Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder resulting in absent puberty and infertility. The genetic architecture is complex with multiple loci involved, variable expressivity, and incomplete penetrance. The majority of cases are sporadic, consistent with a disease affecting fertility. The current study aims to investigate mosaicism as a genetic mechanism for CHH, focusing on de novo rare variants in CHH genes.
We evaluated 60 trios for de novo rare sequencing variants (RSV) in known CHH genes using exome sequencing. Potential mosaicism was suspected among RSVs with altered allelic ratios and confirmed using customized ultradeep sequencing (UDS) in multiple tissues.
Among the 60 trios, 10 probands harbored de novo pathogenic variants in CHH genes. Custom UDS demonstrated that three of these de novo variants were in fact postzygotic mosaicism—two in FGFR1 (p.Leu630Pro and p.Gly348Arg), and one in CHD7 (p.Arg2428*). Statistically significant variation across multiple tissues (DNA from blood, buccal, hair follicle, urine) confirmed their mosaic nature.
We identified a significant number of de novo pathogenic variants in CHH of which a notable number (3/10) exhibited mosaicism. This report of postzygotic mosaicism in CHH patients provides valuable information for accurate genetic counseling.
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Bouvattier C, Maione L, Bouligand J, Dode C, Guiochon-Mantel A, Young J. Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism. Nat Rev Endocrinol. 2011;8:172–182.
Grumbach MM. A window of opportunity: the diagnosis of gonadotropin deficiency in the male infant. J Clin Endocrinol Metab. 2005;90:3122–3127.
Xu C, Lang-Muritano M, Phan-Hug F, et al. Genetic testing facilitates prepubertal diagnosis of congenital hypogonadotropic hypogonadism. Clin Genet. 2017;92:213–216.
Maione L, Dwyer AA, Francou B, et al. Genetics in endocrinology: genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing. Eur J Endocrinol. 2018;178:R55–R80.
Cangiano B, Swee DS, Quinton R, Bonomi M. Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease. Hum Genet. 2020 Mar 21; https://doi.org/10.1007/s00439-020-02147-1 [Epub ahead of print].
Cassatella D, Howard SR, Acierno JS, et al. Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures. Eur J Endocrinol. 2018;178:377–388.
Sykiotis GP, Plummer L, Hughes VA, et al. Oligogenic basis of isolated gonadotropin-releasing hormone deficiency. Proc Natl Acad Sci USA. 2010;107:15140–15144.
Waldstreicher J, Seminara SB, Jameson JL, et al. The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in the human. J Clin Endocrinol Metab. 1996;81:4388–4395.
Acuna-Hidalgo R, Veltman JA, Hoischen A. New insights into the generation and role of de novo mutations in health and disease. Genome Biol. 2016;17:241.
Acuna-Hidalgo R, Bo T, Kwint MP, et al. Post-zygotic point mutations are an underrecognized source of de novo genomic variation. Am J Hum Genet. 2015;97:67–74.
Wright CF, Prigmore E, Rajan D, et al. Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data. Nat Commun. 2019;10:2985.
Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med. 1991;325:1688–1695.
Plant KE, Boye E, Green PM, Vetrie D, Flinter FA. Somatic mosaicism associated with a mild Alport syndrome phenotype. J Med Genet. 2000;37:238–239.
Okajima K, Warman ML, Byrne LC, Kerr DS. Somatic mosaicism in a male with an exon skipping mutation in PDHA1 of the pyruvate dehydrogenase complex results in a milder phenotype. Mol Genet Metab. 2006;87:162–168.
Boehm U, Bouloux PM, Dattani MT, et al. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2015;11:547–564.
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–424.
McNulty SN, Evenson MJ, Corliss MM, et al. Diagnostic utility of next-generation sequencing for disorders of somatic mosaicism: a five-year cumulative cohort. Am J Hum Genet. 2019;105:734–746.
Santoni FA, Makrythanasis P, Nikolaev S, et al. Simultaneous identification and prioritization of variants in familial, de novo, and somatic genetic disorders with VariantMaster. Genome Res. 2014;24:349–355.
Villanueva C, Jacobson-Dickman E, Xu C, et al. Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations. Genet Med. 2015;17:651–659.
Rahbari R, Wuster A, Lindsay SJ, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–133.
Balasubramanian R, Choi JH, Francescatto L, et al. Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency. Proc Natl Acad Sci USA. 2014;111:17953–17958.
Nagy E, Maquat LE. A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem Sci. 1998;23:198–199.
Xu C, Cassatella D, van der Sloot AM, et al. Evaluating CHARGE syndrome in congenital hypogonadotropic hypogonadism patients harboring CHD7 variants. Genet Med. 2018;20:872–881.
Wang F, Zhao S, Xie Y, Yang W, Mo Z. De novo SOX10 nonsense mutation in a patient with Kallmann syndrome, deafness, iris hypopigmentation, and hyperthyroidism. Ann Clin Lab Sci. 2018;48:248–252.
Suzuki E, Yatsuga S, Igarashi M, et al. De novo frameshift mutation in fibroblast growth factor 8 in a male patient with gonadotropin deficiency. Horm Res Paediatr. 2014;81:139–144.
Jongmans MC, van Ravenswaaij-Arts CM, Pitteloud N, et al. CHD7 mutations in patients initially diagnosed with Kallmann syndrome-the clinical overlap with CHARGE syndrome. Clin Genet. 2009;75:65–71.
Zenaty D, Bretones P, Lambe C, et al. Paediatric phenotype of Kallmann syndrome due to mutations of fibroblast growth factor receptor 1 (FGFR1). Mol Cell Endocrinol. 2006;254-255:78–83.
Stamou MI, Cox KH, Crowley WF Jr. Discovering genes essential to the hypothalamic regulation of human reproduction using a human disease model: adjusting to life in the “-omics” era. Endocr Rev. 2016;2016:4–22.
Courage C, Jackson CB, Owczarek-Lipska M, et al. Novel synonymous and missense variants in FGFR1 causing Hartsfield syndrome. Am J Med Genet A. 2019;179:2447–2453.
Dhamija R, Kirmani S, Wang X, et al. Novel de novo heterozygous FGFR1 mutation in two siblings with Hartsfield syndrome: a case of gonadal mosaicism. Am J Med Genet A. 2014;164A:2356–2359.
Sato N, Ohyama K, Fukami M, Okada M, Ogata T. Kallmann syndrome: somatic and germline mutations of the fibroblast growth factor receptor 1 gene in a mother and the son. J Clin Endocrinol Metab. 2006;91:1415–1418.
Bartels CF, Scacheri C, White L, Scacheri PC, Bale S. Mutations in the CHD7 gene: the experience of a commercial laboratory. Genet Test Mol Biomarkers. 2010;14:881–891.
We are grateful to the patients and family members who participated in this research study by donating their samples, medical history, and time. We also thank Alexia Boizot for her technical and laboratory assistance. This work was supported by the Swiss National Science Foundation Project SNF 310030_173260 (to N.P.).
The authors declare no conflicts of interest.
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Acierno, J.S., Xu, C., Papadakis, G.E. et al. Pathogenic mosaic variants in congenital hypogonadotropic hypogonadism. Genet Med (2020). https://doi.org/10.1038/s41436-020-0896-0
- hypogonadotropic hypogonadism
- postzygotic mosaicism
- copy-number variation