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. 2022 Dec;97(6):804-813.
doi: 10.1111/cen.14822. Epub 2022 Sep 30.

Genetic spectrum of Kallmann syndrome: Single-center experience and systematic review

Virendra A Patil  1 , Anurag Ranjan Lila  1 , Nalini Shah  1 , Sneha Arya  1 , Vijaya Sarathi  2 , Ravikumar Shah  1 , Swati S Jadhav  3 , Saba Samad Memon  1 , Manjiri Karlekar  1 , Tushar Bandgar  1
Affiliations

Genetic spectrum of Kallmann syndrome: Single-center experience and systematic review

Virendra A Patil et al. Clin Endocrinol (Oxf). 2022 Dec.

Abstract

Objective: To study phenotype-genotype data of Asian-Indian Kallmann syndrome (KS) from our center and systematically review the studies analyzing multiple congenital hypogonadotropic hypogonadism (CHH) genes in KS cohorts using next-generation sequencing.

Design, patients, measurement: Five hundred twenty-two KS probands (our center n = 78, published studies n = 444) were included in this systematic review. Molecular diagnosis was considered if the likely pathogenic/pathogenic variant in known CHH gene/s was reported in the appropriate allelic state. Varsome prediction tool (following American College of Medical Genetics standards) was used to analyze the variants.

Result: For our center, the molecular diagnosis was seen in 20.5% of probands and was seen more often with severe than partial reproductive phenotype (28.3% vs. 4%, p = .0013). Our center data adds eight novel variants. The molecular diagnosis was seen in 31% as per the systematic review and analysis. It ranged from 16.6% to 72.2% at different centers. The affected genes were FGFR1 (9.8%), ANOS1 (7.5%), PROKR2 (6.1%), CHD7 (5.4%), oligogenic (2.1%), and others <1% each (FGF8, SOX10, PROK2, SEMA3A, IL17RD, and GNRHR). FGFR1 and ANOS1 were the commonly affected genes globally, whereas PROKR2 was commonest in studies from China and CHD7 from Japan, South Korea and Poland.

Conclusion(s): This systematic review highlights that the genetic yield is 31% in KS probands, with distinct regional variations. The association of severe reproductive phenotype with the higher genetic yield needs further validation.

Keywords: Kallmann syndrome; genetics; molecular diagnosis; next-generation sequencing; oligogenicity; severe and partial reproductive phenotype.

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References

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