Abstract
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.
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Acknowledgements
Clinical Exome Sequencing was performed at GenePath Diagnostics, Pune, India.
Funding
Ministry of Science and Technology, Department of Biotechnology, Government of India. (Grant -No.BT/PR8388/MED/12/620/2013).
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Contributors: NSS, ARL, and TRB conceived the idea and designed the study. VAP and NSS wrote the first draft of the report with input from ARL, SA, SJ, and TRB. AVE provided an expert review of the genetic results. VS, SJ, and SM accessed and verified the data, VAP and RS performed the statistical analysis which was verified by NSS and ARL. VAP, RS, ARL, NSS, TRB were involved in the management of patients and data collection. NSS, ARL, SM, SA, and TRB supervised the entire data collection and management and provided inputs in the revision of the draft. All the authors were involved in the critical revision of the manuscript.
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All procedures involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by Institutional Ethics Committee III of Seth G S Medical College and KEM hospital (EC/159/2009). There was no role or influence of the funder in study design, collection, analysis, and interpretation of data, writing of the report, or submission of the report for publication.
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Patil, V.A., Lila, A.R., Shah, N. et al. Regional genotypic variations in normosmic congenital hypogonadotropic hypogonadism: our experience and systematic review. Pituitary 25, 444–453 (2022). https://doi.org/10.1007/s11102-022-01209-z
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DOI: https://doi.org/10.1007/s11102-022-01209-z