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Sequence analysis of 37 candidate genes for male infertility: challenges in variant assessment and validating genes
Author(s) -
Araujo T. F.,
Friedrich C.,
Grangeiro C. H. P.,
Martelli L. R.,
Grzesiuk J. D.,
Emich J.,
Wyrwoll M. J.,
Kliesch S.,
Simões A. L.,
Tüttelmann F.
Publication year - 2020
Publication title -
andrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.947
H-Index - 43
eISSN - 2047-2927
pISSN - 2047-2919
DOI - 10.1111/andr.12704
Subject(s) - azoospermia , male infertility , sanger sequencing , candidate gene , biology , genetics , exome sequencing , gene , infertility , population , in silico , exome , bioinformatics , dna sequencing , medicine , mutation , environmental health , pregnancy
Background The routine genetic analysis for diagnosing male infertility has not changed over the last twenty years, and currently available tests can only determine the etiology of 4% of unselected infertile patients. Thus, to create new diagnostic assays, we must better understand the molecular and genetic mechanisms of male infertility. Although next‐generation sequencing allows for simultaneous analysis of hundreds of genes and the discovery of novel candidates related to male infertility, so far only a few gene candidates have enough sound evidence to support the gene–disease relationship. Objective Since complementary studies are required to validate genes , we aimed to analyze the presence of potentially pathogenic rare variants in a set of candidate genes related to azoospermia in a hitherto understudied South American population. Subjects and Methods We performed whole exome sequencing in a group of 16 patients with non‐obstructive azoospermia from Ribeirão Preto, Brazil. Based on a recent systematic review of monogenic causes of male infertility, we selected a set of 37 genes related to azoospermia, Sertoli‐Cell‐Only histology, and spermatogenic arrest to analyze. The identified variants were confirmed by Sanger sequencing, and their functional consequence was predicted by in silico programs. Results We identified potential pathogenic variants in seven genes in six patients. Two variants, c.671A>G (p.(Asn224Ser)) in DMRT 1 and c.91C>T (p.(Arg31Cys)) in REC 8 , have already been described in association with azoospermia. We also found new variants in genes that already have moderate evidence of being linked to spermatogenic failure ( TEX 15, KLHL 10 ), in genes with limited evidence ( DNMT 3B, TEX 14 ) and in one novel promising candidate gene that has no evidence so far ( SYCE 1L ). Discussion Although this study included a small number of patients, the process of rationally selecting genes allowed us to detect rare potentially pathogenic variants, providing supporting evidence for validating candidate genes associated with azoospermia.