Whole-exome sequencing of a large Chinese azoospermia and severe oligospermia cohort identifies novel infertility causative variants and genes

2020 ◽  
Vol 29 (14) ◽  
pp. 2451-2459
Author(s):  
Shitao Chen ◽  
Guishuan Wang ◽  
Xiaoguo Zheng ◽  
Shunna Ge ◽  
Yubing Dai ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Molecular Characteristics ◽  
Obstructive Azoospermia ◽  
Sequencing Data ◽  
Chinese Han ◽  
Functional Studies ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Rare coding variants have been proven to be one of the significant factors contributing to spermatogenic failure in patients with non-obstructive azoospermia (NOA) and severe oligospermia (SO). To delineate the molecular characteristics of idiopathic NOA and SO, we performed whole-exome sequencing of 314 unrelated patients of Chinese Han origin and verified our findings by comparing to 400 fertile controls. We detected six pathogenic/likely pathogenic variants and four variants of unknown significance, in genes known to cause NOA/SO, and 9 of which had not been earlier reported. Additionally, we identified 20 novel NOA candidate genes affecting 25 patients. Among them, five (BRDT, CHD5, MCM9, MLH3 and ZFX) were considered as strong candidates based on the evidence obtained from murine functional studies and human single-cell (sc)RNA-sequencing data. These genetic findings provide insight into the aetiology of human NOA/SO and pave the way for further functional analysis and molecular diagnosis of male infertility.

Whole‐Exome Sequencing of a Saudi Epilepsy Cohort Reveals Association Signals in Known and Potentially Novel Loci

2021 ◽  
Author(s):  
Amein Kadhem AlAli ◽  
Abdulrahman Al-Enazi ◽  
Ahmed Ammar ◽  
Mahmoud Hajj ◽  
Cyril Cyrus ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
High Rate ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variants ◽  
Unknown Significance ◽  
Rare Genetic Variants

Abstract Background Epilepsy, a serious chronic neurological condition effecting up to 100 million people globally, has clear genetic underpinnings including common and rare variants. In Saudi Arabia the prevalence of epilepsy is high and caused mainly by perinatal and genetic factors. No whole-exome sequencing (WES) studies have been performed to date in Saudi Arabian Epilepsy cohorts. This offers a unique opportunity for the discovery of rare genetic variants impacting this disease as there is a high rate of consanguinity amongst large tribal pedigrees. Results We performed WES on 144 individuals diagnosed with epilepsy, to interrogate known Epilepsy related genes for known and functional novel variants. We also used an American College of Medical Genetics (ACMG) guideline based variant prioritization approach in an attempt to discover putative causative variants. We identified a 32 potentially causative pathogenic variants across 30 different genes in 44/144 (30%) of these Saudi Epilepsy individuals. We also identified 232 variants of unknown significance (VUS) across 101 different genes in 133/144 (92%) subjects. Strong enrichment of variants of likely pathogenicity were observed in previously described epilepsy-associated loci, and a number of putative pathogenic variants in novel loci are also observed. Conclusion Several putative pathogenic variants known to be epilepsy-related loci were identified for the first time in our population, in addition to several potential new loci have been identified which may be prioritized for further investigation.

scholarly journals Biallelic DAB1 Variants Are Associated With Mild Lissencephaly and Cerebellar Hypoplasia

2021 ◽  
Vol 7 (2) ◽  
pp. e558
Author(s):  
Daphne J. Smits ◽  
Rachel Schot ◽  
Martina Wilke ◽  
Marjon van Slegtenhorst ◽  
Marie Claire Y. de Wit ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Splice Variants ◽  
Brain Mri ◽  
Cerebellar Vermis ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Whole Exome

ObjectiveWe aimed to identify pathogenic variants in a girl with epilepsy, developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities with the use of whole-exome sequencing.MethodsWhole-exome trio analysis and molecular functional studies were performed in addition to the clinical findings and neuroimaging studies.ResultsBrain MRI showed mild pachygyria, hypoplasia of the cerebellar vermis, and abnormal foliation of the cerebellar vermis, suspected for a variant in one of the genes of the Reelin pathway. Trio whole-exome sequencing and additional functional studies were performed to identify the pathogenic variants. Trio whole-exome sequencing revealed compound heterozygous splice variants in DAB1, both affecting the highly conserved functional phosphotyrosine-binding domain. Expression studies in patient-derived cells showed loss of normal transcripts, confirming pathogenicity.ConclusionsWe conclude that these variants are very likely causally related to the cerebral phenotype and propose to consider loss-of-function DAB1 variants in patients with RELN-like cortical malformations.

scholarly journals Whole-Exome Sequencing Identified a Novel Compound Heterozygous Genotype in ASL in a Chinese Han Patient with Argininosuccinate Lyase Deficiency

2019 ◽  
Vol 2019 ◽  
pp. 1-7
Author(s):  
Mei Zhao ◽  
Lingling Hou ◽  
Huajing Teng ◽  
Jinchen Li ◽  
Jiesi Wang ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Compound Heterozygous ◽  
Significant Activity ◽  
Argininosuccinate Lyase ◽  
Chinese Han ◽  
Lyase Deficiency ◽  
Pathogenic Variants ◽  
Whole Exome

Pathogenic variants in the argininosuccinate lyase (ASL) gene have been shown to cause argininosuccinate lyase deficiency (ASLD); therefore, sequencing analysis offers advantages for prenatal testing and counseling in families afflicted with this condition. Here, we performed a genetic analysis of an ASLD patient and his family with an aim to offer available information for clinical diagnosis. The research subjects were a 23-month-old patient with a high plasma level of citrulline and his unaffected parents. Whole-exome sequencing identified potential related ASL gene mutations in this trio. Enzymatic activity was detected spectrophotometrically by a coupled assay using arginase and measuring urea production. We identified a novel nonsynonymous mutation (c.206A>G, p.Lys69Arg) and a stop mutation (c.637C>T, p.Arg213∗) in ASL in a Chinese Han patient with ASLD. The enzymatic activity of a p.Lys69Arg ASL construct in human embryonic kidney 293T cells was significantly reduced compared to that of the wild-type construct, and no significant activity was observed for the p.Arg213∗ construct. Compound heterozygous p.Lys69Arg and p.Arg213∗ mutations that resulted in reduced ASL enzyme activity were found in a patient with ASLD. This finding expands the clinical spectrum of ASL pathogenic variants.

Abstract 12059: Incidental Findings in Cardiomyopathy and Channelopathy Genes Among 5891 Individuals Undergoing Whole-exome Sequencing. What Should be Reported?

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Elisa Mastantuono ◽  
Thomas Wieland ◽  
Riccardo Berutti ◽  
Peter Lichtner ◽  
Tim Strom ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Incidental Findings ◽  
Genetic Disorders ◽  
Molecular Diagnostic ◽  
Minor Genes ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Unknown Significance

Background: Whole-exome-sequencing (WES) is becoming a common molecular diagnostic test for patients with genetic disorders. However, this technique allows the identification not only of mutations responsible for the disease under investigation, but also of variants potentially causing other diseases, the so called “incidental findings” (IFs). The American College of Medical Genetics and Genomics (ACMG) stated that IFs should be reported based on clinical validity and utility and indicated a list of 56 actionable genes. Among these, nearly half (20/56) are major genes associated with channelopathies and cardiomyopathies. Despite these recommendations, most of the studies so far published, reported also mutations in minor genes among the actionable findings. Methods: WES was performed in 5891 individuals without known channelopathies or cardiomyopathies. Exome data were first filtered based on genotype quality. Subsequently, a frequency filter was applied, considering 1000 Genomes, ExAC and our internal exome database. Variants reported as pathogenic in ClinVar or novel but expected to be pathogenic (nonsense, frameshift and splice) were further investigated, following the ACMG guidelines. Major (20) and minor (73) genes associated with channelopathies and cardiomyopathies were evaluated. Results: We identified 3514 variants in the 93 genes under investigation, after applying the quality and frequency filters. Eight variants were classified as pathogenic and 52 as likely pathogenic and they were detected in around 1% of the individuals. The vast majority (85%) of pathogenic or likely pathogenic variants were located in the 20 actionable genes indicated by ACMG. The inclusion of minor genes increased the number of variants of unknown significance (VUS), from 865 to 3454. Conclusion: Our data support the ACMG recommendations in reporting only IFs identified in the 20 major cardiac actionable genes. Indeed, the inclusion of minor genes is mainly increasing the number of VUS, without significantly impacting the number of pathogenic and likely pathogenic variants. The percentage of individuals with potentially clinical relevant variants in these genes is too high in relation to the disease-prevalence: a cardiologic evaluation is warranted.

Whole-Exome Sequencing and C9orf72 Analysis in Primary Progressive Aphasia

2021 ◽  
pp. 1-6
Author(s):  
Vanesa Pytel ◽  
Laura Hernández-Lorenzo ◽  
Laura Torre-Fuentes ◽  
Raúl Sanz ◽  
Nieves González ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Primary Progressive Aphasia ◽  
Sequencing Data ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Whole Exome Sequencing Data ◽  
Sporadic Disease

Primary progressive aphasia (PPA) is mainly considered a sporadic disease and few studies have systematically analyzed its genetic basis. We here report the analyses of C9orf72 genotyping and whole-exome sequencing data in a consecutive and well-characterized cohort of 50 patients with PPA. We identified three pathogenic GRN variants, one of them unreported, and two cases with C9orf72 expansions. In addition, one likely pathogenic variant was found in the SQSTM1 gene. Overall, we found 12%of patients carrying pathogenic or likely pathogenic variants. These results support the genetic role in the pathophysiology of a proportion of patients with PPA.

Constitutive mismatch repair defect syndrome: New insights from whole exome sequencing data and functional studies

2016 ◽  
Vol 231 ◽  
pp. S12
Author(s):  
Ahmet Okay Caglayan ◽  
Zeynep E. Erson Omay ◽  
Yavuz Koksal ◽  
Suleyman Coskun ◽  
Ekrem Unal ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Mismatch Repair ◽  
Whole Exome Sequencing ◽  
Sequencing Data ◽  
Functional Studies ◽  
Exome Sequencing Data ◽  
Whole Exome ◽  
Whole Exome Sequencing Data ◽  
Repair Defect

Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies

2019 ◽  
Vol 57 (4) ◽  
pp. 258-268 ◽  
Author(s):  
Massimo Bogliolo ◽  
Roser Pujol ◽  
Miriam Aza-Carmona ◽  
Núria Muñoz-Subirana ◽  
Benjamin Rodriguez-Santiago ◽  
...  
Keyword(s):  
Dna Repair ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Bone Marrow Failure ◽  
Fanconi Anaemia ◽  
Sequencing Data ◽  
Missense Variants ◽  
Functional Studies ◽  
Large Deletions ◽  
Whole Exome

PurposePatients with Fanconi anaemia (FA), a rare DNA repair genetic disease, exhibit chromosome fragility, bone marrow failure, malformations and cancer susceptibility. FA molecular diagnosis is challenging since FA is caused by point mutations and large deletions in 22 genes following three heritability patterns. To optimise FA patients’ characterisation, we developed a simplified but effective methodology based on whole exome sequencing (WES) and functional studies.Methods68 patients with FA were analysed by commercial WES services. Copy number variations were evaluated by sequencing data analysis with RStudio. To test FANCA missense variants, wt FANCA cDNA was cloned and variants were introduced by site-directed mutagenesis. Vectors were then tested for their ability to complement DNA repair defects of a FANCA-KO human cell line generated by TALEN technologies.ResultsWe identified 93.3% of mutated alleles including large deletions. We determined the pathogenicity of three FANCA missense variants and demonstrated that two FANCA variants reported in mutations databases as ‘affecting functions’ are SNPs. Deep analysis of sequencing data revealed patients’ true mutations, highlighting the importance of functional analysis. In one patient, no pathogenic variant could be identified in any of the 22 known FA genes, and in seven patients, only one deleterious variant could be identified (three patients each with FANCA and FANCD2 and one patient with FANCE mutations)ConclusionWES and proper bioinformatics analysis are sufficient to effectively characterise patients with FA regardless of the rarity of their complementation group, type of mutations, mosaic condition and DNA source.

scholarly journals Comprehensive Exonic Sequencing of Hemiplegic Migraine-Related Genes in a Cohort of Suspected Probands Identifies Known and Potential Pathogenic Variants

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2368
Author(s):  
Heidi G. Sutherland ◽  
Neven Maksemous ◽  
Cassie L. Albury ◽  
Omar Ibrahim ◽  
Robert A. Smith ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Factors ◽  
Sequencing Data ◽  
Hemiplegic Migraine ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Whole Exome Sequencing Data

Hemiplegic migraine (HM) is a rare migraine disorder with aura subtype including temporary weakness and visual, sensory, and/or speech symptoms. To date, three main genes—CACNA1A, ATP1A2, and SCN1A—have been found to cause HM. These encode ion channels or transporters, important for regulating neuronal ion balance and synaptic transmission, leading to HM being described as a channelopathy. However, <20% of HM cases referred for genetic testing have mutations in these genes and other genes with roles in ion and solute transport, and neurotransmission has also been implicated in some HM cases. In this study, we performed whole exome sequencing for 187 suspected HM probands referred for genetic testing, but found to be negative for CACNA1A, ATP1A2, and SCN1A mutations, and applied targeted analysis of whole exome sequencing data for rare missense or potential protein-altering variants in the PRRT2, PNKD, SLC1A3, SLC2A1, SLC4A4, ATP1A3, and ATP1A4 genes. We identified known mutations and some potentially pathogenic variants in each of these genes in specific cases, suggesting that their screening improves molecular diagnosis for the disorder. However, the majority of HM patients were found not to have candidate mutations in any of the previously reported HM genes, suggesting that additional genetic factors contributing to the disorder are yet to be identified.

scholarly journals Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

2021 ◽  
Author(s):  
Adam L. Numis ◽  
Gilberto da Gente ◽  
Elliott H. Sherr ◽  
Hannah C. Glass
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
List Type ◽  
Sequencing Analysis ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

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