Regional genotypic variations in normosmic congenital hypogonadotropic hypogonadism: our experience and systematic review

PurposeTo 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.MethodsSixty-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.ResultAt 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.Conclusion(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.