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Civan, Hasret A. y Serhat Seyhan. "Molecular Heterogeneity in Cystic Fibrosis". Journal of Pediatric Genetics 09, n.º 03 (17 de febrero de 2020): 171–76. http://dx.doi.org/10.1055/s-0040-1701646.
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AbstractWe aimed to evaluate type, frequency, and variety of pathogenic variants according to clinical and demographic features of children diagnosed with cystic fibrosis (CF). Twenty-five CF patients were evaluated retrospectively. Patients' demographics, physical examination, imaging, laboratory, and molecular pathogenic variant analysis findings were evaluated. Phe508del was the most frequently (33.3%) detected pathogenic variant, followed by point pathogenic variants E92K, 1898 + lGA/7T/7T, and 2789 + 5GA, respectively. Statistically higher rates of pathogenic variants were detected in male patients. The most frequently detected pathogenic variant was Phe508del. The identification of nine additional pathogenic variants of Phe508del revealed the heterogeneous nature of the CF.
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Alenezi, Wejdan M., Caitlin T. Fierheller, Timothée Revil, Corinne Serruya, Anne-Marie Mes-Masson, William D. Foulkes, Diane Provencher, Zaki El Haffaf, Jiannis Ragoussis y Patricia N. Tonin. "Case Review: Whole-Exome Sequencing Analyses Identify Carriers of a Known Likely Pathogenic Intronic BRCA1 Variant in Ovarian Cancer Cases Clinically Negative for Pathogenic BRCA1 and BRCA2 Variants". Genes 13, n.º 4 (15 de abril de 2022): 697. http://dx.doi.org/10.3390/genes13040697.
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Background: Detecting pathogenic intronic variants resulting in aberrant splicing remains a challenge in routine genetic testing. We describe germline whole-exome sequencing (WES) analyses and apply in silico predictive tools of familial ovarian cancer (OC) cases reported clinically negative for pathogenic BRCA1 and BRCA2 variants. Methods: WES data from 27 familial OC cases reported clinically negative for pathogenic BRCA1 and BRCA2 variants and 53 sporadic early-onset OC cases were analyzed for pathogenic variants in BRCA1 or BRCA2. WES data from carriers of pathogenic BRCA1 or BRCA2 variants were analyzed for pathogenic variants in 10 other OC predisposing genes. Loss of heterozygosity analysis was performed on tumor DNA from variant carriers. Results: BRCA1 c.5407-25T>A intronic variant, identified in two affected sisters and one sporadic OC case, is predicted to create a new splice effecting transcription of BRCA1. WES data from BRCA1 c.5407-25T>A carriers showed no evidence of pathogenic variants in other OC predisposing genes. Sequencing the tumor DNA from the variant carrier showed complete loss of the wild-type allele. Conclusions: The findings support BRCA1 c.5407-25T>A as a likely pathogenic variant and highlight the importance of investigating intronic sequences as causal variants in OC families where the involvement of BRCA1 is highly suggestive.
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Du, Juanjiangmeng, Monica Sudarsanam, Eduardo Pérez-Palma, Andrea Ganna, Laurent Francioli, Sumaiya Iqbal, Lisa-Marie Niestroj et al. "Variant Score Ranker—a web application for intuitive missense variant prioritization". Bioinformatics 35, n.º 21 (25 de abril de 2019): 4478–79. http://dx.doi.org/10.1093/bioinformatics/btz252.
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Abstract Motivation The correct classification of missense variants as benign or pathogenic remains challenging. Pathogenic variants are expected to have higher deleterious prediction scores than benign variants in the same gene. However, most of the existing variant annotation tools do not reference the score range of benign population variants on gene level. Results We present a web-application, Variant Score Ranker, which enables users to rapidly annotate variants and perform gene-specific variant score ranking on the population level. We also provide an intuitive example of how gene- and population-calibrated variant ranking scores can improve epilepsy variant prioritization. Availability and implementation http://vsranker.broadinstitute.org Supplementary information Supplementary data are available at Bioinformatics online.
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Wiggins, George A. R., Logan C. Walker y John F. Pearson. "Genome-Wide Gene Expression Analyses of BRCA1- and BRCA2-Associated Breast and Ovarian Tumours". Cancers 12, n.º 10 (16 de octubre de 2020): 3015. http://dx.doi.org/10.3390/cancers12103015.
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Germline pathogenic variants in BRCA1 and BRCA2 increase cumulative lifetime risk up to 75% for breast cancer and 76% for ovarian cancer. Genetic testing for BRCA1 and BRCA2 pathogenic variants has become an important part of clinical practice for cancer risk assessment and for reducing individual risk of developing cancer. Genetic testing can produce three outcomes: positive (a pathogenic variant), uninformative (no pathogenic variant) and uncertain significance (a variant of unknown clinical significance). More than one third of BRCA1 and BRCA2 variants identified have been classified as variants of uncertain significance, presenting a challenge for clinicians. To address this important clinical challenge, a number of studies have been undertaken to establish a gene expression phenotype for pathogenic BRCA1 and BRCA2 variant carriers in several diseased and normal tissues. However, the consistency of gene expression phenotypes described in studies has been poor. To determine if gene expression analysis has been a successful approach for variant classification, we describe the design and comparability of 23 published gene expression studies that have profiled cells from BRCA1 and BRCA2 pathogenic variant carriers. We show the impact of advancements in expression-based technologies, the importance of developing larger study cohorts and the necessity to better understand variables affecting gene expression profiles across different tissue types.
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Safka Brozkova, Dana, Anna Uhrova Meszarosova, Petra Lassuthova, Lukáš Varga, David Staněk, Silvia Borecká, Jana Laštůvková et al. "The Cause of Hereditary Hearing Loss in GJB2 Heterozygotes—A Comprehensive Study of the GJB2/DFNB1 Region". Genes 12, n.º 5 (1 de mayo de 2021): 684. http://dx.doi.org/10.3390/genes12050684.
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Hearing loss is a genetically heterogeneous sensory defect, and the frequent causes are biallelic pathogenic variants in the GJB2 gene. However, patients carrying only one heterozygous pathogenic (monoallelic) GJB2 variant represent a long-lasting diagnostic problem. Interestingly, previous results showed that individuals with a heterozygous pathogenic GJB2 variant are two times more prevalent among those with hearing loss compared to normal-hearing individuals. This excess among patients led us to hypothesize that there could be another pathogenic variant in the GJB2 region/DFNB1 locus. A hitherto undiscovered variant could, in part, explain the cause of hearing loss in patients and would mean reclassifying them as patients with GJB2 biallelic pathogenic variants. In order to detect an unknown causal variant, we examined 28 patients using NGS with probes that continuously cover the 0.4 Mb in the DFNB1 region. An additional 49 patients were examined by WES to uncover only carriers. We did not reveal a second pathogenic variant in the DFNB1 region. However, in 19% of the WES-examined patients, the cause of hearing loss was found to be in genes other than the GJB2. We present evidence to show that a substantial number of patients are carriers of the GJB2 pathogenic variant, albeit only by chance.
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Rao, Nandana D. y Brian H. Shirts. "Using species richness calculations to model the global profile of unsampled pathogenic variants: Examples from BRCA1 and BRCA2". PLOS ONE 18, n.º 2 (8 de febrero de 2023): e0278010. http://dx.doi.org/10.1371/journal.pone.0278010.
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There have been many surveys of genetic variation in BRCA1 and BRCA2 to identify variant prevalence and catalogue population specific variants, yet none have evaluated the magnitude of unobserved variation. We applied species richness estimation methods from ecology to estimate “variant richness” and determine how many germline pathogenic BRCA1/2 variants have yet to be identified and the frequency of these missing variants in different populations. We also estimated the prevalence of germline pathogenic BRCA1/2 variants and identified those expected to be most common. Data was obtained from a literature search including studies conducted globally that tested the entirety of BRCA1/2 for pathogenic variation. Across countries, 45% to 88% of variants were estimated to be missing, i.e., present in the population but not observed in study data. Estimated variant frequencies in each country showed a higher proportion of rare variants compared to recurrent variants. The median prevalence estimate of BRCA1/2 pathogenic variant carriers was 0.64%. BRCA1 c.68_69del is likely the most recurrent BRCA1/2 variant globally due to its estimated prevalence in India. Modeling variant richness using ecology methods may assist in evaluating clinical targeted assays by providing a picture of what is observed with estimates of what is still unknown.
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Kyo, Chika, Takeshi Usui, Rieko Kosugi, Mizuki Torii, Takako Yonemoto, Tatsuo Ogawa, Masato Kotani et al. "ARMC5 Alterations in Primary Macronodular Adrenal Hyperplasia (PMAH) and the Clinical State of Variant Carriers". Journal of the Endocrine Society 3, n.º 10 (23 de julio de 2019): 1837–46. http://dx.doi.org/10.1210/js.2019-00210.
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Abstract Context Primary macronodular adrenal hyperplasia (PMAH) is a rare type of Cushing or subclinical Cushing syndrome and is associated with bilateral multinodular formation. ARMC5 is one of the responsible genes for PMAH. Objectives This study was performed to identify the genotype-phenotype correlation of ARMC5 in a cohort of Japanese patients. Patients and Methods Fourteen patients with clinically diagnosed PMAH and family members of selected patients were studied for ARMC5 gene alteration and clinical phenotype. The associated nonadrenal tumor tissues were also studied. Results Of fourteen patients with PMAH, 10 had pathogenic or likely pathogenic variants of ARMC5. We found two variants. Five unrelated patients had identical variants (p.R619*). In two patients, the variant was found in offspring with the asymptomatic or presymptomatic state. Six of ten patients who tested positive for the ARMC5 pathogenic or likely pathogenic variant carried nonadrenal tumors; however, no loss of heterozygosity (LOH) or second hit of the ARMC5 gene was evident. The ARMC5 variant–positive group showed a significantly higher basal cortisol level. Furthermore, age-dependent cortisol hypersecretion was seen in the ARMC5 variant–positive group. Conclusions ARMC5 pathogenic variants are common (71%) in Japanese patients with PMAH. p.R619* might be a hot spot in Japanese patients with PMAH. Asymptomatic or presymptomatic pathogenic variant carriers were found among the family members of the patients. Although 50% of ARMC5 variant carriers had nonadrenal neoplastic lesions, no LOH or second hit of ARMC5 in the tumor tissues was evident. The ARMC5 variant–positive mutant group showed a higher basal cortisol level than the negative group.
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Bennett, Mark F., Michael S. Hildebrand, Sayaka Kayumi, Mark A. Corbett, Sachin Gupta, Zimeng Ye, Michael Krivanek et al. "Evidence for a Dual-Pathway, 2-Hit Genetic Model for Focal Cortical Dysplasia and Epilepsy". Neurology Genetics 8, n.º 1 (25 de enero de 2022): e0652. http://dx.doi.org/10.1212/nxg.0000000000000652.
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Background and ObjectivesThe 2-hit model of genetic disease is well established in cancer, yet has only recently been reported to cause brain malformations associated with epilepsy. Pathogenic germline and somatic variants in genes in the mechanistic target of rapamycin (mTOR) pathway have been implicated in several malformations of cortical development. We investigated the 2-hit model by performing genetic analysis and searching for germline and somatic variants in genes in the mTOR and related pathways.MethodsWe searched for germline and somatic pathogenic variants in 2 brothers with drug-resistant focal epilepsy and surgically resected focal cortical dysplasia (FCD) type IIA. Exome sequencing was performed on blood- and brain-derived DNA to identify pathogenic variants, which were validated by droplet digital PCR. In vitro functional assays of a somatic variant were performed.ResultsExome analysis revealed a novel, maternally inherited, germline pathogenic truncation variant (c.48delG; p.Ser17Alafs*70) in NPRL3 in both brothers. NPRL3 is a known FCD gene that encodes a negative regulator of the mTOR pathway. Somatic variant calling in brain-derived DNA from both brothers revealed a low allele fraction somatic variant (c.338C>T; p.Ala113Val) in the WNT2 gene in 1 brother, confirmed by droplet digital PCR. In vitro functional studies suggested a loss of WNT2 function as a consequence of this variant. A second somatic variant has not yet been found in the other brother.DiscussionWe identify a pathogenic germline mTOR pathway variant (NPRL3) and a somatic variant (WNT2) in the intersecting WNT signaling pathway, potentially implicating the WNT2 gene in FCD and supporting a dual-pathway 2-hit model. If confirmed in other cases, this would extend the 2-hit model to pathogenic variants in different genes in critical, intersecting pathways in a malformation of cortical development. Detection of low allele fraction somatic second hits is challenging but promises to unravel the molecular architecture of FCDs.
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Kumar, Anil, Rajni Sharma, Mohammed Faruq, Varun Suroliya, Manoj Kumar, Shilpa Sharma, Ralf Werner, Olaf Hiort y Vandana Jain. "Spectrum of Pathogenic Variants in SRD5A2 in Indian Children with 46,XY Disorders of Sex Development and Clinically Suspected Steroid 5α-Reductase 2 Deficiency". Sexual Development 13, n.º 5-6 (2019): 228–39. http://dx.doi.org/10.1159/000509812.
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The aim of this study was to assess the prevalence of pathogenic variants in the <i>SRD5A2</i> gene in children with 46,XY disorders of sex development (DSD) with normal to high serum testosterone levels and absence of Müllerian structures on imaging and to evaluate the genotype-phenotype correlation. Seventy-five patients with 46,XY DSD and probable clinical diagnosis of 5α-reductase 2 deficiency or androgen insensitivity syndrome were enrolled. Genetic analysis was done for pathogenic variants in <i>SRD5A2</i>, and the genotype-phenotype correlation was studied. As a result, 10 pathogenic or likely pathogenic biallelic variants in <i>SRD5A2, </i>either homozygous or compound heterozygous, were identified in 25 of 75 (33.3%) patients. The hCG stimulated testosterone: dihydrotestosterone (T:DHT) ratio was elevated in all patients with pathogenic variants in <i>SRD5A2</i> and in nearly 90% of those without pathogenic variants in <i>SRD5A2</i> in whom this was assessed. The missense pathogenic variant p.R246Q was a hotspot. One novel pathogenic variant p.Y178*, and a variant p.F194I, not previously reported in patients with 5α-reductase 2 deficiency, were identified. The missense variant p.F194I was predicted as deleterious and damaging by in silico analysis and as likely to reduce the enzyme activity by protein modeling. In conclusion, pathogenic variants in <i>SRD5A2 </i>can be detected in a wide spectrum of Indian patients with 46,XY DSD. Molecular genetic analysis should be considered as a first-line test as the T:DHT ratio lacks specificity and a hotspot variant is present in a vast majority.
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Kumar, Anil, Rajni Sharma, Mohammed Faruq, Manoj Kumar, Shilpa Sharma, Ralf Werner, Olaf Hiort y Jain Vandana. "Clinical, Biochemical, and Molecular Characterization of Indian Children with Clinically Suspected Androgen Insensitivity Syndrome". Sexual Development 16, n.º 1 (22 de octubre de 2021): 34–45. http://dx.doi.org/10.1159/000519047.
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This study describes the clinical, biochemical, and molecular characteristics of Indian children with 46,XY DSD and suspected androgen insensitivity syndrome (AIS). Fifty children (median age 3.0 years, range 0–16.5 years) with 46,XY DSD and a suspected diagnosis of AIS were enrolled. Sanger sequencing was performed to identify pathogenic variants in the androgen receptor (<i>AR</i>) gene and to study genotype-phenotype correlations. All 5 (100%) patients with CAIS and 14/45 (31%) patients with PAIS had pathogenic/likely pathogenic variants in the <i>AR</i> gene (overall, 14 different variants in 19 patients; 38.8%). There was no significant difference in clinical (cryptorchidism, hypospadias, or external masculinizing score) or biochemical parameters (gonadotropins and testosterone) between patients with or without pathogenic variants. However, patients with AIS were more likely to have a positive family history, be assigned female gender at birth, and present with gynaecomastia at puberty. Three novel pathogenic/likely pathogenic variants, including one splice donor site variant c.2318+1G>A, one frameshift variant p.H790Lfs*40, and one missense variant p.G821E, were identified in 3 patients with CAIS. The missense variant p.G821E was predicted as deleterious, damaging, disease-causing, and likely functionally inactive by in silico analysis and protein modelling study. Two previously not reported pathogenic/likely pathogenic variants, including p.R386H and p.G396R, were identified in patients with PAIS. This study contributes in expanding the spectrum of pathogenic variants in the <i>AR</i> gene in patients with AIS. Only 31% patients with a provisional diagnosis of PAIS had pathogenic variants in the <i>AR</i> gene, suggesting other possible mechanisms or candidate genes may be responsible for such a phenotypic presentation.
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Pettinato, Anthony M., Feria A. Ladha, David J. Mellert, Nicholas Legere, Rachel Cohn, Robert Romano, Ketan Thakar, Yu-Sheng Chen y J. Travis Hinson. "Development of a Cardiac Sarcomere Functional Genomics Platform to Enable Scalable Interrogation of Human TNNT2 Variants". Circulation 142, n.º 23 (8 de diciembre de 2020): 2262–75. http://dx.doi.org/10.1161/circulationaha.120.047999.
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Background: Pathogenic TNNT2 variants are a cause of hypertrophic and dilated cardiomyopathies, which promote heart failure by incompletely understood mechanisms. The precise functional significance for 87% of TNNT2 variants remains undetermined, in part, because of a lack of functional genomics studies. The knowledge of which and how TNNT2 variants cause hypertrophic and dilated cardiomyopathies could improve heart failure risk determination, treatment efficacy, and therapeutic discovery, and provide new insights into cardiomyopathy pathogenesis, as well. Methods: We created a toolkit of human induced pluripotent stem cell models and functional assays using CRISPR/Cas9 to study TNNT2 variant pathogenicity and pathophysiology. Using human induced pluripotent stem cell–derived cardiomyocytes in cardiac microtissue and single-cell assays, we functionally interrogated 51 TNNT2 variants, including 30 pathogenic/likely pathogenic variants and 21 variants of uncertain significance. We used RNA sequencing to determine the transcriptomic consequences of pathogenic TNNT2 variants and adapted CRISPR/Cas9 to engineer a transcriptional reporter assay to assist prediction of TNNT2 variant pathogenicity. We also studied variant-specific pathophysiology using a thin filament–directed calcium reporter to monitor changes in myofilament calcium affinity. Results: Hypertrophic cardiomyopathy–associated TNNT2 variants caused increased cardiac microtissue contraction, whereas dilated cardiomyopathy–associated variants decreased contraction. TNNT2 variant–dependent changes in sarcomere contractile function induced graded regulation of 101 gene transcripts, including MAPK (mitogen-activated protein kinase) signaling targets, HOPX , and NPPB . We distinguished pathogenic TNNT2 variants from wildtype controls using a sarcomere functional reporter engineered by inserting tdTomato into the endogenous NPPB locus. On the basis of a combination of NPPB reporter activity and cardiac microtissue contraction, our study provides experimental support for the reclassification of 2 pathogenic/likely pathogenic variants and 2 variants of uncertain significance. Conclusions: Our study found that hypertrophic cardiomyopathy–associated TNNT2 variants increased cardiac microtissue contraction, whereas dilated cardiomyopathy–associated variants decreased contraction, both of which paralleled changes in myofilament calcium affinity. Transcriptomic changes, including NPPB levels, directly correlated with sarcomere function and can be used to predict TNNT2 variant pathogenicity.
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Dines, Jennifer N., Brian H. Shirts, Thomas P. Slavin, Tom Walsh, Mary-Claire King, Douglas M. Fowler y Colin C. Pritchard. "Systematic misclassification of missense variants in BRCA1 and BRCA2 “coldspots”". Genetics in Medicine 22, n.º 5 (8 de enero de 2020): 825–30. http://dx.doi.org/10.1038/s41436-019-0740-6.
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Abstract Purpose Guidelines for variant interpretation incorporate variant hotspots in critical functional domains as evidence for pathogenicity (e.g., PM1 and PP2), but do not use “coldspots,” that is, regions without essential functions that tolerate variation, as evidence a variant is benign. To improve variant classification we evaluated BRCA1 and BRCA2 missense variants reported in ClinVar to identify regions where pathogenic missenses are extremely infrequent, defined as coldspots. Methods We used Bayesian approaches to model variant classification in these regions. Results BRCA1 exon 11 (~60% of the coding sequence), and BRCA2 exons 10 and 11 (~65% of the coding sequence), are coldspots. Of 89 pathogenic (P) or likely pathogenic (LP) missense variants in BRCA1, none are in exon 11 (odds <0.01, 95% confidence interval [CI] 0.0–0.01). Of 34 P or LP missense variants in BRCA2, none are in exons 10–11 (odds <0.01, 95% CI 0.0–0.01). More than half of reported missense variants of uncertain significance (VUS) in BRCA1 and BRCA2 are in coldspots (3115/5301 = 58.8%). Reclassifying these 3115 VUS as likely benign would substantially improve variant classification. Conclusion In BRCA1 and BRCA2 coldspots, missense variants are very unlikely to be pathogenic. Classification schemes that incorporate coldspots can reduce the number of VUS and mitigate risks from reporting benign variation as VUS.
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Laddach, Anna, Joseph Chi Fung Ng y Franca Fraternali. "Pathogenic missense protein variants affect different functional pathways and proteomic features than healthy population variants". PLOS Biology 19, n.º 4 (28 de abril de 2021): e3001207. http://dx.doi.org/10.1371/journal.pbio.3001207.
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Missense variants are present amongst the healthy population, but some of them are causative of human diseases. A classification of variants associated with “healthy” or “diseased” states is therefore not always straightforward. A deeper understanding of the nature of missense variants in health and disease, the cellular processes they may affect, and the general molecular principles which underlie these differences is essential to offer mechanistic explanations of the true impact of pathogenic variants. Here, we have formalised a statistical framework which enables robust probabilistic quantification of variant enrichment across full-length proteins, their domains, and 3D structure-defined regions. Using this framework, we validate and extend previously reported trends of variant enrichment in different protein structural regions (surface/core/interface). By examining the association of variant enrichment with available functional pathways and transcriptomic and proteomic (protein half-life, thermal stability, abundance) data, we have mined a rich set of molecular features which distinguish between pathogenic and population variants: Pathogenic variants mainly affect proteins involved in cell proliferation and nucleotide processing and are enriched in more abundant proteins. Additionally, rare population variants display features closer to common than pathogenic variants. We validate the association between these molecular features and variant pathogenicity by comparing against existing in silico variant impact annotations. This study provides molecular details into how different proteins exhibit resilience and/or sensitivity towards missense variants and provides the rationale to prioritise variant-enriched proteins and protein domains for therapeutic targeting and development. The ZoomVar database, which we created for this study, is available at fraternalilab.kcl.ac.uk/ZoomVar. It allows users to programmatically annotate missense variants with protein structural information and to calculate variant enrichment in different protein structural regions.
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Chiang, Jianbang, Tze Hao Chia, Jeanette Yuen, Tarryn Shaw, Shao-Tzu Li, Nur Diana Binte Ishak, Ee Ling Chew, Siao Ting Chong, Sock Hoai Chan y Joanne Ngeow. "Impact of Variant Reclassification in Cancer Predisposition Genes on Clinical Care". JCO Precision Oncology, n.º 5 (marzo de 2021): 577–84. http://dx.doi.org/10.1200/po.20.00399.
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PURPOSE Genetic testing has clinical utility in the management of patients with hereditary cancer syndromes. However, the increased likelihood of encountering a variant of uncertain significance in individuals of non-European descent such as Asians may be challenging to both clinicians and patients. This study aims to evaluate the impact of variant reclassification in an Asian country with variants of uncertain significance reported in cancer predisposition genes. METHODS A retrospective analysis of patients seen at the Cancer Genetics Service at the National Cancer Centre Singapore between February 2014 and March 2020 was conducted. The frequency, direction, and time to variant reclassification were evaluated by comparing the reclassified report against the original report. RESULTS A total of 1,412 variants of uncertain significance were reported in 49.9% (845 of 1,695) of patients. Over 6 years, 6.7% (94 of 1,412) of variants were reclassified. Most variants of uncertain significance (94.1%, 80 of 85) were downgraded to benign or likely benign variant, with a smaller proportion of variants of uncertain significance (5.9%, 5 of 85) upgraded to pathogenic or likely pathogenic variant. Actionable variants of uncertain significance upgrades and pathogenic or likely pathogenic variant downgrades, which resulted in management changes, happened in 31.0% (39 of 126) of patients. The median and mean time taken for reclassification were 1 and 1.62 year(s), respectively. CONCLUSION We propose a clinical guideline to standardize management of patients reported to have variants of uncertain significance. Management should be based on the patient’s personal history, family history, and variant interpretation. For clinically relevant or suspicious variants of uncertain significance, follow-up is recommended every 2 years, as actionable reclassifications may happen during this period.
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Aldubayan, Saud H., Jake Conway, Leora Witkowski, Eric Kofman, Brendan Reardon, Sabrina Camp, Seunghun Han et al. "Expanding the diagnostic yield of germline genetic testing in cancer patients using deep learning." Journal of Clinical Oncology 38, n.º 15_suppl (20 de mayo de 2020): 1518. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.1518.
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1518 Background: Germline genetic analysis is an essential tool for implementing precision cancer prevention and treatment. However, only a small fraction of cancer patients, even those with features suggestive of a cancer-predisposition syndrome, have detectable pathogenic germline events, which may in part reflect incomplete pathogenic variant detection by current gold-standard methods. Here, we leveraged deep learning approaches to expand the diagnostic utility of genetic analysis in cancer patients. Methods: Systematic analysis of the detection rate of pathogenic cancer-predisposition variants using the standard clinical variant detection method and a deep learning approach in germline whole-exome sequencing data of 2367 cancer patients (n = 1072 prostate cancer, 1295 melanoma). Results: Of 1072 prostate cancer patients, deep learning variant detection identified 16 additional prostate cancer patients with clinically actionable pathogenic cancer-predisposition variants that went undetected by the gold-standard method (198 vs. 182), yielding higher sensitivity (94.7% vs. 87.1%), specificity (64.0% vs. 36.0%), positive predictive value (95.7% vs. 91.9%), and negative predictive value (59.3% vs. 25.0%). Similarly, germline genetic analysis of 1295 melanoma patients showed that, compared with the standard method, deep learning detected 19 additional patients with validated pathogenic variants (93 vs. 74) with fewer false-positive calls (78 vs. 135) leading to a higher diagnostic yield. Collectively, deep learning identified one additional patient with a pathogenic cancer-risk variant, that went undetected by the standard method, for every 52 to 67 cancer patients undergoing germline analysis. Superior performance of deep learning, for detecting putative loss-of-function variants, was also seen across 5197 clinically relevant Mendelian genes in these cohorts. Conclusions: The gold-standard germline variant detection method, universally used in clinical and research settings, has significant limitations for identifying clinically relevant pathogenic disease-causing variants. We determined that deep learning approaches have a clinically significant increase in the diagnostic yield across commonly examined Mendelian gene sets.
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Chorich, Lynn P., Michael P. Diamond, Janet E. Hall, Kenneth S. Korach, Lawrence C. Layman, Yin Li, Haitao Liu y Robert A. Roman. "OR06-3 ESR1 Pathogenic Variant With Incomplete Estrogen Insensitivity". Journal of the Endocrine Society 6, Supplement_1 (1 de noviembre de 2022): A677—A678. http://dx.doi.org/10.1210/jendso/bvac150.1401.
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Abstract Introduction Estrogen is vital to human reproduction and acts primarily through two receptors: estrogen receptor alpha (ERα, encoded by ESR1) and estrogen receptor beta (ERβ, encoded by ESR2). Surprisingly, very few human ESR1 pathogenic variants have been recognized, despite the existence of >1000 different androgen receptor pathogenic variants causing androgen insensitivity syndrome. Functional analysis of an ESR1 homozygous missense variant (p.Glu375His) in the ERα ligand-binding domain (LBD) showed a 240-fold decrease in estrogen response in a patient with complete estrogen insensitivity and abnormal pubertal development. We predict that less severe ESR1 variants will present with unexplained infertility. Previously, we performed whole exome sequencing on 200 females with unexplained infertility and identified 4 likely pathogenic ESR1 heterozygous missense variants confirmed by Sanger sequencing, including one variant (p.Thr313Met) in the LBD. In this study, we performed in vitro functional analysis to evaluate if the p.Thr313Met likely pathogenic variant found in a patient with unexplained infertility causes incomplete estrogen insensitivity. Hypothesis We hypothesize that the p.Thr313Met likely pathogenic variant in the ERa LBD will result in incomplete estrogen insensitivity. Methods The p.Thr313Met variant plasmid was constructed using site-directed mutagenesis (SDM), and confirmed by Sanger sequencing. An in vitro cell model was used to evaluate estrogenic activity. HepG2 cells were transiently transfected with WT ESR1, p.Thr313Met, or p.Glu375His plasmid, along with the Firefly estrogen response element (ERE) luciferase reporter (3X ERE TATA luc) and Renilla luciferase (pRL-TK luc) plasmids using the Effectene transfection protocol. Cells were treated with 17β-estradiol (0.01, 0.1, 1, 10, and 100 nM). A dual luciferase reporter assay was used to compare relative Firefly and Renilla luciferase activity between WT ESR1, p.Thr313Met, and p.Glu375His plasmids using a luminometer. Estrogen dose response curves were generated, and a two-way ANOVA with Tukey's test was performed to compare the relative luciferase activity across WT and variant plasmids using GraphPad Prism v.9. Differences were considered significant at p<0.05. Results Estrogen response curves were generated for WT, p.Thr313Met, and p.Glu375His plasmids. The p.Thr313Met variant showed lower overall activity with a right shifted dose response curve with a statistically significant decrease in relative luciferase activity in comparison to WT (p<0.05). The p.Thr313Met variant was more active at higher doses (1 and 10 nM) with a left shifted dose curve when compared to the p.Glu375His variant (p<0.05). Conclusion We have identified a human ESR1 variant that impairs estrogen signaling in vitro, suggesting incomplete estrogen insensitivity as a putative mechanism for unexplained infertility. The identification of ESR1 pathogenic variants and the evaluation of their functionality could provide improved diagnosis and genetic counseling for patients with unexplained infertility. Presentation: Saturday, June 11, 2022 12:00 p.m. - 12:15 p.m.
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Accetturo, Matteo, Nicola Bartolomeo y Alessandro Stella. "In-silico Analysis of NF1 Missense Variants in ClinVar: Translating Variant Predictions into Variant Interpretation and Classification". International Journal of Molecular Sciences 21, n.º 3 (22 de enero de 2020): 721. http://dx.doi.org/10.3390/ijms21030721.
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Background: With the advent of next-generation sequencing in genetic testing, predicting the pathogenicity of missense variants represents a major challenge potentially leading to misdiagnoses in the clinical setting. In neurofibromatosis type 1 (NF1), where clinical criteria for diagnosis may not be fully present until late infancy, correct assessment of variant pathogenicity is fundamental for appropriate patients’ management. Methods: Here, we analyzed three different computational methods, VEST3, REVEL and ClinPred, and after extracting predictions scores for 1585 NF1 missense variants listed in ClinVar, evaluated their performances and the score distribution throughout the neurofibromin protein. Results: For all the three methods, no significant differences were present between the scores of “likely benign”, “benign”, and “likely pathogenic”, “pathogenic” variants that were consequently collapsed into a single category. The cutoff values for pathogenicity were significantly different for the three methods and among benign and pathogenic variants for all methods. After training five different models with a subset of benign and pathogenic variants, we could reclassify variants in three sharply separated categories. Conclusions: The recently developed metapredictors, which integrate information from multiple components, after gene-specific fine-tuning, could represent useful tools for variant interpretation, particularly in genetic diseases where a clinical diagnosis can be difficult.
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Zhang, Yi, Yizhuo Wang, Dongsheng Huang, Jianmin Ma, Weiling Zhang, Huali Gu, Yan Zhou, You Yi y Pinwei Zhang. "Correlation between Family RB1 Gene Pathogenic Variant with Clinical Features and Prognosis of Retinoblastoma under 5 Years Old". Disease Markers 2021 (12 de julio de 2021): 1–10. http://dx.doi.org/10.1155/2021/9981028.
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Retinoblastoma (RB) is the most common primary intraocular malignant tumor in infants and the prototype of human hereditary tumors. Its occurrence and development are closely related to the pathogenic variant of tumor suppressor RB1 gene. We aim to analyze the characteristics of RB1 gene pathogenic variant and clinical phenotype in retinoblastoma patients and their relatives. Children with RB were recruited from August 2007 to November 2017. QT-PCR, probing, and gene sequencing were used to analyze the sequence of RB1 gene in RB children, their parents, or grandparents with a clear history of illness. The SPSS20.0 software was used to analyze the correlation between polymorphisms of RB1 gene and the incidence and prognosis of the enrolled children and relatives. 40 RB children (20 males and 20 females) were recruited, unilateral RB accounted for 52.5% (21/40), bilateral RB accounted for 42.5% (17/40), and trilateral RB accounted for 5.0% (2/40). 6 patients had a clear family history (15.0%, 6/40). It had been verified that 19 probands (47.5%) have RB1 gene pathogenic variants (11 frameshift and 8 missense pathogenic variants), of which germline inheritance accounted for 47.4% (9/19) and nongermline heredity accounted for 52.6% (10/19). Pathogenic variants of 10 nucleic acid sites without reported were found, among which c.2455C>G (p.L819V) was confirmed to have heterozygous pathogenic variants in both a bilateral RB patient and his mother with unilateral RB. Family genetic high-risk factors, bilateral/trilateral RB, >12-month-onset RB have a higher proportion of RB1 gene pathogenic variant than children with no family history, unilateral RB, and ≤12-month ( P = 0.021 , 0.001,0.034). The proportion of pedigree inheritance of infantile retinoblastoma with bilateral disease is high. There was a certain proportion of RB1 gene pathogenic variant in 3-5-year-old children with bilateral RB, even if they had no family genetic history. Therefore, the detection of RB1 gene pathogenic variant should not only focus on infants but also on the phenotype of RB1 gene pathogenic variant in children over 3 years old with bilateral eye disease.
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Ohata, Yasuhisa y Yasuki Ishihara. "Pathogenic Variants of the PHEX Gene". Endocrines 3, n.º 3 (8 de agosto de 2022): 498–511. http://dx.doi.org/10.3390/endocrines3030040.
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Twenty-five years ago, a pathogenic variant of the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene was identified as the cause of X-linked hypophosphatemic rickets (XLH). Subsequently, the overproduction of fibroblast growth factor 23 (FGF23) due to PHEX defects has been found to be associated with XLH pathophysiology. However, the mechanism by which PHEX deficiency contributes to the upregulation of FGF23 and the function of PHEX itself remain unclear. To date, over 700 pathogenic variants have been identified in patients with XLH, and functional assays and genotype–phenotype correlation analyses based on pathogenic variant data derived from XLH patients have been reported. Genetic testing for XLH is useful for the diagnosis. Not only have single-nucleotide variants causing missense, nonsense, and splicing variants and small deletion/insertion variants causing frameshift/non-frameshift alterations been observed, but also gross deletion/duplication variants causing copy number variants have been reported as pathogenic variants in PHEX. With the development of new technologies including next generation sequencing, it is expected that an increasing number of pathogenic variants will be identified. This chapter aimed to summarize the genotype of PHEX and related analyses and discusses the pathophysiology of PHEX defects to seek clues on unsolved questions.
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Marshall, Charla, Kimberly Sturk-Andreaggi, Joseph D. Ring, Arne Dür y Walther Parson. "Pathogenic Variant Filtering for Mitochondrial Genome Haplotype Reporting". Genes 11, n.º 10 (28 de septiembre de 2020): 1140. http://dx.doi.org/10.3390/genes11101140.
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Given the enhanced discriminatory power of the mitochondrial DNA (mtDNA) genome (mitogenome) over the commonly sequenced control region (CR) portion, the scientific merit of mitogenome sequencing is generally accepted. However, many laboratories remain beholden to CR sequencing due to privacy policies and legal requirements restricting the use of disease information or coding region (codR) information. In this report, we present an approach to obviate the reporting of sensitive codR data in forensic haplotypes. We consulted the MitoMap database to identify 92 mtDNA codR variants with confirmed pathogenicity. We determined the frequencies of these pathogenic variants in literature-quality and forensic-quality databases to be very low, at 1.2% and 0.36%, respectively. The observed effect of pathogenic variant filtering on random match statistics in 2488 forensic-quality mitogenome haplotypes from four populations was nil. We propose that pathogenic variant filtering should be incorporated into variant calling algorithms for mitogenome haplotype reporting to maximize the discriminatory power of the locus while minimizing the reveal of sensitive genetic information.
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Shah, Ravi A., Babken Asatryan, Ghaith Sharaf Dabbagh, Nay Aung, Mohammed Y. Khanji, Luis R. Lopes, Stefan van Duijvenboden et al. "Frequency, Penetrance, and Variable Expressivity of Dilated Cardiomyopathy–Associated Putative Pathogenic Gene Variants in UK Biobank Participants". Circulation 146, n.º 2 (12 de julio de 2022): 110–24. http://dx.doi.org/10.1161/circulationaha.121.058143.
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Background: There is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional, and arrhythmic disease features. Methods: UK Biobank participants who had undergone whole exome sequencing, ECG, and cardiovascular magnetic resonance imaging were selected for study. Three variant-calling strategies (1 primary and 2 secondary) were used to identify participants with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded DCM (clinical or cardiovascular magnetic resonance diagnosis); early DCM features, including arrhythmia or conduction disease, isolated ventricular dilation, and hypokinetic nondilated cardiomyopathy; or phenotype-negative. Results: Among 18 665 individuals included in the study, 1463 (7.8%) possessed ≥1 putative pathogenic variant in 44 DCM genes by the main variant calling strategy. A clinical diagnosis of DCM was present in 0.34% and early DCM features in 5.7% of individuals with putative pathogenic variants. ECG and cardiovascular magnetic resonance analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in an additional 15.9% of individuals with putative pathogenic variants. Arrhythmias or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic nondilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was ≤30% with all 3 variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes as compared with those with variants in moderate/limited evidence genes. Conclusions: In the UK Biobank, ≈1 of 6 of adults with putative pathogenic variants in DCM genes exhibited early DCM features potentially associated with DCM genotype, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction.
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Shakil, Muhammad, Abida Akbar, Nazish Mahmood Aisha, Intzar Hussain, Muhammad Ikram Ullah, Muhammad Atif, Haiba Kaul et al. "Delineating Novel and Known Pathogenic Variants in TYR, OCA2 and HPS-1 Genes in Eight Oculocutaneous Albinism (OCA) Pakistani Families". Genes 13, n.º 3 (12 de marzo de 2022): 503. http://dx.doi.org/10.3390/genes13030503.
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Oculocutaneous albinism (OCA) is associated with a wide range of clinical presentations and has been categorized with syndromic and non-syndromic features. The most common causative genes in non-syndromic OCA are TYR and OCA2 and HSP1 is in the syndromic albinism. The objective of this study was to identify pathogenic variants in congenital OCA families from Pakistan. Eight consanguineous families were recruited, and clinical and ophthalmological examination was carried out to diagnose the disease. Whole blood was collected from the participating individuals, and genomic DNA was extracted for sequencing analysis. TruSight one-panel sequencing was carried out on one affected individual of each family, and termination Sanger sequencing was carried out to establish the co-segregation of the causative gene or genes. In silico analysis was conducted to predict the causative pathogenic variants. Two families were found to have novel genetic pathogenic variants, and six families harbored previously reported variants. One novel compound heterozygous pathogenic variant in the TYR gene, c.1002delA; p.Ala335LeufsTer20, a novel frameshift deletion pathogenic variant and c.832C>T; and p.Arg278Ter (a known pathogenic variant) were found in one family, whereas HPS1; c.437G>A; and p.Trp146Ter were detected in another family. The identification of new and previous pathogenic variants in TYR, OCA2, and HPS1 genes are causative of congenital OCA, and these findings are expanding the heterogeneity of OCA.
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Bryant, Nicole, Nicole Malpeli, Julia Ziaee, Cornelis Blauwendraat, Zhiyong Liu y Andrew B. West. "Identification of LRRK2 missense variants in the accelerating medicines partnership Parkinson’s disease cohort". Human Molecular Genetics 30, n.º 6 (27 de febrero de 2021): 454–66. http://dx.doi.org/10.1093/hmg/ddab058.
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Abstract Pathogenic missense variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified through linkage analysis in familial Parkinson disease (PD). Subsequently, other missense variants with lower effect sizes on PD risk have emerged, as well as non-coding polymorphisms (e.g. rs76904798) enriched in PD cases in genome-wide association studies. Here we leverage recent whole-genome sequences from the Accelerating Medicines Partnership-Parkinson’s Disease (AMP-PD) and the Genome Aggregation (gnomAD) databases to characterize novel missense variants in LRRK2 and explore their relationships with known pathogenic and PD-linked missense variants. Using a computational prediction tool that successfully classifies known pathogenic LRRK2 missense variants, we describe an online web-based resource that catalogs characteristics of over 1200 LRRK2 missense variants of unknown significance. Novel high-pathogenicity scoring variants, some identified exclusively in PD cases, tightly cluster within the ROC-COR-Kinase domains. Structure–function predictions support that some of these variants exert gain-of-function effects with respect to LRRK2 kinase activity. In AMP-PD participants, all p.R1441G carriers (N = 89) are also carriers of the more common PD-linked variant p.M1646T. In addition, nearly all carriers of the PD-linked p.N2081D missense variant are also carriers of the LRRK2 PD-risk variant rs76904798. These results provide a compendium of LRRK2 missense variants and how they associate with one another. While the pathogenic p.G2019S variant is by far the most frequent high-pathogenicity scoring variant, our results suggest that ultra-rare missense variants may have an important cumulative impact in increasing the number of individuals with LRRK2-linked PD.
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Suzuki, Hisato, Kenji Kurosawa, Keiichi Fukuda, Kazumoto Ijima, Ryo Sumazaki, Shinji Saito, Rika Kosaki et al. "Japanese pathogenic variant database: DPV". Translational Science of Rare Diseases 3, n.º 3-4 (20 de diciembre de 2018): 133–37. http://dx.doi.org/10.3233/trd-180027.
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Nicholas Russo, S., Ekta G. Shah, William C. Copeland y Mary Kay Koenig. "A new pathogenic POLG variant". Molecular Genetics and Metabolism Reports 32 (septiembre de 2022): 100890. http://dx.doi.org/10.1016/j.ymgmr.2022.100890.
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Koch, Linda. "Pathogenic non-coding variant identification". Nature Reviews Genetics 17, n.º 10 (15 de septiembre de 2016): 583. http://dx.doi.org/10.1038/nrg.2016.124.
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Siraj, Abdul K., Rong Bu, Maham Arshad, Kaleem Iqbal, Sandeep Kumar Parvathareddy, Tariq Masoodi, Laila Omar Ghazwani, Saif S. Al-Sobhi, Fouad Al-Dayel y Khawla S. Al-Kuraya. "POLE and POLD1 pathogenic variants in the proofreading domain in papillary thyroid cancer". Endocrine Connections 9, n.º 9 (septiembre de 2020): 923–32. http://dx.doi.org/10.1530/ec-20-0258.
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Thyroid cancer is the most frequent endocrine cancer with an increasing incidence rate worldwide and is the second most common malignancy among females in Saudi Arabia. Papillary thyroid cancer (PTC) is the most common subtype. Germline pathogenic variants in the proofreading domain of the POLE and POLD1 genes predispose to several types of cancers. However, the role of pathogenic variants of these two genes in PTC remains unknown. Capture sequencing, Sanger sequencing and immunohistochemistry were performed on 300 PTC cases from the Middle Eastern region. One germline pathogenic variant each of POLE (1/300, 0.33%) and POLD1 (1/300, 0.33%) genes was identified. Low expression of POLD1 was detected in 46.5% (133/286) of cases and was significantly associated with the follicular variant of PTC (P = 0.0006), distant metastasis (P = 0.0033) and stage IV tumours (P = 0.0081). However, no somatic pathogenic variant was detected in POLE gene. Furthermore, low expression of POLE was noted in 61.7% (175/284) of cases with no significant clinicopathological associations. Our study shows that pathogenic variant in the POLE and POLD1 proofreading domain is a cause of PTC and low expression of POLD1 is associated with poor prognostic markers in the Middle Eastern population. Further studies from different geographic populations are needed to determine the frequency and spectrum of proofreading domain pathogenic variants in POLE and POLD1 genes and in PTC from different ethnicities.
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Mallack, Eric J., Kerry Gao, Marc Engelen y Stephan Kemp. "Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy". Cells 11, n.º 2 (14 de enero de 2022): 283. http://dx.doi.org/10.3390/cells11020283.
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The progressive neurometabolic disorder X-linked adrenoleukodystrophy (ALD) is caused by pathogenic variants in the ABCD1 gene, which encodes the peroxisomal ATP-binding transporter for very-long-chain fatty acids. The clinical spectrum of ALD includes adrenal insufficiency, myelopathy, and/or leukodystrophy. A complicating factor in disease management is the absence of a genotype–phenotype correlation in ALD. Since 1999, most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database. In 2017, following the expansion of ALD newborn screening, the database was rebuilt. To add an additional level of confidence with respect to pathogenicity, for each variant, it now also reports the number of cases identified and, where available, experimental data supporting the pathogenicity of the variant. The website also provides information on a number of ALD-related topics in several languages. Here, we provide an updated analysis of the known variants in ABCD1. The order of pathogenic variant frequency, overall clustering of disease-causing variants in exons 1–2 (transmembrane domain spanning region) and 6–9 (ATP-binding domain), and the most commonly reported pathogenic variant p.Gln472Argfs*83 in exon 5 are consistent with the initial reports of the mutation database. Novel insights include nonrandom clustering of high-density missense variant hotspots within exons 1, 2, 6, 8, and 9. Perhaps more importantly, we illustrate the importance of collaboration and utility of the database as a scientific, clinical, and ALD-community-wide resource.
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Arya, Sneha, Ankita Tiwari, Anurag Ranjan Lila, Vijaya Sarathi, Vishwambhar Vishnu Bhandare, Bajarang Vasant Kumbhar, Khushnandan Rai et al. "Homozygous p.Val89Leu plays an important pathogenic role in 5α-reductase type 2 deficiency patients with homozygous p.Arg246Gln in SRD5A2". European Journal of Endocrinology 183, n.º 3 (septiembre de 2020): 275–84. http://dx.doi.org/10.1530/eje-19-1050.
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Objective: To evaluate the pathogenic role of a few benign variants and hypomorphic pathogenic variants in SRD5A2. Design and methods: We retrospectively analyzed phenotypes and genotypes in 23 Indian patients with genetically proven steroid 5α-reductase 2 (SRD5A2) deficiency. The interactions of the SRD5A2 enzymes resulting due to the most common benign variant (p.Val89Leu), the most common (hypomorphic) pathogenic variant (p.Arg246Gln) and the double variants (p.Val89Leu and p.Arg246Gln) in SRD5A2 were compared with that of the wild type (WT) enzyme by molecular dynamics (MD) simulation. Results: The majority (n = 19, 82.61%) of patients presented for atypical genitalia and had male gender identity (16/20). Including the two novel ones (p.Leu83Pro, p.Ala28Leufs*103), a total of nine different pathogenic variants were observed. p.Arg246Gln was the most common pathogenic variant (n = 12). Homozygous p.Arg246Gln (n = 9) variant was associated with milder undervirilization (Sinnecker score of ≤3a: 8/9 vs 6/14, P = 0.04) and had concurrent homozygous p.Val89Leu in all patients. Interestingly, asymptomatic fathers of two index patients were homozygous for p.Arg246Gln which questioned the pathogenicity of the variation as a sole factor. Unlike all symptomatic homozygous p.Arg246Gln patients who were also homozygous for p.Val89Leu, asymptomatic homozygous p.Arg246Gln fathers were heterozygous for p.Val89Leu. On MD simulation SRD5A2 p.Val89Leu-Testeosterone (T) and SRD5A2 p.Arg246Gln-T complexes, but not SRD5A2 p.Val89Leu and p.Arg246Gln-T complex, demonstrated close interaction between NADPH and T as that of SRD5A2 WT-T. Conclusions: p.Arg246Gln may not be pathogenic as a sole variation even in the homozygous state; additional contribution of homozygous p.Val89Leu variant may be essential for the pathogenicity of p.Arg246Gln in SRD5A2.
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Bianchessi, Donatella, Maria Cristina Ibba, Veronica Saletti, Stefania Blasa, Tiziana Langella, Rosina Paterra, Giulia Anna Cagnoli et al. "Simultaneous Detection of NF1, SPRED1, LZTR1, and NF2 Gene Mutations by Targeted NGS in an Italian Cohort of Suspected NF1 Patients". Genes 11, n.º 6 (19 de junio de 2020): 671. http://dx.doi.org/10.3390/genes11060671.
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Neurofibromatosis type 1 (NF1) displays overlapping phenotypes with other neurocutaneous diseases such as Legius Syndrome. Here, we present results obtained using a next generation sequencing (NGS) panel including NF1, NF2, SPRED1, SMARCB1, and LZTR1 genes on Ion Torrent. Together with NGS, the Multiplex Ligation-Dependent Probe Amplification Analysis (MLPA) method was performed to rule out large deletions/duplications in NF1 gene; we validated the MLPA/NGS approach using Sanger sequencing on DNA or RNA of both positive and negative samples. In our cohort, a pathogenic variant was found in 175 patients; the pathogenic variant was observed in NF1 gene in 168 cases. A SPRED1 pathogenic variant was also found in one child and in a one year old boy, both NF2 and LZTR1 pathogenic variants were observed; in addition, we identified five LZTR1 pathogenic variants in three children and two adults. Six NF1 pathogenic variants, that the NGS analysis failed to identify, were detected on RNA by Sanger. NGS allows the identification of novel mutations in five genes in the same sequencing run, permitting unambiguous recognition of disorders with overlapping phenotypes with NF1 and facilitating genetic counseling and a personalized follow-up.
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Hernandez-Gonzalez, Ignacio, Jair Tenorio-Castano, Nuria Ochoa-Parra, Natalia Gallego, Carmen Pérez-Olivares, Mauro Lago-Docampo, Julian Palomino Doza, Diana Valverde, Pablo Lapunzina y Pilar Escribano-Subias. "Novel Genetic and Molecular Pathways in Pulmonary Arterial Hypertension Associated with Connective Tissue Disease". Cells 10, n.º 6 (13 de junio de 2021): 1488. http://dx.doi.org/10.3390/cells10061488.
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Pulmonary Arterial Hypertension (PAH) is a severe complication of Connective Tissue Disease (CTD), with remarkable morbidity and mortality. However, the molecular and genetic basis of CTD-PAH remains incompletely understood. This study aimed to screen for genetic defects in a cohort of patients with CTD-PAH, using a PAH-specific panel of 35 genes. During recruitment, 79 patients were studied, including 59 Systemic Sclerosis patients (SSc) and 69 females. Disease-associated variants were observed in nine patients: 4 pathogenic/likely pathogenic variants in 4 different genes (TBX4, ABCC8, KCNA5 and GDF2/BMP9) and 5 Variants of Unknown Significance (VUS) in 4 genes (ABCC8, NOTCH3, TOPBP1 and CTCFL). One patient with mixed CTD had a frameshift pathogenic variant in TBX4. Two patients with SSc-PAH carried variants in ABCC8. A patient diagnosed with Systemic Lupus Erythematous (SLE) presented a pathogenic nonsense variant in GDF2/BMP9. Another patient with SSc-PAH presented a pathogenic variant in KCNA5. Four patients with SSc-PAH carried a VUS in NOTCH1, CTCFL, CTCFL and TOPBP1, respectively. These findings suggest that genetic factors may contribute to Pulmonary Vascular Disease (PVD) in CTD patients.
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Moyon, Lambert, Camille Berthelot, Alexandra Louis, Nga Thi Thuy Nguyen y Hugues Roest Crollius. "Classification of non-coding variants with high pathogenic impact". PLOS Genetics 18, n.º 4 (29 de abril de 2022): e1010191. http://dx.doi.org/10.1371/journal.pgen.1010191.
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Whole genome sequencing is increasingly used to diagnose medical conditions of genetic origin. While both coding and non-coding DNA variants contribute to a wide range of diseases, most patients who receive a WGS-based diagnosis today harbour a protein-coding mutation. Functional interpretation and prioritization of non-coding variants represents a persistent challenge, and disease-causing non-coding variants remain largely unidentified. Depending on the disease, WGS fails to identify a candidate variant in 20–80% of patients, severely limiting the usefulness of sequencing for personalised medicine. Here we present FINSURF, a machine-learning approach to predict the functional impact of non-coding variants in regulatory regions. FINSURF outperforms state-of-the-art methods, owing in particular to optimized control variants selection during training. In addition to ranking candidate variants, FINSURF breaks down the score for each variant into contributions from individual annotations, facilitating the evaluation of their functional relevance. We applied FINSURF to a diverse set of 30 diseases with described causative non-coding mutations, and correctly identified the disease-causative non-coding variant within the ten top hits in 22 cases. FINSURF is implemented as an online server to as well as custom browser tracks, and provides a quick and efficient solution to prioritize candidate non-coding variants in realistic clinical settings.
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Nash, Benjamin M., To Ha Loi, Milan Fernando, Amin Sabri, James Robinson, Anson Cheng, Steven S. Eamegdool et al. "Evaluation for Retinal Therapy for RPE65 Variation Assessed in hiPSC Retinal Pigment Epithelial Cells". Stem Cells International 2021 (13 de diciembre de 2021): 1–12. http://dx.doi.org/10.1155/2021/4536382.
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Human induced pluripotent stem cells (hiPSCs) generated from patients and the derivative retinal cells enable the investigation of pathological and novel variants in relevant cell populations. Biallelic pathogenic variants in RPE65 cause early-onset severe retinal dystrophy (EOSRD) or Leber congenital amaurosis (LCA). Increasingly, regulatory-approved in vivo RPE65 retinal gene replacement therapy is available for patients with these clinical features, but only if they have biallelic pathological variants and sufficient viable retinal cells. In our cohort of patients, we identified siblings with early-onset severe retinal degeneration where genomic studies revealed compound heterozygous variants in RPE65, one a known pathogenic missense variant and the other a novel synonymous variant of uncertain significance. The synonymous variant was suspected to affect RNA splicing. Since RPE65 is very poorly expressed in all tissues except the retinal pigment epithelium (RPE), we generated hiPSC-derived RPE cells from the parental carrier of the synonymous variant. Sequencing of RNA obtained from hiPSC-RPE cells demonstrated heterozygous skipping of RPE65 exon 2 and the introduction of a premature stop codon in the mRNA. Minigene studies confirmed the splicing aberration. Results from this study led to reclassification of the synonymous variant to a pathogenic variant, providing the affected patients with access to RPE65 gene replacement therapy.
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Renaux, Alexandre, Sofia Papadimitriou, Nassim Versbraegen, Charlotte Nachtegael, Simon Boutry, Ann Nowé, Guillaume Smits y Tom Lenaerts. "ORVAL: a novel platform for the prediction and exploration of disease-causing oligogenic variant combinations". Nucleic Acids Research 47, W1 (31 de mayo de 2019): W93—W98. http://dx.doi.org/10.1093/nar/gkz437.
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Abstract A tremendous amount of DNA sequencing data is being produced around the world with the ambition to capture in more detail the mechanisms underlying human diseases. While numerous bioinformatics tools exist that allow the discovery of causal variants in Mendelian diseases, little to no support is provided to do the same for variant combinations, an essential task for the discovery of the causes of oligogenic diseases. ORVAL (the Oligogenic Resource for Variant AnaLysis), which is presented here, provides an answer to this problem by focusing on generating networks of candidate pathogenic variant combinations in gene pairs, as opposed to isolated variants in unique genes. This online platform integrates innovative machine learning methods for combinatorial variant pathogenicity prediction with visualization techniques, offering several interactive and exploratory tools, such as pathogenic gene and protein interaction networks, a ranking of pathogenic gene pairs, as well as visual mappings of the cellular location and pathway information. ORVAL is the first web-based exploration platform dedicated to identifying networks of candidate pathogenic variant combinations with the sole ambition to help in uncovering oligogenic causes for patients that cannot rely on the classical disease analysis tools. ORVAL is available at https://orval.ibsquare.be.
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Rahmani, Nasim, Saeed Talebi, Nakysa Hooman y Arezou Karamzade. "Familial Hypomagnesemia with Hypercalciuria, Nephrocalcinosis, and Bilateral Chorioretinal Atrophy in a Patient with Homozygous p.G75S Variant in CLDN19". Journal of Pediatric Genetics 10, n.º 03 (26 de julio de 2021): 230–35. http://dx.doi.org/10.1055/s-0041-1733852.
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Abstract Introduction Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare disorder caused by perturbation in renal reabsorption of magnesium and calcium. Biallelic pathogenic variants either in gene CLDN16 or CLDN19 are responsible for molecular defects. Most patients with CLDN19 variants have been associated with ocular involvements (FHHNCOI). Patient and Methods We had a pediatric patient with hypercalciuric hypomagnesemia and bilateral chorioretinal atrophy. Metabolic profiling and radiology examinations were performed, in addition to whole exome sequencing (WES) used for detection of the causative variant. Results Analysis of WES revealed a homozygous c.223G > A (p.G75S) variant in CLDN19. MutationTaster and Combined Annotation-Dependent Depletion support its deleterious effect and SHERLOC's criteria put it in pathogenic category. This variant is previously reported in compound heterozygous state with other known pathogenic variant. As far as we know, it is the first report of this variant in homozygous state. Conclusion The variant found in our patient is pathogenic and compatible with FHHNCOI characteristics. WES is an advantageous tool in molecular diagnosis and finding genetic pathology of this disease. In line with other reports, ocular abnormalities are variable in patients with CLDN19 mutations, and chronic kidney disease and retinal damages must be considered in this group.
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Yan, Lulu, Ru Shen, Zongfu Cao, Chunxiao Han, Yuxin Zhang, Yingwen Liu, Xiangchun Yang, Min Xie y Haibo Li. "A Novel Missense Variant in the Gene PPP2R5D Causes a Rare Neurodevelopmental Disorder with Increased Phenotype". BioMed Research International 2021 (11 de febrero de 2021): 1–7. http://dx.doi.org/10.1155/2021/6661860.
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PPP2R5D-related neurodevelopmental disorder, which is mainly caused by de novo missense variants in the PPP2R5D gene, is a rare autosomal dominant genetic disorder with about 100 patients and a total of thirteen pathogenic variants known to exist globally so far. Here, we present a 24-month-old Chinese boy with developmental delay and other common clinical characteristics of PPP2R5D-related neurodevelopmental disorder including hypotonia, macrocephaly, intellectual disability, speech impairment, and behavioral abnormality. Trio-whole exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variant. The pathogenicity of the variant was evaluated using bioinformatics tools. We identified a novel pathogenic variant in the PPP2R5D gene (c.620G>T, p.Trp207Leu). The variant is located in the variant hotspot region of this gene and is predicted to cause PPP2R5D protein dysfunction due to an increase in local hydrophobicity and unstable three-dimensional structure. We report a novel pathogenic variant of PPP2R5D associated with PPP2R5D-related neurodevelopmental disorder from a Chinese family. Our findings expanded the phenotypic and mutational spectrum of PPP2R5D-related neurodevelopmental disorder.
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Bender, Chelsea, Elizabeth Geena Woo, Bin Guan, Ehsan Ullah, Eric Feng, Amy Turriff, Santa J. Tumminia, Paul A. Sieving, Catherine A. Cukras y Robert B. Hufnagel. "Predominant Founder Effect among Recurrent Pathogenic Variants for an X-Linked Disorder". Genes 13, n.º 4 (12 de abril de 2022): 675. http://dx.doi.org/10.3390/genes13040675.
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For disorders with X-linked inheritance, variants may be transmitted through multiple generations of carrier females before an affected male is ascertained. Pathogenic RS1 variants exclusively cause X-linked retinoschisis (XLRS). While RS1 is constrained to variation, recurrent variants are frequently observed in unrelated probands. Here, we investigate recurrent pathogenic variants to determine the relative burden of mutational hotspot and founder allele events to this phenomenon. A cohort RS1 variant analysis and standardized classification, including variant enrichment in the XLRS cohort and in RS1 functional domains, were performed on 332 unrelated XLRS probands. A total of 108 unique RS1 variants were identified. A subset of 19 recurrently observed RS1 variants were evaluated in 190 probands by a haplotype analysis, using microsatellite and single nucleotide polymorphisms. Fourteen variants had at least two probands with common variant-specific haplotypes over ~1.95 centimorgans (cM) flanking RS1. Overall, 99/190 of reportedly unrelated probands had 25 distinct shared haplotypes. Examination of this XLRS cohort for common RS1 haplotypes indicates that the founder effect plays a significant role in this disorder, including variants in mutational hotspots. This improves the accuracy of clinical variant classification and may be generalizable to other X-linked disorders.
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Lerner-Ellis, Jordan, Victoria Sopik, Andrew Wong, Conxi Lázaro, Steven A. Narod y George S. Charames. "Retesting of women who are negative for a BRCA1 and BRCA2 mutation using a 20-gene panel". Journal of Medical Genetics 57, n.º 6 (29 de noviembre de 2019): 380–84. http://dx.doi.org/10.1136/jmedgenet-2019-106403.
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BackgroundThe value of retesting women who previously tested negative for a pathogenic variant (mutation) in BRCA1 and BRCA2 using an expanded panel of breast and ovarian cancer genes is unclear.MethodsWe studied 110 BRCA1/2-negative women who were retested using a panel of 20 breast and/or ovarian cancer susceptibility genes at the Advanced Molecular Diagnostics Laboratory (AMDL) at Mount Sinai Hospital in Toronto between March 2017 and March 2019. All patients had previously tested negative for BRCA pathogenic variants at the AMDL between January 2012 and March 2018 and were subsequently referred for retesting by their physician.ResultsOverall, six pathogenic variants in genes other than BRCA1 and BRCA2 were found (prevalence 5.5%). There were two pathogenic variants found in RAD51C, and one found in each of BRIP1, PALB2, PMS2 and PTEN. The prevalence of pathogenic variants was 6.5% for women affected with cancer (6 of 93), including 4.9% for women with breast cancer (4 of 82) and 22.2% for women with ovarian cancer (2 of 9). None of the 17 unaffected women had a clinically significant or pathogenic variant. There were 44 women (40%) for whom the result of the panel test was inconclusive due to the detection of a variant of uncertain significance.ConclusionsOur findings indicate that the retesting of BRCA1/2-negative individuals with an expanded panel of 20 breast and ovarian cancer genes can produce clinically relevant results, with a yield of 5.5% for pathogenic variants in genes other than BRCA1 and BRCA2.
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Yang, Xiaofei, Qingyu Kong, Cuifen Zhao, Zhifeng Cai y Minmin Wang. "New pathogenic variant of BMPR2 in pulmonary arterial hypertension". Cardiology in the Young 29, n.º 4 (abril de 2019): 462–66. http://dx.doi.org/10.1017/s1047951119000015.
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AbstractObjectives:The aim of this study was to evaluate the variant frequency of pulmonary arterial hypertension-related genes and provide theoretical basis for genetic screening of patients with pulmonary arterial hypertension further.Methods:Ten genes associated with pulmonary arterial hypertension were sequenced in 7 cases of idiopathic pulmonary arterial hypertension and 34 cases of congenital heart disease (CHD) associated with pulmonary arterial hypertension by next-generation high-throughput sequencing. Function prediction and gene variant amino acid conservation were carried out by bioinformatics software. Family study was performed on the patients with the variant.Results:A new bone morphogenetic protein receptor type 2(BMPR2) variant (c.344T>C, p. F115S) was discovered in a girl who was diagnosed with idiopathic pulmonary arterial hypertension. Her second aunt and third aunt carried the same variant and were confirmed as patients with pulmonary arterial hypertension as well. No variants or single nucleotide polymorphisms were found in other pulmonary arterial hypertension-associated genes.Conclusions:BMPR2 variant is the most common variant of pulmonary arterial hypertension. Genetic screening of BMPR2 variant and family survey in patients with pulmonary arterial hypertension is suggested for the sake of definite cause and better treatment.
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DiBacco, Melissa L., Ana Pop, Gajja S. Salomons, Ellen Hanson, Jean-Baptiste Roullet, K. Michael Gibson y Phillip L. Pearl. "Novel ALDH5A1 variants and genotype". Neurology 95, n.º 19 (4 de septiembre de 2020): e2675-e2682. http://dx.doi.org/10.1212/wnl.0000000000010730.
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ObjectiveTo determine genotype–phenotype correlation in succinic semialdehyde dehydrogenase (SSADH) deficiency.MethodsALDH5A1 variants were studied with phenotype correlation in the SSADH natural history study. Assignment of gene variant pathogenicity was based on in silico testing and in vitro enzyme activity after site-directed mutagenesis and expression in HEK293 cells. Phenotypic scoring used a Clinical Severity Score (CSS) designed for the natural history study.ResultsTwenty-four patients were enrolled (10 male, 14 female, median age 8.2 years). There were 24 ALDH5A1 variants, including 7 novel pathogenic variants: 2 missense, 3 splice site, and 2 frameshift. Four previously reported variants were identified in >5% of unrelated families. There was a correlation with age and presence (p = 0.003) and severity (p = 0.002) of epilepsy and with obsessive-compulsive disorder (OCD) (p = 0.016). The median IQ score was 53 (Q25–Q75, 49–61). There was no overall correlation between the gene variants and the CSS, although a novel missense variant was associated with the mildest phenotype by CSS in the only patient with a normal IQ, whereas a previously reported variant was consistently associated with the most severe phenotype.ConclusionsSeven novel pathogenic and one previously unpublished benign ALDH5A1 variants were detected. There is an age-dependent association with worsening of epilepsy and presence of OCD in SSADH deficiency. Overall, there does not appear to be a correlation between genotype and phenotypic severity in this cohort of 24 patients. We did find a suspected correlation between a novel pathogenic missense variant and high functionality, and a previously reported pathogenic missense variant and maximal severity.
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Mirabello, Lisa, Payal P. Khincha, Steven R. Ellis, Neelam Giri, Seth Brodie, Settara C. Chandrasekharappa, Frank X. Donovan et al. "Novel and known ribosomal causes of Diamond-Blackfan anaemia identified through comprehensive genomic characterisation". Journal of Medical Genetics 54, n.º 6 (9 de marzo de 2017): 417–25. http://dx.doi.org/10.1136/jmedgenet-2016-104346.
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BackgroundDiamond-Blackfan anaemia (DBA) is an inherited bone marrow failure syndrome (IBMFS) characterised by erythroid hypoplasia. It is associated with congenital anomalies and a high risk of developing specific cancers. DBA is caused predominantly by autosomal dominant pathogenic variants in at least 15 genes affecting ribosomal biogenesis and function. Two X-linked recessive genes have been identified.ObjectivesWe aim to identify the genetic aetiology of DBA.MethodsOf 87 families with DBA enrolled in an institutional review board-approved cohort study (ClinicalTrials.gov Identifier:NCT00027274), 61 had genetic testing information available. Thirty-five families did not have a known genetic cause and thus underwent comprehensive genomic evaluation with whole exome sequencing, deletion and CNV analyses to identify their disease-associated pathogenic variant. Controls for functional studies were healthy mutation-negative individuals enrolled in the same study.ResultsOur analyses uncovered heterozygous pathogenic variants in two previously undescribed genes in two families. One family had a non-synonymous variant (p.K77N) inRPL35; the second family had a non-synonymous variant (p. L51S) inRPL18. Both of these variants result in pre-rRNA processing defects. We identified heterozygous pathogenic variants in previously known DBA genes in 16 of 35 families. Seventeen families who underwent genetic analyses are yet to have a genetic cause of disease identified.ConclusionsOverall, heterozygous pathogenic variants in ribosomal genes were identified in 44 of the 61 families (72%). De novo pathogenic variants were observed in 57% of patients with DBA. Ongoing studies of DBA genomics will be important to understand this complex disorder.
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Kumar, Anil, Vandana Jain, Madhumita Roy Chowdhury, Manoj Kumar, Punit Kaur y Madhulika Kabra. "Pathogenic/likely pathogenic variants in the SHOX, GHR and IGFALS genes among Indian children with idiopathic short stature". Journal of Pediatric Endocrinology and Metabolism 33, n.º 1 (28 de enero de 2020): 79–88. http://dx.doi.org/10.1515/jpem-2019-0234.
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AbstractBackgroundOur objective was to estimate the prevalence of pathogenic/likely pathogenic variants in the SHOX, GHR, and IGFALS genes among Indian children with idiopathic short stature (ISS), and assess the genotype-phenotype correlation.MethodsWe recruited 61 children with short stature, who were born appropriate for gestational age, had no obvious dysmorphism or disproportion, and in whom step-wise investigative work-up (including provocative growth hormone test) was normal. Multiplex ligation-dependent probe amplification was undertaken for identifying deletions/duplications in the SHOX gene. Bidirectional sequencing was performed for identifying variants in the SHOX and GHR genes in all, and for the IGFALS gene in those with serum insulin-like growth factor-1 (IGF-1) <−1 standard deviation. The genotype-phenotype correlation was studied.ResultsFour children (6.5%) had pathogenic heterozygous variants in the SHOX gene, with one child each having duplication of exon 5, splice site point variant c.278-1G > C in exon 3, partial deletion and complete deletion. None of the patients had pathogenic variants in the GHR gene. Of the 39 patients in whom the IGFALS gene was sequenced, novel heterozygous likely pathogenic variants were found in two children. One had the frameshift variant c.764_765insT, p.A265Gfs*114. The second had the missense variant c.1793G > A, p.R598H predicted by MutationTaster as ‘disease causing’, and indicated by the protein-modelling study as having compromised binding with IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) due to altered conformation of the interacting loop.ConclusionsPathogenic variants in the SHOX and IGFALS genes account for a significant proportion of Indian children with ISS. Further molecular studies using next generation sequencing are needed to gain insight into pathophysiological mechanisms and effective treatment strategies for ISS.
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Li, Jinying, Hongen Xu, Jianfeng Sun, Yongan Tian, Danhua Liu, Yaping Qin, Huanfei Liu et al. "Missense Variant of Endoplasmic Reticulum Region of WFS1 Gene Causes Autosomal Dominant Hearing Loss without Syndromic Phenotype". BioMed Research International 2021 (4 de marzo de 2021): 1–9. http://dx.doi.org/10.1155/2021/6624744.
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Objective. Genetic variants in the WFS1 gene can cause Wolfram syndrome (WS) or autosomal dominant nonsyndromic low-frequency hearing loss (HL). This study is aimed at investigating the molecular basis of HL in an affected Chinese family and the genotype-phenotype correlation of WFS1 variants. Methods. The clinical phenotype of the five-generation Chinese family was characterized using audiological examinations and pedigree analysis. Target exome sequencing of 129 known deafness genes and bioinformatics analysis were performed among six patients and four normal subjects to screen suspected pathogenic variants. We built a complete WFS1 protein model to assess the potential effects of the variant on protein structure. Results. A novel heterozygous pathogenic variant NM_006005.3 c.2020G>T (p.Gly674Trp) was identified in the WFS1 gene, located in the C-terminal domain of the wolframin protein. We further showed that HL-related WFS1 missense variants were mainly concentrated in the endoplasmic reticulum (ER) domain. In contrast, WS-related missense variants are randomly distributed throughout the protein. Conclusions. In this family, we identified a novel variant p.Gly674Trp of WFS1 as the primary pathogenic variant causing the low-frequency sensorineural HL, enriching the mutational spectrum of the WFS1 gene.
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McDonnell, Kevin, Christine Hong, Joseph D. Bonner, Sidney Smith Lindsey, Ilana Solomon, Heather Hampel, Wai Park, Gregory Idos, Stacy W. Gray y Stephen B. Gruber. "Germline mutational landscape of non-highly penetrant Fanconi anemia genes unveiled from sequencing of 5,044 patients with solid tumor cancer." Journal of Clinical Oncology 40, n.º 16_suppl (1 de junio de 2022): 10521. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.10521.
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10521 Background: Nearly two dozen Fanconi anemia (FA) genes work in concert to mediate critical DNA repair steps. Previous investigations have well described germline pathogenic variation and associated solid tumor cancer predisposition in the highly penetrant (HP)-FA genes, BRCA1 (FANCS), BRCA2 (FANCD1) and PALB2 (FANCN). To date, understanding of pathogenic variation and cancer association among non-HP-FA genes remains incomplete. In this study we investigated the germline mutational landscape of non-HP-FA genes in patients with a personal/family history of a solid tumor. Methods: Unselected, consented patients with a personal/personal history of solid tumor cancer underwent germline testing through a sponsored program of universal access. Testing used a custom panel to detect pathogenic single nucleotide variants, short insertions/deletions and exon-level deletions/duplications of 155 cancer-predisposition genes including 15 non-HP-FA genes [ FANCA, FANCB, FANCC, FAND2, FANCE, FANCF, FANCG, FANCI, FANCJ (BRIP1), FANCL, FANCM, FANCO (RAD51C), FANCP (SLX4), FANCQ (ERCC4) and FANCU (XRCC2)]. Here we summarize germline pathogenic variant frequency in non-HP-FA genes and describe the mutational landscape across solid tumors. Additionally, we report the clinical actionability (on- and off-label FDA approved drug availability and/or clinical trial eligibility) of identified variants. Results: 5044 patients consented and completed germline genetic testing. 1014/5044 (20.1%) of patients carried a pathogenic variant in a cancer predisposition gene. 116/1014 (11.4%) of germline positive patients carried a pathogenic variant in a non-HP-FA gene. Non-HP-FA genes with highest frequencies included: FANCA (28 patients), FANCM (19 patients), BRIP1 (FANCJ) (19 patents) and FANCC (14 patients). Testing identified germline non-HP-FA pathogenic variants in eighteen different tumor types. The tumor types associated with the highest percentages of associated germline non-HP-FA pathogenic variants included: squamous cell cancers (8.2%), bladder/urothelial cancer (5.0%), breast cancer (3.5%) and ovarian/fallopian tube cancers (3.5%). Moreover, 19 patients carrying a non-HP-FA germline pathogenic variant qualified for an on- or off-label FDA-approved drug; 101 patients achieved clinical trial eligibility by virtue of their non-HP-FA variant. Conclusions: Our study offers a landscape view of germline pathogenic variants in non-HP-FA genes in patients with a history of a solid tumor. Furthermore, this investigation provides a basis for further examination of associations between these germline pathogenic variants and solid tumor cancer predisposition. Finally, importantly, our work underscores the value of expanded germline non-HP-FA gene testing to optimize therapeutic and clinical trial opportunities for cancer patients.
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Stojovska, Marija, Nadica Matevska-Geshkovska, Elizabeta Krstevska Bozhinovikj, Biljana Grozdanovska, Nenad Mitrevski y Aleksandar Dimovski. "Variants of unknown significance (VUS) in patients with hereditary CRC without a known pathogenic variant." Journal of Clinical Oncology 40, n.º 16_suppl (1 de junio de 2022): 10599. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.10599.
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10599 Background: Nearly 5-10% of all newly diagnosed colorectal cancer (CRC) cases develop due to the presence of a highly penetrant pathogenic variant in one of the hereditary colorectal cancer (hCRC) associated genes. NGS technology raised the opportunity for fast and efficient detection of these variants, but still in ̃20-30% of patients with hCRC the genetic defect remains unknown. Recent data shows that 6-8% of these cases harbor pathogenic/VUS variant in low/moderate penetrance genes not directly associated with hCRC. Methods: A total of 109 patients with hCRC (43 with polyposis and 66 with non-polyposis syndromes) were analyzed by NGS covering coding and exon/intron sequences of 109 genes, of which 25 associated with known hCRC syndromes and 83 other cancer predisposition genes. Results: Pathogenic variants were detected in 63/109 (57.7%) of analyzed patients; 54/63 (85.7%) of these had a pathogenic variant in one of the genes associated with hCRC (APC, MMR genes, MUTYH, NTHL1, BMPR1A) and 9/63 (14.3%) had a pathogenic variant detected in genes not directly related to hCRC (CHEK2, FANCL, FANCM, ERCC2, BRIP1, FLCN, BLM). In 26/109 (23.8%) patients a rare VUS variant was detected, of which 14/26 (53.8%) in double strand repair (DRG) genes (BLM, CHEK2, PALB2, ATM, MRE11A, BRIP1, FANCM, FANCL and ERCC2), 8/26 (30.8%) in one of the known hCRC genes (APC, MSH6, PMS2 and POLE) and 4/26 (15.4%) in other cancer predisposition genes (KIT, NSD1, CDH1, EZH1 and FH). VUS variants in DRG genes were more common in patients with MSI- HNPCC (9/15, 60%), compared to patients with polyposis syndromes (6/15, 40%). The VUS variants in other cancer predisposition genes were dominantly present in patients with oligopolyposis. Most (21/26, 80.8%) VUS variants were detected as single variants, while only five patients (5/26, 19.2%) had two different variants in two different genes. In 20/109 (18.3%) patients who presented primarily with MSI- HNPCC or oligopolyposis phenotypes, no pathogenic and/or VUS variants were detected in the 109 analyzed genes. Conclusions: Genetic basis of hereditary CRC was not clearly defined in a large proportion (42.3%) of patients in our cohort. Although a VUS variant was detected in a significant portion (23.8%), a major fraction (18.3%) of patients had no known genetic variant detected. The presence of a high frequency of VUS variants in DRG genes indicates that this pathway plays an important role in CRC carcinogenesis. Although we cannot exclude the presence of deep intronic and/or regulatory region pathogenic variants in the analyzed genes, it appears that the current list of identified cancer predisposition genes responsible for the hereditary CRC is far from being complete. The influence of environmental factors in conjunction with polygenic inheritance might also play a key role in a fraction of hCRC in our population.
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Stojovska, Marija, Nadica Matevska-Geshkovska, Elizabeta Krstevska Bozhinovikj, Biljana Grozdanovska, Nenad Mitrevski y Aleksandar Dimovski. "Variants of unknown significance (VUS) in patients with hereditary CRC without a known pathogenic variant." Journal of Clinical Oncology 40, n.º 16_suppl (1 de junio de 2022): 10599. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.10599.
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10599 Background: Nearly 5-10% of all newly diagnosed colorectal cancer (CRC) cases develop due to the presence of a highly penetrant pathogenic variant in one of the hereditary colorectal cancer (hCRC) associated genes. NGS technology raised the opportunity for fast and efficient detection of these variants, but still in ̃20-30% of patients with hCRC the genetic defect remains unknown. Recent data shows that 6-8% of these cases harbor pathogenic/VUS variant in low/moderate penetrance genes not directly associated with hCRC. Methods: A total of 109 patients with hCRC (43 with polyposis and 66 with non-polyposis syndromes) were analyzed by NGS covering coding and exon/intron sequences of 109 genes, of which 25 associated with known hCRC syndromes and 83 other cancer predisposition genes. Results: Pathogenic variants were detected in 63/109 (57.7%) of analyzed patients; 54/63 (85.7%) of these had a pathogenic variant in one of the genes associated with hCRC (APC, MMR genes, MUTYH, NTHL1, BMPR1A) and 9/63 (14.3%) had a pathogenic variant detected in genes not directly related to hCRC (CHEK2, FANCL, FANCM, ERCC2, BRIP1, FLCN, BLM). In 26/109 (23.8%) patients a rare VUS variant was detected, of which 14/26 (53.8%) in double strand repair (DRG) genes (BLM, CHEK2, PALB2, ATM, MRE11A, BRIP1, FANCM, FANCL and ERCC2), 8/26 (30.8%) in one of the known hCRC genes (APC, MSH6, PMS2 and POLE) and 4/26 (15.4%) in other cancer predisposition genes (KIT, NSD1, CDH1, EZH1 and FH). VUS variants in DRG genes were more common in patients with MSI- HNPCC (9/15, 60%), compared to patients with polyposis syndromes (6/15, 40%). The VUS variants in other cancer predisposition genes were dominantly present in patients with oligopolyposis. Most (21/26, 80.8%) VUS variants were detected as single variants, while only five patients (5/26, 19.2%) had two different variants in two different genes. In 20/109 (18.3%) patients who presented primarily with MSI- HNPCC or oligopolyposis phenotypes, no pathogenic and/or VUS variants were detected in the 109 analyzed genes. Conclusions: Genetic basis of hereditary CRC was not clearly defined in a large proportion (42.3%) of patients in our cohort. Although a VUS variant was detected in a significant portion (23.8%), a major fraction (18.3%) of patients had no known genetic variant detected. The presence of a high frequency of VUS variants in DRG genes indicates that this pathway plays an important role in CRC carcinogenesis. Although we cannot exclude the presence of deep intronic and/or regulatory region pathogenic variants in the analyzed genes, it appears that the current list of identified cancer predisposition genes responsible for the hereditary CRC is far from being complete. The influence of environmental factors in conjunction with polygenic inheritance might also play a key role in a fraction of hCRC in our population.
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Wolf, Katherine I., Michelle F. Jacobs, Rohit Mehra, Priya Begani, Matthew S. Davenport, Lawrence J. Marentette, Gregory J. Basura, David T. Hughes y Tobias Else. "A Family With a Carotid Body Paraganglioma and Thyroid Neoplasias With a New SDHAF2 Germline Variant". Journal of the Endocrine Society 3, n.º 11 (5 de septiembre de 2019): 2151–57. http://dx.doi.org/10.1210/js.2018-00353.
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Abstract At least 30% of all pheochromocytomas (PCCs)/paragangliomas (PGLs) arise in patients with a germline predisposition syndrome. Variants in succinate dehydrogenase subunits A, B, C, and D (SDHA, SDHB, SDHC, and SDHD) are the most common pathogenic germline alterations. Few pathogenic variants have been reported in succinate dehydrogenase assembly factor 2 (SDHAF2). Here, we describe a 30-year-old female patient who presented with a left-sided neck mass, which was later characterized as a carotid body PGL. Genetic testing revealed a likely pathogenic SDHAF2 variant (c.347G>A;p.W116X). Two sisters carried the same pathologic variant, and screening protocols were recommended. Whole-body MRI revealed thyroid nodules; this testing was followed by fine-needle aspiration, which confirmed papillary thyroid carcinoma in one sister and a follicular adenoma in the other. The two sisters then underwent hemithyroidectomy and total thyroidectomy, respectively. Because evidence for pathogenic variants in SDHAF2 causing predisposition to PCC/PGL is limited, we discuss the challenges in mutational variant interpretation and decision making regarding screening for associated tumors.
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Kriulina, T., E. Alexeeva, T. Dvoryakovskaya, I. Kriulin, K. Isaeva, R. Denisova, O. Lomakina et al. "AB0727 STUDY OF MEFV GENE MUTATIONS IN A COHORT OF CHILDREN: A SINGLE CENTER". Annals of the Rheumatic Diseases 80, Suppl 1 (19 de mayo de 2021): 1394.2–1395. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2259.
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Background:Familial Mediterranean fever (FMF) is a monogenic autoinflammatory hereditary disease characterized by recurrent episodes of fever with sterile peritonitis, pleural inflammation, arthritis, and/or erysipelas-like rash. Among all variants of the MEFV gene, according to the literature, five pathogenic ones have been identified, which in 75% of cases lead to the development of a typical clinical presentation: V726A, M694V, M694I, M680I, and E148Q. Among them, the M694V variant is the most common and occurs in patients with FMF in 20-65% of cases. At the same time, approximately 10 to 20% of patients meeting the diagnostic criteria for FMF do not have pathogenic variants in the MEFV gene. Despite the fact that the molecular genetic, pathogenetic and clinical features of the disease have been studied detailed, the diagnosis remains difficult due to the lack of a clear correlation between the patient’s clinical and genetic data.Objectives:To analyze the obtained genetic data of patients with pathogenic variants in the MEFV gene.Methods:The study included 103 patients who are mainly observed at the rheumatology department of the National Medical Research Center of Children’s Health of Ministry of Health of the Russian Federation in Moscow. All patients underwent analysis of the MEFV gene using Sanger sequencing with further statistical processing of the data obtained.Results:Of 103 patients, the pathogenic variant of the MEFV gene was found in 93 patients (90.3%), in 10 patients (9.7%) - the pathogenicity of the revealed variant was contradictory. Of 93 patients with the pathogenic variant of MEFV, the clinical presentation of the disease fits to FMF in 37 patients (39.6%). 11 (29.7%) of them had a mutation in M694V. Out of 37 children who met the criteria for FMF diagnosis, 15 (40.5%) children had a homozygous pathogenic variant of MEVF, and 22 (59.5%) children had two mutations in a heterozygous state. 57 patients who do not have a typical clinical presentation, which is specifical for FMF are observed at the departments of rheumatology, cardiology and nephrology, 13 patients are on an outpatient observation, and 6 patients at the time of the study are over 18 years old. 8 (14%) of them had a mutation in M694V. Among 57 patients with pathogenic heterozygous variants in a, 22 patients (38.6%) are observed in the rheumatology department, among them:• Enthesitis-related arthritis - 2 patients (9%);• Systemic juvenile arthritis - 13 patients (59%);• Oligoarthritis - 5 patients (23%);• Polyarthritis- 2 patients (9%).Conclusion:Analysis of the obtained data showed that FMF is characterized by a combination of the clinical presentation and the pathogenic variant in the MEFV gene. However, the disease manifests itself not only in the homozygous pathogenic variant, but also in the combination of two mutations in heterozygous. The presence of one heterozygous mutation, generally, does not lead to the development of FMF.References:[1]Konstantopoulos, A. Kanta, C. Deltas, V. Atamian, D. Mavrogianni, A.G. Tzioufas, I. Kollainis, K. Ritis, H.M. Moutsopoulos, Familial Mediterranean fever associated pyrin mutations in Greece Ann. Rheum. Dis., 62 (2003), pp. 479-481, 10.1136/ard.62.5.479.[2]Gershoni-Baruch R, Brik R, Zacks N, Shinawi M, Lidar M, Livneh A: The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with Mediterranean Fever,Seminars in Arthritis and Rheumatism,Volume 43, Issue 3, 2013, Pages 387-391familial Mediterranean fever. Arthritis Rheum 2003; 48: 1149–1155.[3]Booty MG, Chae JJ, Masters SL, et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum 2009; 60:185.Disclosure of Interests:None declared
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Bulfamante, Gaetano Pietro, Laura Carpenito, Emma Bragantini, Silvia Graziani, Maria Bellizzi, Christoph Peter Bagowski, Moneef Shoukier, Francesca Rivieri, Massimo Soffiati y Mattia Barbareschi. "Generalized Arterial Calcification of Infancy Type 1 (GACI1): Identification of a Novel Pathogenic Variant (c.1715T>C (p.Leu572Ser))". Diagnostics 11, n.º 6 (4 de junio de 2021): 1034. http://dx.doi.org/10.3390/diagnostics11061034.
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Generalized Arterial Calcification of Infancy (GACI) is a rare disease inherited in a recessive manner, with severe and diffuse early onset of calcifications along the internal elastic lamina in large and medium size arteries. The diagnosis results are from clinical manifestations, imaging, histopathologic exams, and genetic tests. GACI is predominantly caused by biallelic pathogenic variant in the ENPP1 gene (GACI1, OMIM#208000) and, to a lesser extent, by pathogenic variants in the ABCC6 gene (GACI2, OMIM#614473). We present a novel variation in the ENPP1 gene identified in a patient clinically diagnosed with GACI and confirmed by genetic investigation and autopsy as GACI type 1. The sequence analysis of the patient’s ENPP1 gene detected two heterozygous variants c.1412A>G (p.Tyr471Cys) and c.1715T>C (p.Leu572Ser). The variant c.1715T>C (p.Leu572Ser) has not been described yet in the literature and in mutation databases. A genetic analysis was also carried out for the parents of the newborn; the heterozygous pathogenic variant c.1412A>G (p.Tyr471Cys) was detected in the mother’s ENPP1 gene, and a sequence analysis of the father’s ENPP1 gene revealed the novel heterozygous variant c.1715T>C (p.Leu572Ser). Our results showed that the variant c.1715T>C (p.Leu572Ser) may have a pathogenic role in the development of GACI type1 (GACI1, OMIM#208000), at least when associated with the pathogenic c.1412A>G (p.Tyr471Cys) variant. The identification of novel mutations potentially enabled genotype/phenotype associations that will ultimately have an impact on clinical management and prognosis for the disease.
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Atake, Yusa, Masayuki Nagahashi, Haruka Kanaoka, Akira Hattori, Ayako Bun, Reiko Fukui, Hiromi Ozawa et al. "Abstract P5-12-02: Germline variants detected by next-generation sequencing-based multigene panel testing in patients with suspected hereditary breast cancer at a University Hospital in Japan". Cancer Research 83, n.º 5_Supplement (1 de marzo de 2023): P5–12–02—P5–12–02. http://dx.doi.org/10.1158/1538-7445.sabcs22-p5-12-02.
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Abstract Background: The usefulness of prophylactic surgery and surveillance for hereditary breast cancer has been demonstrated, and germline testing for BRCA1 and BRCA2 had been covered by insurance since 2020 in Japan. In addition to BRCA1 and BRCA2, several other genes are also associated with an increased risk of developing breast cancer, such as PALB2, ATM, BARD1, CHEK2, PTEN, and TP53. Next-generation sequencing-enabled multigene panel tensing provides information about these gene variants at the same time, and at a low cost. Although germline testing of BRCA1 and BRCA2 has become widespread in Japan, multi-panel gene testing for germline variants has been conducted only in a limited number of facilities, partly due to the difficulty associated with dealing with the gene variant information obtained from the test. The aim of this study was to clarify the current status of multigene panel testing in our institute, and reveal the characteristics of the variants detected in patients with, or predisposed to, hereditary breast cancer. Methods: This retrospective study included 37 individuals who underwent next-generation sequencing-based multigene panel testing in order to investigate any inherited genetic variants due to a suspicion of hereditary breast cancer. Eighteen patients had a diagnosis of breast cancer with a family history of breast and/or ovarian cancer, nine patients had a diagnosis of breast cancer without family history of breast or ovarian cancer, and 10 patients had a family history of breast cancer but had not developed breast cancer themselves. Results: Utilizing mutigene panel testing, at least one alteration was found in 24 genes, and a total of 39 variants were found in the 37 patients. Of these 37 patients, nine (24.3%) had a pathogenic/likely pathogenic variant with or without other variants of uncertain significance (VUS), 15 (40.5%) had VUS, and 13 (35.1%) had negative genetic test results. Among the nine patients with pathogenic/likely pathogenic variants, seven had variants in either BRCA1 or BRCA2 (one BRCA1 pathogenic variant, five BRCA2 pathogenic variants, and one BRCA2 likely pathogenic variant), while the remaining positive results were attributed to other genes (one MLH1 pathogenic variant, and one SDHB pathogenic variant). VUS included BRCA1 and BRCA2, as well as other breast cancer-associated genes, such as ATM (n=2), CDH1 (n=2), NF1 (n=2), PALB2 (n=1), CHEK2 (n=1), NBN (n=1), and RAD51D (n=1). VUS also included other cancer syndrome-related genes, such as MLH1 (n=2), MUTYH (n=2), APC (n=1), and RET (n=1). Conclusion: Multigene panel tests in our institute revealed pathogenic/likely pathogenic variants in 24.3% of individuals who suspected hereditary breast cancer. As expected, multigene panel tests also revealed more VUS than pathogenic variants and 40.5% individuals were detected with VUS, which included many genes associated with hereditary breast cancer and other cancer syndromes, in addition to BRCA1 and BRCA2. Individuals with VUS will need to cope with new information if the interpretation of the variant changes in the future. We need to be aware of the characteristics and limitations of this type of panel testing, and to properly utilize the test results and information obtained for good quality patient care. Citation Format: Yusa Atake, Masayuki Nagahashi, Haruka Kanaoka, Akira Hattori, Ayako Bun, Reiko Fukui, Hiromi Ozawa, Yukie Fujimoto, Tomoko Higuchi, Michiko Imamura, Keiko Murase, Yuichi Takatsuka, Mina Kashima, Chiho Okada, Chinatsu Kinjo, Mikako Miyata, Ayako Miyazaki, Mako Ueda, Hiroshi Tsubamoto, Hideaki Sawai, Yasuo Miyoshi. Germline variants detected by next-generation sequencing-based multigene panel testing in patients with suspected hereditary breast cancer at a University Hospital in Japan [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-12-02.