Defects in the GnRH Neuronal Migration factor, CCDC141, Lead to Self-Limited Delayed Puberty

GnRH neuronal biology has been identified as a critical element in the pathogenesis of self-limited DP, previously implicated exclusively in the pathophysiology of idiopathic hypogonadotropic hypogonadism (IHH). We hypothesise that this condition may be inherited via genetic variants discoverable through whole-exome sequencing (WES), by focusing on genes involved in GnRH neuron development and function, and genes reported in IHH. We analysed WES data from large Finnish cohort with familial self-limited DP, focusing on genes recently reported in IHH. WES data of 100 DP families have been analysed with a total of 193 individuals: 100 probands, 158 affected and 35 unaffected family members. Potentially pathogenic rare variants segregating within cohort families were identified using a virtual panel of recently reported IHH genes (n=13). This analysis identified 6 rare potentially pathogenic variants in CCDC141 in 25 individuals of 8 families which account for almost 10% of self-limited DP cases in this cohort, without variants identified in cohort control cases. Previous studies reported that homozygous or compound heterozygous mutations of CCDC141 cause Kallmann syndrome and IHH, due to impaired GnRH neuronal migration. In this study, all 6 CCDC141 variants were heterozygous missense variants predicted to be deleterious by in silico prediction tools. Most probands were male (n=7) with typical features of self-limited DP, with absence of secondary sexual characteristics, delayed bone age, and low gonadotropins and sex steroids at first presentation and spontaneous entry into puberty later than age of 14 years without treatment. The majority of pedigrees displayed good segregation of variants with the DP trait, following an autosomal dominant inheritance pattern. However, in two families, there was a complex inheritance pattern with compound heterozygosity (p.Ser55Cys and p.Asp767Asn) and possible incomplete penetrance. In vitro study showed that the overexpression of four key CCDC141 variants in HEK293 cells delayed cell migration, 72% in p.Ser55Cys (p=0.04), 66% in p.Gln507His (p=0.04), 65% in p.Asp767Asn (p=0.02), and 83% in p.Ala1073Thr (p=0.01), when compared to WT (100%). Moreover, WT-overexpressed cells increased the rate of cell migration when compared to non-transfected cells (100% vs 65%, p=0.005), reaffirming that CCDC141 has a role in cell migration. In conclusion, heterozygous deficiency of CCDC141, previously reported to cause IHH, can cause self-limited DP due to abnormal GnRH migration during foetal development.