Abstract
Background/Objectives: Syndromic retinitis pigmentosa (SRP) presents a significant diagnostic challenge due to marked clinical and genetic heterogeneity. This study aimed to characterize the molecular spectrum of SRP in the previously understudied Bulgarian population, to define its regional allelic architecture and to relate the genetic findings to the main clinical forms of the disease. Methods: A single-centre, retrospective cohort study included 31 patients from 28 unrelated families diagnosed with SRP at the Department of Ophthalmology, University Hospital “Alexandrovska,” Sofia, Bulgaria. The clinical diagnosis was established by ophthalmological and systemic assessment. Molecular diagnosis was established using whole-exome sequencing of nuclear and mitochondrial DNA and/or targeted inherited retinal disease panel sequencing, complemented by copy number variation analysis. Variants were filtered according to rarity and sequencing quality and classified according to ACMG criteria. Results: The underlying etiology was resolved in all 31 patients across ten ciliary and mitochondrial loci (USH2A, USH1C, ADGRV1, CDH23, IFT54, BBS1, BBS4, BBS10, MKKS, and MT-ATP6). Usher syndrome accounted for 77.41% of cases, followed by Bardet–Biedl syndrome (16.13%), Senior-Løken syndrome spectrum (3.23%), and NARP syndrome (3.23%). Six novel variants were identified. A diagnostic latency of approximately 30 years was observed between the clinical diagnosis and the genetic verification, although the first manifestations, mostly extraocular (congenital hearing loss or polydactyly), appeared in childhood. The allelic landscape demonstrated regional enrichment of the Slavic founder USH2A variant p.(Trp3955*) and the p.(Gly3142*) nonsense variant, while the Western European c.2299delG allele was less prominent. Conclusions: This study defines the molecular spectrum of SRP in a Bulgarian cohort and demonstrates a distinct regional allelic architecture. Recognition of early extraocular manifestations and regional variant frequencies may facilitate earlier diagnosis, improve genetic counseling, and support multidisciplinary management and mutation-specific therapeutic approaches.