Analysis of copy number variation in men with non‐obstructive azoospermia

Background Recent findings demonstrate that single nucleotide variants can cause non‐obstructive azoospermia (NOA). In contrast, copy number variants (CNVs) were only analysed in few studies in infertile men. Some have reported a higher prevalence of CNVs in infertile versus fertile men. Objectives...

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Published in:	Andrology (Oxford) Vol. 10; no. 8; pp. 1593 - 1604
Main Authors:	Wyrwoll, M. J., Wabschke, R., Röpke, A., Wöste, M., Ruckert, C., Perrey, S., Rotte, N., Hardy, J., Astica, L., Lupiáñez, D. G., Wistuba, J., Westernströer, B., Schlatt, S., Berman, A. J., Müller, A. M., Kliesch, S., Yatsenko, A. N., Tüttelmann, F., Friedrich, C.
Format:	Journal Article
Language:	English
Published:	Hoboken Wiley Subscription Services, Inc 01-11-2022
Subjects:	CNV Infertility meiotic arrest non‐obstructive azoospermia SCO SYCE1 WES
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Summary:	Background Recent findings demonstrate that single nucleotide variants can cause non‐obstructive azoospermia (NOA). In contrast, copy number variants (CNVs) were only analysed in few studies in infertile men. Some have reported a higher prevalence of CNVs in infertile versus fertile men. Objectives This study aimed to elucidate if CNVs are associated with NOA. Materials and methods We performed array‐based comparative genomic hybridisation (aCGH) in 37 men with meiotic arrest, 194 men with Sertoli cell‐only phenotype, and 21 control men. We filtered our data for deletions affecting genes and prioritised the affected genes according to the literature search. Prevalence of CNVs was compared between all groups. Exome data of 2,030 men were screened to detect further genetic variants in prioritised genes. Modelling was performed for the protein encoded by the novel candidate gene TEKT5 and we stained for TEKT5 in human testicular tissue. Results We determined the cause of infertility in two individuals with homozygous deletions of SYCE1 and in one individual with a heterozygous deletion of SYCE1 combined with a likely pathogenic missense variant on the second allele. We detected heterozygous deletions affecting MLH3, EIF2B2, SLX4, CLPP and TEKT5, in one subject each. CNVs were not detected more frequently in infertile men compared with controls. Discussion While SYCE1 and MLH3 encode known meiosis‐specific proteins, much less is known about the proteins encoded by the other identified candidate genes, warranting further analyses. We were able to identify the cause of infertility in one out of the 231 infertile men by aCGH and in two men by using exome sequencing data. Conclusion As aCGH and exome sequencing are both expensive methods, combining both in a clinical routine is not an effective strategy. Instead, using CNV calling from exome data has recently become more precise, potentially making aCGH dispensable.
Bibliography:	These authors contributed equally and should be considered joint First Authors. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS All authors contributed to the research, writing and editing of the manuscript. All authors approved the final version of the manuscript.
ISSN:	2047-2919 2047-2927
DOI:	10.1111/andr.13267