PT - JOURNAL ARTICLE AU - Chencheng Yao AU - Chao Yang AU - Liangyu Zhao AU - Peng Li AU - Ruhui Tian AU - Huixing Chen AU - Ying Guo AU - Yuhua Huang AU - Erlei Zhi AU - Jing Zhai AU - Hongfang Sun AU - Jianxiong Zhang AU - Yan Hong AU - Li Zhang AU - Zhiyong Ji AU - Feng Zhang AU - Zhi Zhou AU - Zheng Li TI - Bi-allelic <em>SHOC1</em> loss-of-function mutations cause meiotic arrest and non-obstructive azoospermia AID - 10.1136/jmedgenet-2020-107042 DP - 2020 Sep 08 TA - Journal of Medical Genetics PG - jmedgenet-2020-107042 4099 - http://jmg.bmj.com/content/early/2020/09/07/jmedgenet-2020-107042.short 4100 - http://jmg.bmj.com/content/early/2020/09/07/jmedgenet-2020-107042.full AB - Background The genetic causes of human idiopathic non-obstructive azoospermia (NOA) with meiotic arrest remain unclear.Methods Two Chinese families with infertility participated in the study. In family 1, two brothers were affected by idiopathic NOA. In family 2, the proband was diagnosed with idiopathic NOA, and his elder sister suffered from infertility. Whole-exome sequencing (WES) was conducted in the two patients in family 1, the proband in family 2 and 362 additional sporadic patients with idiopathic NOA. Sanger sequencing was used to verify the WES results. Periodic acid–Schiff (PAS), immunohistochemistry (IHC) and meiotic chromosomal spread analyses were carried out to evaluate the stage of spermatogenesis arrested in the affected cases.Results We identified compound heterozygous loss of function (LoF) variants of SHOC1 (c.C1582T:p.R528X and c.231_232del:p.L78Sfs*9, respectively) in both affected cases with NOA from family 1. In family 2, homozygous LoF variant in SHOC1 (c.1194delA:p.L400Cfs*7) was identified in the siblings with infertility. PAS, IHC and meiotic chromosomal spread analyses demonstrated that the spermatogenesis was arrested at zygotene stage in the three patients with NOA. Consistent with the autosomal recessive mode of inheritance, all of these SHOC1 variants were inherited from heterozygous parental carriers. Intriguingly, WES of 362 sporadic NOA cases revealed one additional NOA case with a bi-allelic SHOC1 LoF variant (c.1464delT:p.D489Tfs*13).Conclusion To the best of our knowledge, this is the first report identifying SHOC1 as the causative gene for human NOA. Furthermore, our study showed an autosomal recessive mode of inheritance in the NOA caused by SHOC1 deficiency.