SUN-125 - Deletions in Key Neurodevelopmental Genes Drive the Risk for Congenital Hypogonadotropic Hypogonadism .

Introduction: Rare copy number variants (CNVs, i.e. deletions and duplications that span > 50 base-pairs) have been shown to contribute to the genetic background of congenital hypogonadotropic hypogonadism (CHH). However, the impact of such CNVs in a disease cohort compared to reproductively healthy controls has not been investigated. In this study, we aim to define the contribution of rare CNVs (deletions and duplications) in 82 known CHH genes in a large CHH cohort (cases) compared to reproductively normal controls.

Methods: Whole exome sequencing (WES) data from 1,188 cases (813 males and 375 females) and 5,830 reproductively normal controls (3,041 males and 2,789 females) was joint-called and analyzed with the GATK-gCNV pipeline. WES data was investigated for rare CNVs [minor allele frequency (MAF) < 1%] in 82 known CHH genes.

Results: Cases were significantly enriched for rare CNVs in the known CHH genes compared to controls. In detail, we identified 23 probands (~2% of the cohort) with rare CNVs in known CHH genes compared to 26 controls (0.4% of the cohort) (23/1188 vs. 26/5830, OR 4.4, CI 2.5 to 7.7, p = 3.57e-6). Apart from 1 CHH proband who harbored 2 CNVs (1 deletion and 1 duplication) in 2 different CHH genes, all other cases carried a rare CNV affecting 1 CHH gene. CHH probands were enriched for rare deletions in CHH known genes compared to controls (17/1,188 cases vs. 3/5,830 controls, OR 28.1, CI 8.2 to 96.3, p = 4.76e-11), but not for rare duplications (7/1,188 cases vs. 23/5,830 controls, OR 1.4, CI 0.6 to 3.4, p = 0.35). Among the 23 probands with rare CNVs, 16 were males and 7 were females, while 17 were diagnosed with anosmia (13 males and 4 females) and 6 had normosmic CHH (4 males and 3 females). Interestingly, the genes affected by the rare deletions in the cases differed from the ones that were affected in the controls. Specifically, cases harbored rare deletions in ANOS1 (N=6), FGFR1 (N=5), EMX2 (N=1), GNRHR (N=1), NDNF (N=1) SIN3A (N=1), TCF12 (N=1) and WDR11 (N=1). However, the controls only harbored rare deletions in SEMA3A (N=1), TCF12 (N=1) and NTN1 (N=1).


Conclusions: Rare CNVs in known CHH genes are significantly enriched in probands with CHH compared to reproductively normal controls, with deletions driving this association. The higher prevalence of CNVs in males compared to females can be attributed to the high frequency or rare chrX deletions spanning ANOS1. Similarly, the high occurrence of anosmia among the probands likely reflects the high frequency of deletions in CHH neurodevelopmental genes, including ANOS1 and FGFR1. Finally, the marked predominance of rare deletions affecting ANOS1 and FGFR1, together with the absence of such variants in the controls, is consistent with the strong negative selection against loss of these genes in the general population and highlights their essential role in human reproductive function.

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