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 CHHᵥd, a curated database. In parallel, we developed CHHᵥip, a custom-built computational pipeline for variant annotation and classification, which integrates data from CHHᵥd 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 CHHᵥd (publicly available) and reclassified using CHHᵥip according to ACMG/AMP guidelines and ClinGen SVI working group recommendations. Changes in classifications of clinical relevance from/to Pathogenic, Likely Pathogenic, or HighVUS (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 CHHᵥd, 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 CHHᵥip, a reproducible platform for compiling and interpreting variation data, may optimize the filtering and classification processes, thereby reducing diagnostic turnaround time.
Brunello et al. (Thu,) studied this question.