Microdeletion and microduplication syndromes, including recurrent rearrangements at 16p11.2 and 22q11.21, are enriched in unexplained male infertility

Abstract STUDY QUESTION What is the impact of undiagnosed microdeletion and microduplication syndromes (MMS) for men with idiopathic low sperm count? SUMMARY ANSWER Among idiopathic male infertility, ∼2% of cases harbour known disease-causing microdeletions and duplications linked to clinically well-established syndromes, representing ∼2.5-fold higher prevalence than in the general population. WHAT IS KNOWN ALREADY While infertility affects up to 10% of men, a substantial proportion of cases remain with no identifiable underlying cause. Recurrent submicroscopic losses or gains cause MMS, some of which also impact reproductive phenotypes, including cryptorchidism and reduced fertility. STUDY DESIGN, SIZE, DURATION This retrospective study investigated the proportion of undiagnosed MMS among idiopathic male infertility cases. Patients with unexplained low total sperm counts (TSC; defined as ≤39 million sperm per ejaculate) were recruited to the ESTonian ANDrology (ESTAND) cohort at the Andrology Clinic of Tartu University Hospital (AC-TUH) in Estonia. A total of 504 men were included in the analysis, and the study capitalized on available whole-exome sequencing (WES) data to explore large (>500 kb) chromosomal deletions and duplications. PARTICIPANTS/MATERIALS, SETTING, METHODS Copy number variant (CNV) calling was executed on the WES dataset, followed by a stringent, custom-developed filtering pipeline that retained only high-confidence CNVs larger than 500 kb. Candidate CNVs were validated by chromosomal microarray analysis (CMA) or whole-genome sequencing (WGS). Prevalence of identified MMS-linked deletions and duplications in the ESTAND cohort was compared to general population literature data. MAIN RESULTS AND THE ROLE OF CHANCE A total of nine patients (1.8%) carried losses and gains linked to clinically well-characterized MMS—recurrent microdeletions at 16p11.2 (two cases), 2q13-14.1, and 15q13.2-13.3, and microduplications at 22q11.21 (three cases), 16p11.2, and 8p23.1. The total burden of MMS among infertile men was ∼2.5-fold higher compared to the general population (P = 0.01, χ2 test). Cryptorchidism was a novel shared feature among all individuals with 16p11.2 rearrangements, suggesting a potential role in disrupting testicular development. Three subjects with MMS-linked microduplications, but none with a microdeletion, had achieved biological fatherhood. An oligozoospermia case (TSC 1.92 × 106/ej.) with 16p11.2 duplication had a naturally conceived child in youthhood. For two men carrying 22q11.21 duplication (TSC 0 and 4.2 × 106/ej., respectively), implementation of ARTs–ICSI with or without preceding testicular sperm aspiration—resulted in successful conception and childbirth. Evidence for a plausible link to male gonadal development and function has been reported for MAZ and KCTD13 at 16p11.2, and LZTR1 at 22q11.21. As an additional finding, a novel ∼3.8 Mb microduplication at 3p25.1 was identified in an oligozoospermia patient and his azoospermic son, conceived naturally at the age of 28 years. This region encompasses a triplosensitive gene, NR2C2, linked to affected meiosis and oligozoospermia in mouse models. LIMITATIONS, REASONS FOR CAUTION WES may not detect all structural variations, such as inversions or balanced translocations. As some MMS CNVs were only identified in singleton cases (8p23.1 duplication, 2q13-14.1 and 15q13.2-13.3 deletions), the link to male infertility could not be clarified. Further data are needed about the novel large 3p25.1 microduplication to understand its effect on spermatogenesis. WIDER IMPLICATIONS OF THE FINDINGS The yield of identified MMS in idiopathic cases with low sperm counts (∼2%) was close to the carriership of Y-chromosome microdeletions, tested in routine infertility workup. Early identification of MMS can inform genetic counselling regarding congenital health risks to the patient and future offspring and options for decision-making in ART. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Estonian Research Council (Grant number PRG1021 to M.L.). The authors declare that they have no conflict of interest in relation to the data in this paper. TRIAL REGISTRATION NUMBER N/A