Journal of assisted reproduction and genetics · 2026
Homozygous C12orf40 variant contributes to severe oligoasthenoteratozoospermia and sperm sex chromosome aneuploidy.
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Chen Yixin, Guo Jing, Wang Jing, Cai Bing, Xu Yan, Zeng Yanhong, Gao Jun, Wang Qiong, Mai Qingyun, Xu Yanwen
Аннотация
PURPOSE: Recurrent pregnancy loss (RPL) is frequently associated with embryonic aneuploidy, yet paternal genetic contributors remain poorly understood. In this study, we investigated the genetic cause of a couple with oligoasthenoteratozoospermia (OAT) and a history of RPL involving recurrent sex chromosome aneuploidies.
METHODS: Evaluation included preimplantation genetic testing for aneuploidy (PGT-A) with parental origin analysis, semen analysis, and sperm fluorescence in situ hybridization (FISH). Whole-exome sequencing (WES) was performed to identify pathogenic variants, which were subsequently validated by Sanger sequencing.
RESULTS: WES revealed a homozygous C12orf40 frameshift variant (c.232_233insTT) in the proband and his affected brother. Both brothers exhibited markedly elevated sperm sex chromosome error rates (proband nullisomy:18.8%; brother disomy:10.3%). Across three PGT-A cycles, only 41.7% (5/12) of the blastocysts were euploid, and 85.7% (6/7) of the aneuploid embryos involved sex chromosome abnormalities. Parental origin analysis indicated 72.7% of abnormalities were paternal in origin.
CONCLUSION: This study identified a previously unreported phenotype of the C12orf40 c.232_233insTT variant, expanding its spectrum from complete meiotic arrest to incomplete arrest with severe meiotic errors and residual spermatogenesis. It provides the first evidence linking this variant to severe OAT and RPL, highlighting a crucial paternal genetic contributor to reproductive failure.
METHODS: Evaluation included preimplantation genetic testing for aneuploidy (PGT-A) with parental origin analysis, semen analysis, and sperm fluorescence in situ hybridization (FISH). Whole-exome sequencing (WES) was performed to identify pathogenic variants, which were subsequently validated by Sanger sequencing.
RESULTS: WES revealed a homozygous C12orf40 frameshift variant (c.232_233insTT) in the proband and his affected brother. Both brothers exhibited markedly elevated sperm sex chromosome error rates (proband nullisomy:18.8%; brother disomy:10.3%). Across three PGT-A cycles, only 41.7% (5/12) of the blastocysts were euploid, and 85.7% (6/7) of the aneuploid embryos involved sex chromosome abnormalities. Parental origin analysis indicated 72.7% of abnormalities were paternal in origin.
CONCLUSION: This study identified a previously unreported phenotype of the C12orf40 c.232_233insTT variant, expanding its spectrum from complete meiotic arrest to incomplete arrest with severe meiotic errors and residual spermatogenesis. It provides the first evidence linking this variant to severe OAT and RPL, highlighting a crucial paternal genetic contributor to reproductive failure.