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

Purpose 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. Methods 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. Result 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. 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.