How human genetic context can inform pathogenicity classification: FGFR1 variation in idiopathic hypogonadotropic hypogonadism

AbstractPrecision medicine requires precise genetic variant interpretation, yet many disease-associated genes have unresolved variants of unknown significance (VUS). We analyzed variants in a well-studied gene,FGFR1, a common cause of Idiopathic Hypogonadotropic Hypogonadism (IHH) and examined whether regional genetic enrichment of missense variants could improve variant classification.FGFR1 rare sequence variants (RSVs) were examined in a large cohort to (i) define regional genetic enrichment, (ii) determine pathogenicity based on the American College of Medical Genetics/Association for Molecular Pathology (ACMG/AMP) variant classification framework, and (iii) characterize the phenotype ofFGFR1 variant carriers by variant classification. A total of 143FGFR1 RSVs were identified in 175 IHH probands (n = 95 missense,n = 48 protein-truncating variants).FGFR1 missense RSVs showed regional enrichment across biologically well-defined domains: D1, D2, D3, and TK domains and linker regions (D2 –D3, TM–TK). Using these defined regions of enrichment to augment the ACMG/AMP classification reclassifies 37% (20/54) ofFGFR1 missense VUS as pathogenic or likely pathogenic (PLP). Non-proband carriers ofFGFR1 missense VUS variants that were reclassified as PLP were more likely to express IHH or IHH-associated phenotypes [anosmia or delayed puberty] than non-proband carriers ofFGFR1 missense variants that remained as VUS (76.9% vs 34.7%,p = 0.035). Using the largest cohort ofF...
Source: Human Genetics - Category: Genetics & Stem Cells Source Type: research