SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility.

Am J Hum Genet
Authors
Keywords
Abstract

Unexplained infertility affects 2%-3% of reproductive-aged couples. One approach to identifying genes involved in infertility is to study subjects with this clinical phenotype and a de novo balanced chromosomal aberration (BCA). While BCAs may reduce fertility by production of unbalanced gametes, a chromosomal rearrangement may also disrupt or dysregulate genes important in fertility. One such subject, DGAP230, has severe oligozoospermia and 46,XY,t(20;22)(q13.3;q11.2). We identified exclusive overexpression of SYCP2 from the der(20) allele that is hypothesized to result from enhancer adoption. Modeling the dysregulation in budding yeast resulted in disrupted structural integrity of the synaptonemal complex, a common cause of defective spermatogenesis in mammals. Exome sequencing of infertile males revealed three heterozygous SYCP2 frameshift variants in additional subjects with cryptozoospermia and azoospermia. In sum, this investigation illustrates the power of precision cytogenetics for annotation of the infertile genome, suggests that these mechanisms should be considered as an alternative etiology to that of segregation of unbalanced gametes in infertile men harboring a BCA, and provides evidence of SYCP2-mediated male infertility in humans.

Year of Publication
2020
Journal
Am J Hum Genet
Volume
106
Issue
1
Pages
41-57
Date Published
2020 01 02
ISSN
1537-6605
DOI
10.1016/j.ajhg.2019.11.013
PubMed ID
31866047
PubMed Central ID
PMC7042487
Links
Grant list
P01 GM061354 / GM / NIGMS NIH HHS / United States
R15 GM116109 / GM / NIGMS NIH HHS / United States
P30 CA006516 / CA / NCI NIH HHS / United States
R15 GM104827 / GM / NIGMS NIH HHS / United States
F31 HD090780 / HD / NICHD NIH HHS / United States