Department of Obstetrics and Gynaecology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China.
Am J Hum Genet. 2021 Feb 4;108(2):337-345. doi: 10.1016/j.ajhg.2020.12.014.
Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.
Mayer-Rokitansky-Küster-Hauser 综合征 (MRKHS) 与先天性子宫、宫颈和阴道上部缺失有关；它是一种性连锁特征。多因素机制导致 Müllerian 管 (MD)/Wolffian 管 (WD) 发育中断被认为是 MRKHS 的基础。在这项研究中，对一个中国发现队列（442 名受影响的受试者和 941 名女性对照受试者）和一个复制的 MRKHS 队列（来自北美、南美和欧洲的 150 名混合种族受影响的受试者）进行了外显子组测序 (ES)。对 PAX8 相关先天性甲状腺功能减退症 (CH) 的女性生殖系统进行了额外的表型随访（n = 5，中国）。通过分析 19 个对 MD/WD 发育至关重要的候选基因，我们在 7 个基因中发现了 12 个可能的基因破坏性 (LGD) 变体：PAX8（n = 4）、BMP4（n = 2）、BMP7（n = 2）、TBX6（n = 1）、HOXA10（n = 1）、EMX2（n = 1）和 WNT9B（n = 1），而在对照样本中未检测到这些基因中的 LGD 变体（p = 1.27E-06）。有趣的是，在多个家庭中观察到了具有父系遗传的性别限制外显率。从复制队列中发现了一个额外的 PAX8 LGD 变体，从两个队列中发现了两个错义变体，这些变体导致蛋白失去功能。从 PAX8 相关的 CH 队列中，我们发现了一名个体表现出 CH 和 MRKHS 并存的综合征（CH-MRKHS）。我们的研究证明了综合利用发育生物学知识来阐明遗传扰动，即涉及相同基因座的罕见致病性等位基因，有助于人类出生缺陷。
