Updated compendium of genes and variants associated with congenital hypogonadotropic hypogonadism: systematic review, classification pipeline, and network analysis

To advance the understanding of Congenital Hypogonadotropic Hypogonadism (CHH), we aimed to refine the catalog of causal genes and variants. We systematically collected variants reported in the literature and created CHH_vd, a curated database. In parallel, we developed CHH_vip, a custom-built computational pipeline for variant annotation and classification, which integrates data from CHH_vd and external sources. Gene network and term enrichment analyses were applied to generate disease-specific gene panels. Our systematic review retrieved 352 scientific studies, documenting 1937 patients carrying a total of 2603 variants, of which 1518 were unique, distributed across 143 genes. All variants were incorporated into CHH_vd (publicly available) and reclassified using CHH_vip according to ACMG/AMP guidelines and ClinGen SVI working group recommendations. Changes in classifications of clinical relevance [from/to Pathogenic, Likely Pathogenic, or High_VUS (Variant of Uncertain Significance with High Probability of Pathogenicity)] were identified for 238 variants when comparing with InterVar, a bioinformatics tool for clinical interpretation of genetic variants. The genes GNRHR, ANOS1, PLXNA1, and SEMA7A were particularly implicated in pathogenicity reassignment, having a comparatively high number of variants downgraded (to more benign). Through CHH_vd, we provide an updated view of the genes impacted by genetic variation in CHH, highlighting marked genetic heterogeneity. The implementation of curated gene panels, combined with CHH_vip, a reproducible platform for compiling and interpreting variation data, may optimize the filtering and classification processes, thereby reducing diagnostic turnaround time.