Pathogenic mosaic variants in congenital hypogonadotropic hypogonadism



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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Fig. 1: Pathogenic mosaic variants and copy-number variants (CNVs) in congenital hypogonadotropic hypogonadism (CHH) patients.
Fig. 2: Transcription reporter activity of FGFR1 WT and G348R.
Fig. 3: Gene schematic for regions surrounding mosaic variants and copy-number variants (CNVs).


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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.).

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Correspondence to Nelly Pitteloud MD.

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Acierno, J.S., Xu, C., Papadakis, G.E. et al. Pathogenic mosaic variants in congenital hypogonadotropic hypogonadism. Genet Med (2020).

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  • hypogonadotropic hypogonadism
  • postzygotic mosaicism
  • copy-number variation
  • FGFR1
  • CHD7