Health Management Center, Xiangya Hospital Central South University, Changsha, Hunan, China.
Central South University School of Life Sciences, Changsha, Hunan, China.
J Med Genet. 2021 Jan;58(1):66-72. doi: 10.1136/jmedgenet-2019-106786. Epub 2020 May 10.
FGF8-FGFR1 signalling is involved in multiple biological processes, while impairment of this signalling is one of the main reasons for isolated hypogonadotropic hypogonadism (IHH). Recently, several negative modulators of FGF8-FGFR1 signalling were also found to be involved in IHH, including , , and . The aim of this study was to investigate the genotypic and phenotypic spectra of these genes in a large cohort of Chinese patients with IHH.
A total of 196 patients with IHH were enrolled in this study. Whole-exome sequencing was performed to identify variants, which was verified by PCR and Sanger sequencing.
Four heterozygous variants (p.S157I, p.R83Q, p.P188L and p.N355I) were found in six patients. Cryptorchidism, dental agenesis, syndactyly and blue colour blindness were commonly observed in patients with mutations. Six heterozygous variants (p.P191L, p.G35V, p.S671L, p.A221T, p.I329M and p.I329V) were found in seven patients. Segregation analysis indicated that 100% (5/5) of probands inherited the variants from their unaffected parents, and oligogenicity was found in 4/7 patients. One rare variant (p.T68S) was found in a female patient with Kallmann syndrome who also carried a mutation.
Our study greatly enriched the genotypic and phenotypic spectra of , and in IHH. Mutations in alone seem sufficient to cause IHH in an autosomal dominant manner, whereas or mutations may cause IHH phenotypes in synergy with variants in other IHH-associated genes.
FGF8-FGFR1 信号参与多种生物学过程，而该信号的损伤是孤立性促性腺激素低下性性腺功能减退症（IHH）的主要原因之一。最近，几种 FGF8-FGFR1 信号的负调节剂也被发现与 IHH 有关，包括、、和。本研究旨在调查这些基因在一大群中国 IHH 患者中的基因型和表型谱。
共纳入 196 例 IHH 患者。进行外显子组测序以鉴定变异，通过 PCR 和 Sanger 测序验证。
在 6 例患者中发现了 4 个杂合性 变异（p.S157I、p.R83Q、p.P188L 和 p.N355I）。突变患者常伴有隐睾、牙缺失、并指和蓝色色盲。在 7 例患者中发现了 6 个杂合性 变异（p.P191L、p.G35V、p.S671L、p.A221T、p.I329M 和 p.I329V）。分离分析表明，5/5 例先证者均从无症状父母遗传了 变异，4/7 例患者存在寡基因性。1 例携带 Kallmann 综合征的女性患者发现了一个罕见的 变异（p.T68S），同时还携带 突变。
本研究极大地丰富了 IHH 中、和的基因型和表型谱。单独的 突变似乎足以以常染色体显性方式引起 IHH，而 或 突变可能与其他 IHH 相关基因的变异协同引起 IHH 表型。
