Congenital hypogonadotropic hypogonadism (CHH (MIM161110)) due to GnRH deficiency is a rare genetic disorder (affects ~1/30 000) characterised by abnormal pubertal development and infertility. Over 60% cases have anosmia (Kallmann syndrome) and some exhibit additional phenotypes. CHH is a genetically heterogeneous developmental disease. Most cases present sporadically, although familial forms (AD, AR, and X-linked) with incomplete penetrance and variable expressivity occur. Research suggests it is emerging as a digenic or oligogenic disease, rather than a monogenic trait. Genetic testing for this condition has hitherto been costly, time-consuming and incomplete, with mutations identified in <30%.
In this study, we investigated three simplex cases (2M with partial anosmia, 1F) who presented with delayed puberty and hypogonadism due to isolated GnRH deficiency. Whole exome sequencing (WES) was performed on each patient using the Illumina HiSeq2500 platform and the Agilent SureSelect Human All Exon v5 Kit. Following alignment to the human genome, an in-house pipeline applied a virtual panel to restrict the genes to be analysed based on the clinical presentation (22 CHH genes). Variants were filtered to identity potential pathogenic mutations, which were subsequently confirmed by Sanger sequencing.
Results: Seven variants in four CHH genes (FGFR1, GNRHR, HS6ST1 and IL17RD) were identified. One case had four separate variants in total. Variants in these genes are recognised to result in deficient GnRH activity, confirming that a Kallmann phenotype can result from mutations in CHH genes other than KAL1.
Conclusion: We demonstrate that WES, with analysis limited to relevant genes, can successfully and efficiently confirm a molecular diagnosis in a genetically and phenotypically complex disease, such as CHH. Further studies will increase our understanding of the functional consequence of gene variants, to help inform prognosis, enable family studies and timely intervention. In the future it may inform choice of optimal treatment.