Genetics of Kallmann syndrome: Single-center Experience with Review of NGS based Genetic Studies

Abstract Purpose: To describe phenotype-genotype data of Asian-Indian Kallmann syndrome (KS) from our center and perform a systematic review of genetic studies using next-generation sequencing (NGS) in KS. Methods: Seventy-eight KS probands from our center and 398 probands from published studies were included. Per-patient genetic variants were analyzed as per ACMG-guidelines. Molecular diagnosis was defined as the presence of pathogenic or likely pathogenic variant(s) in known CHH gene/s following zygosity status as per the known mode of genetic inheritance. Result: Molecular diagnosis at our center was observed in 20.5% probands ( ANOS1 :10.2%, FGFR1 : 6.4%, PROKR2 : 2.5%, and PROK2 , SOX10 , FGF8 , GNRHR : 1.3% each). Molecular diagnosis was reached more often in patients with severe than partial reproductive phenotype (28.3% vs. 4%, p=0.0013). Our center adds eight novel variants. In a per-patient systematic review (including our cohort), the molecular diagnosis was reached in 30.8%, ranging from 16.6-72.2% at different centers. The affected genes were FGFR1 (9.6%), ANOS1 (7.7%), PROKR2 (6.5%), CHD7 (4.6%), oligogenic (1.9%), FGF8 (1%), SOX10 (1%), and others ( PROK2 , SEMA3A, IL17RD , GNRHR :<1% each). FGFR1 was the most commonly affected gene in most cohorts except Asia and Brazil, where PROKR2 (in China and Japan) and ANOS1 (in India and Brazil) were the commonest. Conclusion(s): The global molecular diagnosis rate was 30.8% in KS cohorts whereas that in our cohort was 20.5% with a higher rate (28.3%) in those with severe reproductive phenotype. The most commonly affected gene in KS patients was FGFR1 globally, PROKR2 in East Asia, and ANOS1 in India and Brazil.