Abstract
Gonadal failure, along with early pregnancy loss and perinatal death, may be an important filter that limits the propagation of harmful mutations in the human population. We hypothesized that men with spermatogenic impairment, a disease with unknown genetic architecture and a common cause of male infertility, are enriched for rare deleterious mutations compared to men with normal spermatogenesis. After assaying genomewide SNPs and CNVs in 323 Caucasian men with idiopathic spermatogenic impairment and more than 1,100 controls, we estimate that each rare autosomal deletion detected in our study multiplicatively changes a man's risk of disease by 10% (OR 1.10 [1.04–1.16], p<2×10−3), rare X-linked CNVs by 29%, (OR 1.29 [1.11–1.50], p<1×10−3), and rare Y-linked duplications by 88% (OR 1.88 [1.13–3.13], p<0.03). By contrasting the properties of our case-specific CNVs with those of CNV callsets from cases of autism, schizophrenia, bipolar disorder, and intellectual disability, we propose that the CNV burden in spermatogenic impairment is distinct from the burden of large, dominant mutations described for neurodevelopmental disorders. We identified two patients with deletions of DMRT1, a gene on chromosome 9p24.3 orthologous to the putative sex determination locus of the avian ZW chromosome system. In an independent sample of Han Chinese men, we identified 3 more DMRT1 deletions in 979 cases of idiopathic azoospermia and none in 1,734 controls, and found none in an additional 4,519 controls from public databases. The combined results indicate that DMRT1 loss-of-function mutations are a risk factor and potential genetic cause of human spermatogenic failure (frequency of 0.38% in 1306 cases and 0% in 7,754 controls, p = 6.2×10−5). Our study identifies other recurrent CNVs as potential causes of idiopathic azoospermia and generates hypotheses for directing future studies on the genetic basis of male infertility and IVF outcomes.
Highlights
Male infertility is a multifaceted disorder affecting nearly 5% of men of reproductive age
Rare copy number variants (CNVs) burden is a feature of spermatogenic failure When restricting our analysis to CNVs with a call frequency of less than 5%, a subset likely to be enriched for pathogenic events, Author Summary
These data demonstrate that rare CNVs are a major risk factor for spermatogenic impairment, and while confirming the central role of the Y chromosome in modulating spermatogenic output, our risk estimates for autosomal and X-linked CNVs indicate that this phenotype is influenced by rare variation across the entire genome
Summary
Male infertility is a multifaceted disorder affecting nearly 5% of men of reproductive age. In spite of its prevalence and a considerable research effort over the past several decades, the underlying cause of male infertility is uncharacterized in up to half of all cases [1]. Spermatogenesis is a complex multistep process that requires germ cells to (a) maintain a stable progenitor population through frequent mitotic divisions, (b) reduce ploidy of the spermatogonial progenitors from diploid to haploid through meiotic divisions, and (c) assume highly specialized sperm morphology and function through spermiogenesis These steps involve the expression of thousands of genes and carefully orchestrated interactions between germ cells and somatic cells within the seminiferous tubules [2]. It is likely that a large proportion of idiopathic cases of spermatogenic failure are of uncharacterized genetic origin, but measuring the heritability of infertility phenotypes has been challenging
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