Atypical Biallelic Inheritance in “Dominant” Genes: Evidence From a Large‐Scale Consanguineus Exome Cohort

Exome sequencing (ES) has improved Mendelian disease diagnosis, but in consanguineous populations, biallelic variants in typically dominant genes remain underrecognized. This study characterized their clinical and molecular features and explored pathway-level patterns of dual inheritance. Exome data from 1450 individuals analyzed between 2022 and 2024 were retrospectively reviewed. Biallelic variants were filtered in genes annotated as autosomal dominant in OMIM. A pathway-based analysis using Gene Ontology and STRING identified functionally related genes, and those showing both dominant and recessive inheritance were further evaluated with gnomAD constraint metrics to explore shared mechanisms. Five consanguineous families carried biallelic variants in genes typically associated with dominant inheritance, accounting for ~3.1% of all homozygous pathogenic variants. Mechanisms included hypomorphic effects (TERC, ASH1L), semidominant dosage sensitivity (LRP5), structural or positional effects (FBN1), and complete loss of function with pleiotropy (SMAD6). Pathway analysis revealed dosage-sensitive dynamics in telomere maintenance, extracellular matrix, Wnt/BMP signaling, and histone modification, supporting dual-inheritance behavior driven by gene dosage and functional impact. Our findings show that genes labeled autosomal dominant can also cause disease biallelically, reflecting a dosage-sensitive continuum. Including such analyses in diagnostic pipelines, especially in consanguineous populations, can refine understanding of inheritance in rare disorders.