Investigation of the genetic etiology in male infertility with apparently balanced chromosomal structural rearrangements by genome sequencing
作者机构：Department of Obstetrics and GynaecologyThe Chinese University of Hong KongHong KongChina Shenzhen Research InstituteThe Chinese University of Hong KongShenzhen 518057China Hong Kong Hub of Paediatric ExcellenceThe Chinese University of Hong KongHong KongChina Genetics and Prenatal Diagnosis CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China The Chinese University of Hong Kong-Baylor College of Medicine Joint Center for Medical GeneticsHong KongChina
出 版 物：《Asian Journal of Andrology》 (亚洲男性学杂志（英文版）)
年 卷 期：2022年第24卷第3期
页 面：248-254页
核心收录：
基 金：supported by the National Natural Science Foundation of China(No.31801042) the Health and Medical Research Fund(No.04152666 and No.07180576) General Research Fund(No.14115418),and Direct Grant(No.2020.052).
主 题：azoospermia balanced structural rearrangements genome sequencing male infertility severe oligospermia
摘 要：Apparently balanced chromosomal structural rearrangements are known to cause male infertility and account for approximately 1%of azoospermia or severe oligospermia.However,the underlying mechanisms of pathogenesis and etiologies are still largely unknown.Herein,we investigated apparently balanced interchromosomal structural rearrangements in six cases with azoospermia/severe oligospermia to comprehensively identify and delineate cryptic structural rearrangements and the related copy number variants.In addition,high read-depth genome sequencing(GS)(30-fold)was performed to investigate point mutations causative of male infertility.Mate-pair GS(4-fold)revealed additional structural rearrangements and/or copy number changes in 5 of 6 cases and detected a total of 48 rearrangements.Overall,the breakpoints caused truncations of 30 RefSeq genes,five of which were associated with spermatogenesis.Furthermore,the breakpoints disrupted 43 topological-associated domains.Direct disruptions or potential dysregulations of genes,which play potential roles in male germ cell development,apoptosis,and spermatogenesis,were found in all cases(n=6).In addition,high read-depth GS detected dual molecular findings in case MI6,involving a complex rearrangement and two point mutations in the gene DNAH1.Overall,our study provided the molecular characteristics of apparently balanced interchromosomal structural rearrangements in patients with male infertility.We demonstrated the complexity of chromosomal structural rearrangements,potential gene disruptions/dysregulation and single-gene mutations could be the contributing mechanisms underlie male infertility.
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