scholarly journals Whole exome sequencing identifies genes associated with non-obstructive azoospermia

2020 ◽  
Author(s):  
Hongguo Zhang ◽  
Hui Huang ◽  
Xinyue Zhang ◽  
Wei Li ◽  
Yuting Jiang ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Association Study ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variant ◽  
Biological Study ◽  
Obstructive Azoospermia ◽  
Novel Genes ◽  
Rare Variant Association ◽  
Whole Exome

AbstractBackgroundGenetic etiology is the main cause of non-obstructive azoospermia, but little is known about the landscape of the disease causative genes.ObjectiveTo identify the association of non-obstructive azoospermia and the putative causative genetic factors.Design, setting, and participantsA single-center perspective case-control study of 133 patients, with clinicopathologic non-obstructive azoospermia and 495 fertile men control was performed. Eleven trio families were available and enrolled from the 133 patients’ families.Outcome measurements and statistical analysisWhole exome sequencing based rare variant association study between the cases and controls was performed by means of gene burden association testing. Linkage analysis on the trio family was also described to screen the causative genes.Results and limitationsTotally 80 genes (p < 0.05) were identified associated with non-obstructive azoospermia (2 of which were previously reported), meanwhile 5 novel genes out of which were also found potentially causative through the linkage analysis on the trio families. The pathway enrichment analysis was also provided to assess the potential interaction between genes identified in this study and previously reported together. The 5 novel identified overlap genes by both above mentioned test with the rare mutations account for an overall 20% (26 /133 patients) incidence, together with the 2 known genes together would account for an overall 20% incidence for non-obstructive azoospermia in this study. The study is limited by the lack of functional biological study.ConclusionsFive novel genes were identified associated with non-obstructive azoospermia by means of both rare variant association study and linkage analysis through trio families. They could account for about 20% clinical incidence among the patients in our study.Patient summary133 infertile patients (11 of them with parents enrolled) with idiopathic non-obstructive azoospermia and 300 fertile male controls were recruited from single clinic center.All patients underwent semen analyses at least on three different occasions.

scholarly journals Rare Variant, Gene-Based Association Study of Hereditary Melanoma Using Whole-Exome Sequencing

2017 ◽  
Vol 109 (12) ◽  
Author(s):  
Mykyta Artomov ◽  
Alexander J Stratigos ◽  
Ivana Kim ◽  
Raj Kumar ◽  
Martin Lauss ◽  
...  
Keyword(s):  
Association Study ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variant ◽  
Whole Exome ◽  
Variant Gene

scholarly journals Whole-exome sequencing and gene-based rare variant association tests suggest that PLA2G4E might be a risk gene for panic disorder

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Yoshiro Morimoto ◽  
Mihoko Shimada-Sugimoto ◽  
Takeshi Otowa ◽  
Shintaro Yoshida ◽  
Akira Kinoshita ◽  
...  
Keyword(s):  
Panic Disorder ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variant ◽  
Rare Variant Association ◽  
Association Tests ◽  
Risk Gene ◽  
Whole Exome

scholarly journals High-Frequency Exon Deletion of DNA Cross-Link Repair 1C Accounting for Severe Combined Immunodeficiency May Be Missed by Whole-Exome Sequencing

2021 ◽  
Vol 12 ◽  
Author(s):  
Feifan Xiao ◽  
Yulan Lu ◽  
Bingbing Wu ◽  
Bo Liu ◽  
Gang Li ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variant ◽  
Severe Combined Immunodeficiency ◽  
Cell Receptor ◽  
Homozygous Deletion ◽  
Combined Immunodeficiency ◽  
Cross Link ◽  
Single Nucleotide Variants ◽  
Whole Exome

Next-generation sequencing (NGS) has been used to detect severe combined immunodeficiency (SCID) in patients, and some patients with DNA cross-link repair 1C (DCLRE1C) variants have been identified. Moreover, some compound variants, such as copy number variants (CNV) and single nucleotide variants (SNV), have been reported. The purpose of this study was to expand the genetic data related to patients with SCID carrying the compound DCLRE1C variant. Whole-exome sequencing (WES) was performed for genetic analysis, and variants were verified by performing Sanger sequencing or quantitative PCR. Moreover, we searched PubMed and summarized the data of the reported variants. Four SCID patients with DCLRE1C variants were identified in this study. WES revealed a homozygous deletion in the DCLRE1C gene from exons 1–5 in patient 1, exons 1–3 deletion and a novel rare variant (c.92T&gt;C, p.L31P) in patient 2, exons 1–3 deletion and a novel rare variant (c.328C&gt;G, p.L110V) in patient 3, and exons 1–4 deletion and a novel frameshift variant (c.449dup, p.His151Alafs*20) in patient 4. Based on literature review, exons 1–3 was recognized as a hotspot region for deletion variation. Moreover, we found that compound variations (CNV + SNV) accounted for approximately 7% variations in all variants. When patients are screened for T-cell receptor excision circles (TRECs), NGS can be used to expand genetic testing. Deletion of the DCLRE1C gene should not be ignored when a variant has been found in patients with SCID.

DMC1 mutation that causes human non-obstructive azoospermia and premature ovarian insufficiency identified by whole-exome sequencing

2018 ◽  
Vol 55 (3) ◽  
pp. 198-204 ◽  
Author(s):  
Wen-Bin He ◽  
Chao-Feng Tu ◽  
Qiang Liu ◽  
Lan-Lan Meng ◽  
Shi-Min Yuan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Male Patient ◽  
Histological Analysis ◽  
Pedigree Analysis ◽  
Obstructive Azoospermia ◽  
Ovarian Insufficiency ◽  
Causative Gene ◽  
Whole Exome

BackgroundThe genetic causes of the majority of male and female infertility caused by human non-obstructive azoospermia (NOA) and premature ovarian insufficiency (POI) with meiotic arrest are unknown.ObjectiveTo identify the genetic cause of NOA and POI in two affected members from a consanguineous Chinese family.MethodsWe performed whole-exome sequencing of DNA from both affected patients. The identified candidate causative gene was further verified by Sanger sequencing for pedigree analysis in this family. In silico analysis was performed to functionally characterise the mutation, and histological analysis was performed using the biopsied testicle sample from the male patient with NOA.ResultsWe identified a novel homozygous missense mutation (NM_007068.3: c.106G>A, p.Asp36Asn) in DMC1, which cosegregated with NOA and POI phenotypes in this family. The identified missense mutation resulted in the substitution of a conserved aspartic residue with asparaginate in the modified H3TH motif of DMC1. This substitution results in protein misfolding. Histological analysis demonstrated a lack of spermatozoa in the male patient’s seminiferous tubules. Immunohistochemistry using a testis biopsy sample from the male patient showed that spermatogenesis was blocked at the zygotene stage during meiotic prophase I.ConclusionsTo the best of our knowledge, this is the first report identifying DMC1 as the causative gene for human NOA and POI. Furthermore, our pedigree analysis shows an autosomal recessive mode of inheritance for NOA and POI caused by DMC1 in this family.

Linkage analysis and whole exome sequencing reveals AHNAK2 as a novel genetic cause for autosomal recessive CMT in a Malaysian family

Neurogenetics ◽  
2019 ◽  
Vol 20 (3) ◽  
pp. 117-127 ◽  
Author(s):  
Shelisa Tey ◽  
Nortina Shahrizaila ◽  
Alexander P. Drew ◽  
Sarimah Samulong ◽  
Khean-Jin Goh ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Recessive ◽  
Whole Exome ◽  
Autosomal Recessive Cmt

scholarly journals Azoospermia and reciprocal translocations: should whole-exome sequencing be recommended?

2021 ◽  
Vol 31 (1) ◽  
Author(s):  
Farah Ghieh ◽  
Anne-Laure Barbotin ◽  
Julie Prasivoravong ◽  
Sophie Ferlicot ◽  
Béatrice Mandon-Pepin ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Y Chromosome ◽  
Whole Exome Sequencing ◽  
Chromosome Rearrangements ◽  
Testicular Sperm Extraction ◽  
Comparative Genome Hybridization ◽  
Obstructive Azoospermia ◽  
Meiotic Arrest ◽  
Whole Exome ◽  
Gene Defects

Abstract Background Although chromosome rearrangements are responsible for spermatogenesis failure, their impact depends greatly on the chromosomes involved. At present, karyotyping and Y chromosome microdeletion screening are the first-line genetic tests for patients with non-obstructive azoospermia. Although it is generally acknowledged that X or Y chromosome rearrangements lead to meiotic arrest and thus rule out any chance of sperm retrieval after a testicular biopsy, we currently lack markers for the likelihood of testicular sperm extraction (TESE) in patients with other chromosome rearrangements. Results We investigated the use of a single nucleotide polymorphism comparative genome hybridization array (SNP-CGH) and whole-exome sequencing (WES) for two patients with non-obstructive azoospermia and testicular meiotic arrest, a reciprocal translocation: t(X;21) and t(20;22), and an unsuccessful TESE. No additional gene defects were identified for the t(X;21) carrier - suggesting that t(X;21) alone damages spermatogenesis. In contrast, the highly consanguineous t(20;22) carrier had two deleterious homozygous variants in the TMPRSS9 gene; these might have contributed to testicular meiotic arrest. Genetic defect was confirmed with Sanger sequencing and immunohistochemical assessments on testicular tissue sections. Conclusions Firstly, TMPRSS9 gene defects might impact spermatogenesis. Secondly, as a function of the chromosome breakpoints for azoospermic patients with chromosome rearrangements, provision of the best possible genetic counselling means that genetic testing should not be limited to karyotyping. Given the risks associated with TESE, it is essential to perform WES - especially for consanguineous patients.

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