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From azoospermia to macrozoospermia, a phenotypic continuum due to mutations in the ZMYND15 gene


1 Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, Grenoble 38000, France
2 CHU Grenoble Alpes, UM GI-DPI, Grenoble 38000, France
3 CHR Metz Thionville Hospital, 1 allée Château, METZ 57000, France
4 CHU Grenoble Alpes, UM of Chromosomic Genetics, Grenoble 38000, France
5 Univ. Grenoble Alpes, CNRS, TIMC-IMAG, Grenoble F-38000, France

Correspondence Address:
Pierre F Ray,
Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, Grenoble 38000; CHU Grenoble Alpes, UM GI-DPI, Grenoble 38000
France
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aja202194

PMID: 35017390

Thanks to tremendous advances in sequencing technologies and in particular to whole exome sequencing (WES), many genes have now been linked to severe sperm defects. A precise genetic diagnosis is obtained for a minority of patients and only for the most severe defects like azoospermia or macrozoospermia which is very often due to defects in the aurora kinase C (AURKC gene. Here, we studied a subject with a severe oligozoospermia and a phenotypic diagnosis of macrozoospermia. AURKC analysis did not reveal any deleterious variant. WES was then initiated which permitted to identify a homozygous loss of function variant in the zinc finger MYND-type containing 15 (ZMYND15 gene. ZMYND15 has been described to serve as a switch for haploid gene expression, and mice devoid of ZMYND15 were shown to be sterile due to nonobstructive azoospermia (NOA). In man, ZMYND15 has been associated with NOA and severe oligozoospermia. We confirm here that the presence of a bi-allelic ZMYND15 variant induces a severe oligozoospermia. In addition, we show that severe oligozoospermia can be associated macrozoospermia, and that a phenotypic misdiagnosis is possible, potentially delaying the genetic diagnosis. In conclusion, genetic defects in ZMYND15 can induce complete NOA or severe oligozoospermia associated with a very severe teratozoospermia. In our experience, severe oligozoospermia is often associated with severe teratozoospermia and can sometimes be misinterpreted as macrozoospermia or globozoospermia. In these instances, specific AURKC or dpy-19 like 2 (DPY19L2) diagnosis is usually negative and we recommend the direct use of a pan-genomic techniques such as WES.


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