Center for Human Genetics, 840 Memorial Dr, Ste 101, Cambridge, MA, 02139, USA.
Department of Obstetrics and Gynecology, Tufts University School of Medicine, Boston, MA, USA.
J Assist Reprod Genet. 2020 Feb;37(2):471-475. doi: 10.1007/s10815-019-01685-6. Epub 2020 Jan 9.
Non-obstructive azoospermia accounts for 10-15% of male infertility, resulting in 60% of all cases of azoospermia and affecting about 1% of the male population. About 30% of these cases are due to Y chromosome microdeletions, chromosome abnormalities, or hormonal disorders. Pathogenic variants in genes on the sex chromosomes have key roles in spermatogenic failure. The co-occurrence of azoospermia and congenital cataracts ranges between 1 in 165,000 and 1 in 500,000. Our 28-year-old patient with normal intelligence and abnormally shaped teeth presented with both disorders. A microarray revealed a microdeletion at Xp23.13 with a whole NHS gene deletion as well as a contiguous deletion of two other genes [SCML1 and RAI2]. This observation represents the first report of non-obstructive azoospermia with congenital cataracts and a contiguous deletion of the SCML1 gene, a transcript of which is exclusively expressed in the testis. SCML1 is the putative culprit gene, which requires functional study or animal experiments. Our analysis of 60 known spermatogenesis failure-related genes by whole-exome sequencing revealed no other candidate. The Nance-Horan syndrome due to pathogenic variants in the NHS gene at Xp23.13 including whole gene deletion does not have azoospermia as a feature. Our report adds to the completeness of genetic counseling for an individual with azoospermia and congenital cataracts.
非梗阻性无精子症约占男性不育症的 10-15%,导致 60%的无精子症病例,并影响约 1%的男性人口。这些病例中约有 30%是由于 Y 染色体微缺失、染色体异常或激素紊乱引起的。性染色体上基因的致病变异在精子发生失败中起着关键作用。无精子症和先天性白内障同时发生的比例在 1/165000 到 1/500000 之间。我们这位 28 岁的患者智力正常,牙齿形状异常,同时患有这两种疾病。微阵列分析显示 Xp23.13 处存在微缺失,导致整个 NHS 基因缺失以及另外两个基因 [SCML1 和 RAI2] 的连续缺失。这一观察结果代表了首例非梗阻性无精子症伴先天性白内障和 SCML1 基因连续缺失的报告,该基因的转录物仅在睾丸中表达。SCML1 是可能的罪魁祸首基因,需要进行功能研究或动物实验。我们通过全外显子组测序对 60 个已知的与精子发生失败相关的基因进行分析,未发现其他候选基因。由于 Xp23.13 上 NHS 基因的致病性变异导致的 Nance-Horan 综合征,包括整个基因缺失,并不以无精子症为特征。我们的报告增加了对同时患有无精子症和先天性白内障的个体进行遗传咨询的完整性。