Shima Hirohito, Tokuhiro Etsuro, Okamoto Shingo, Nagamori Mariko, Ogata Tsutomu, Narumi Satoshi, Nakamura Akie, Izumi Yoko, Jinno Tomoko, Suzuki Erina, Fukami Maki
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 157-8535 Tokyo, Japan.
Department of Pediatrics, Fujisawa City Hospital, 251-8550, Fujisawa, Japan.
J Endocr Soc. 2021 Mar 30;5(7):bvab056. doi: 10.1210/jendso/bvab056. eCollection 2021 Jul 1.
Kallmann syndrome (KS) is a genetically heterogeneous condition characterized by hypogonadotropic hypogonadism (HH) and olfactory dysfunction. Although , a causative gene for Waardenburg syndrome (WS) and peripheral demyelinating neuropathy, central demyelination, WS, and Hirschsprung disease (PCWH) has previously been implicated in KS, the clinical significance of variants as the cause of KS remains uncertain.
A total of 117 patients with KS underwent mutation screening of and 14 other causative genes for KS/HH. Rare variants were subjected to in silico and in vitro analyses. We also examined clinical data of the patients and their parents with variants.
Sequence analysis identified 2 heterozygous variants of (c.1225G > T, p.Gly409* and c.475C > T, p.Arg159Trp) in patients 1-3, as well as in the parents of patients 1 and 3. The variants were assessed as pathogenic/likely pathogenic, according to the American College of Medical Genomics guidelines. Both variants lacked in vitro transactivating activity for the promoter and exerted no dominant-negative effects. Patients 1-3 carried no pathogenic variants in other genes examined. The patients presented with typical KS, while such features were absent in the parents of patients 1 and 3. None of the 5 variant-positive individuals exhibited hypopigmentation, while 1 and 2 individuals exhibited complete and partial hearing loss, respectively.
These results provide evidence that haploinsufficiency accounts for a small percentage of KS cases. haploinsufficiency is likely to be associated with a broad phenotypic spectrum, which includes KS without other clinical features of WS/PCWH.
卡尔曼综合征（KS）是一种具有遗传异质性的疾病，其特征为低促性腺激素性性腺功能减退（HH）和嗅觉功能障碍。尽管先前有研究表明，瓦登伯革综合征（WS）和周围性脱髓鞘性神经病、中枢性脱髓鞘、WS及先天性巨结肠（PCWH）的致病基因与KS有关，但作为KS病因的该基因变异的临床意义仍不明确。
共117例KS患者接受了该基因及其他14个KS/HH致病基因的突变筛查。对罕见的该基因变异进行了计算机模拟和体外分析。我们还检查了携带该基因变异的患者及其父母的临床资料。
序列分析在患者1 - 3以及患者1和3的父母中鉴定出该基因的2个杂合变异（c.1225G > T，p.Gly409*和c.475C > T，p.Arg159Trp）。根据美国医学基因组学学会的指南，这些变异被评估为致病/可能致病。这两个变异均缺乏对该基因启动子的体外反式激活活性，且未表现出显性负效应。患者1 - 3在其他检测基因中未携带致病变异。患者表现出典型的KS症状，而患者1和3的父母没有这些特征。5名变异阳性个体中无人出现色素减退，而分别有1人和2人出现完全性和部分性听力丧失。
这些结果提供了证据，表明该基因单倍体不足占KS病例的比例较小。该基因单倍体不足可能与广泛的表型谱相关，其中包括无WS/PCWH其他临床特征的KS。
