Department of Endocrinology, Seth G S Medical College and KEM Hospital, Parel, Mumbai, 400012, Maharashtra, India.
Clinical and Molecular Genetics, Kamalnayan Bajaj Hospital, Aurangabad, India.
Pituitary. 2022 Jun;25(3):444-453. doi: 10.1007/s11102-022-01209-z. Epub 2022 Feb 8.
To describe phenotype-genotype data of Asian-Indian normosmic congenital hypogonadotropic hypogonadism (nCHH) from our centre and perform a systematic review of genetic studies using next-generation sequencing (NGS) in nCHH.
Sixty-eight nCHH probands from our center, and 370 nCHH probands from published studies were included. Per-patient genetic variants were analyzed as per ACMG guidelines. Molecular diagnosis was defined as presence of a pathogenic or likely pathogenic variant in a known CHH gene following zygosity status as per known mode of genetic inheritance.
At our centre molecular diagnosis was observed in 35.3% of probands {GNRHR:16.2%, FGFR1:7.3%, KISS1R:4.4%, GNRH1:2.9%, TACR3:2.9%, CHD7:1.4%}. Molecular diagnosis was observed more often (44.7% vs 14.3%, p = 0.026) with severe than partial reproductive-phenotype. The study adds 12 novel variants and suggests GNRHR p.Thr32Ala variant may have a founder effect. In per-patient systematic review (including our cohort), the molecular diagnosis was reached in 23.2%, ranging from 3.5 to 46.7% at different centers. The affected genes were FGFR1:6.4%, GNRHR:4.3%, PROKR2:3.6%, TACR3:1.8%, CHD7:1.6%, KISS1R:1.4%, GNRH1:1.4% and others (PROK2, SOX3, SOX10, SOX11, IL17RD, IGSF10, TAC3, ANOS1, oligogenic): < 1% each. FGFR1 was the most commonly affected gene in most cohorts except Asia, whereas PROKR2 (in China and Japan) and GNRHR (in India) were the commonest.
(s): The global molecular diagnosis rate was 23.2% in nCHH cohorts whereas that in our cohort was 35% with a higher rate (44.7%) in those with severe reproductive-phenotype. The most commonly affected gene in nCHH patients was FGFR1 globally while it was PROKR2 in East Asia and GNRHR in India.
描述我们中心亚洲印度正常体型先天性促性腺激素低下性性腺功能减退症（nCHH）的表型-基因型数据，并对使用下一代测序（NGS）进行 nCHH 的遗传研究进行系统综述。
纳入了来自我们中心的 68 名 nCHH 先证者和来自已发表研究的 370 名 nCHH 先证者。根据 ACMG 指南分析每位患者的遗传变异。分子诊断定义为在已知的 CHH 基因中存在致病性或可能的致病性变异，同时根据已知的遗传模式确定同卵性状态。
在我们中心，35.3%的先证者（GNRHR：16.2%，FGFR1：7.3%，KISS1R：4.4%，GNRH1：2.9%，TACR3：2.9%，CHD7：1.4%）得到了分子诊断。具有严重生殖表型的先证者中（44.7%比 14.3%，p=0.026），分子诊断的发生率更高。该研究增加了 12 个新变异，并表明 GNRHR p.Thr32Ala 变异可能存在创始效应。在每位患者的系统综述（包括我们的队列）中，在不同中心，分子诊断率为 23.2%，范围为 3.5%至 46.7%。受影响的基因包括 FGFR1：6.4%，GNRHR：4.3%，PROKR2：3.6%，TACR3：1.8%，CHD7：1.6%，KISS1R：1.4%，GNRH1：1.4%和其他基因（PROK2、SOX3、SOX10、SOX11、IL17RD、IGSF10、TAC3、ANOS1、多基因）：每个基因都<1%。FGFR1 是大多数队列中最常受影响的基因，除了亚洲，而在亚洲，PROKR2（在中国和日本）和 GNRHR（在印度）是最常见的。
（s）在 nCHH 队列中，全球分子诊断率为 23.2%，而我们队列中的诊断率为 35%，具有严重生殖表型的患者的诊断率更高（44.7%）。在 nCHH 患者中，最常受影响的基因是 FGFR1 ，在全球范围内，而在东亚是 PROKR2，在印度是 GNRHR。
