Isolated hypogonadotropic hypogonadism (IHH), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) constitute a disease spectrum whose etiology remains largely unknown. This study aimed to clarify whether mutations in SMCHD1, an epigenetic regulator gene, might underlie this disease spectrum. SMCHD1 is a causative gene for Bosma arhinia microphthalmia syndrome characterized by arhinia, microphthalmia and IHH. We performed mutation screening of SMCHD1 in patients with etiology-unknown IHH (n = 31) or CPHD (n = 43, 19 of whom also satisfied the SOD diagnostic criteria). Rare variants were subjected to in silico analyses and classified according to the American College of Medical Genetics and Genomics guidelines. Consequently, a rare likely pathogenic variant, p.Asp398Asn, was identified in one patient. The patient with p.Asp398Asn exhibited CPHD, optic nerve hypoplasia, and a thin retinal nerve fiber layer, and therefore satisfied the criteria of SOD. This patient showed a relatively low DNA methylation level of the 52 SMCHD1-target CpG sites at the D4Z4 locus. Exome sequencing for the patient excluded additional variants in other IHH/CPHD-causative genes. In vitro assays suggested functional impairment of the p.Asp398Asn variant. These results provide the first indication that SMCHD1 mutations represent a rare genetic cause of the HH-related disease spectrum.

单纯性性腺功能减退性腺功能减退症（IHH），垂体激素缺乏症（CPHD）和视光发育不良（SOD）构成了一个病因谱，其病因仍是未知之数。本研究旨在阐明表观遗传调控基因SMCHD1中的突变是否可能是该疾病谱的基础。SMCHD1是Bosma Arhinia小眼症候群的致病基因，其特征为Arhinia，小眼症和IHH。我们进行了SMCHD1的突变筛选病因不明的IHH（n = 31）或CPHD（n = 43，其中19个也满足SOD诊断标准）的患者。对稀有变体进行计算机分析并根据美国医学遗传学和基因组学指南进行分类。因此，在一名患者中发现了一种罕见的可能的病原体变体p.Asp398Asn。p.Asp398Asn患者表现出CPHD，视神经发育不全和视网膜神经纤维薄层，因此符合SOD标准。该患者在D4Z4处显示52个SMCHD1靶CpG位点的DNA甲基化水平相对较低轨迹。患者的外显子组测序排除了其他引起IHH / CPHD的基因中的其他变异。体外测定表明p.Asp398Asn变体功能受损。这些结果首次表明SMCHD1突变代表HH相关疾病谱的罕见遗传原因。