Inherited retinal disease genes with dual inheritance patterns: insights from the IRD-PT registry.

Abstract

Background: Inherited retinal diseases (IRDs) typically follow a single inheritance pattern, but some genes cause disease through both autosomal recessive (AR) and autosomal dominant (AD) patterns, challenging genetic counselling. This study aims to identify dual inheritance genes in a Portuguese cohort and characterise the prevalence of each inheritance mode and associated phenotypes.

Methods: Cross-sectional study at Portugal's largest IRD referral centre. Genes reported with dual inheritance were identified through literature search and screened in IRD-PT registry. For each gene, AR versus AD proportion was determined and clinical features were analysed to establish genotype-phenotype correlations.

Results: Among 40 genes reported with dual inheritance, 22 were present in the IRD-PT registry and nine displayed both patterns (102 families, 141 patients). PRPH2 (95.0% AD) was associated with retinitis pigmentosa (RP) and macular dystrophies. ABCC6 (91.3% AR) was linked to pseudoxanthoma elasticum (PXE). BEST1 (91.7% AD) mainly caused Best disease, while PROM1 (76.9% AR) was linked to RP, macular dystrophy and cone-rod dystrophy. PRPF31 (88.9% AD) was exclusively associated with RP. IMPG2 (75.0% AR) and IMPG1 (87.5% AD) caused RP and adult-onset vitelliform macular dystrophy. NR2E3 (85.7% AR) was linked to enhanced S-cone syndrome and RP, and RP1 was detected in two families (one AR, one AD), presenting with RP.

Conclusions: Dual inheritance genes accounted for 12% of our genetic diagnoses. This spectrum, modulated by variant location and allele dosage, determines phenotypes and contributes to IRD heterogeneity. Deep phenotyping and comprehensive molecular diagnosis are essential for accurate genetic counselling and patient management.