://dx.doi.org/10.3329/bmrcb.v49i2.62712.

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Background: Down's syndrome is a genetic condition marked by distinctive physical characteristics and some degree of cognitive impairment. Down's syndrome is mostly caused by trisomy of chromosome 21, while chromosome translocations are also frequent. Objective: To evaluate a rare 2;21 translocation in the proband's family that was associated with Down syndrome. Methods: Chromosomal analysis was carried out using the G-banding technique and traditional peripheral lymphocyte culture. Case: The proband was a 9 months baby boy of non-consanguineous parents. The doctors clinically diagnosed him as having Down's syndrome with all typical features. The proband was found to have trisomy 21 associated with a 2;21 translocation inherited from his mother because his mother has the same type of translocation without any phenotypic features. Maternal age at the time of the study was 35 years and first pregnancy ended in stillbirth at 26th weeks of gestation, the proband was the second issue. His maternal aunt and cousin brother both had the same type of translocation. In chromosomal analysis, the proband's father and uncle had normal genotypic distribution. The current example was a Down's syndrome case with one normal 21 no chromosome and one Reciprocal translocation t (2;21). Conclusion: The present case of Down’s syndrome occurs due to reciprocal translocation (2;21) probably has arisen by familial transmission. Once an imbalanced translocation in the fetus/child has been found, the prenatal cytogenetic analysis is critical for the next pregnancies. Bangladesh Medical Res Counc Bull 2023; 49(2): 143-147

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