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While the role of single nucleotide variants (SNVs) in causal genes for Idiopathic Hypogonadotropic hypogonadism (IHH) is known, the contribution of copy number variants (CNVs) to IHH has not been systematically studied. Here, we examined the prevalence of CNVs in a large IHH cohort and their associated phenotypic spectrum. Methods: Exome sequencing (ES) from 1,441 IHH probands was analyzed using the GATK-gCNV pipeline to identify CNVs that spanned known IHH genes with a site frequency of &amp;lt;1%. ES data was also analyzed for rare SNVs in all IHH genes. IHH subjects were evaluated for reproductive and non-reproductive phenotypes (kidney, eye, cardiovascular, midline/ facial, bone and neurological abnormalities). Results: (i) CNV prevalence in IHH: Three percent of the IHH probands (46/1441 probands, 38 males and 8 females) harbored CNVs in 19/36 high confidence IHH genes (26 deletions 20 duplications). The vast majority of CNVs disrupted either the ANOS1 (26%) or FGFR1 (17%) genes. Intriguingly, CHD7 (a gene that carries SNVs in ~12% of our IHH subjects) did not harbor any CNVs. (ii) Phenotypic analysis: We found that CNVs were more common in IHH subjects with anosmia (Kallmann syndrome, N=33) compared to normosmic IHH (N=13). More than half of the subjects with CNVs affecting IHH genes carried at least 1 non-reproductive feature (26/46 IHH subjects, 56%). A syndromic presentation with multiple non-reproductive phenotypes was more common in IHH subjects harboring multigenic CNVs (IHH gene &amp; additional genes) compared to IHH subjects with single IHH gene CNV or SNV in a single IHH gene (61% vs. 12% or 18%, respectively; p 0.0006). Conclusions: CNVs in known IHH genes contribute to 3% of the IHH genetic architecture in our cohort. IHH subjects with larger multigenic CNVs displayed phenotypes consistent with contiguous gene syndromes. The absence of genic CNVs in genes frequently found to carry SNVs, such as CHD7, requires additional analysis to establish the biologic or mechanistic reasons for their rarity.

Contribution of Copy Number Variation in Idiopathic Hypogonadotropic Hypogonadism