A comprehensive overview of genetic mutations in Iranian patients with Bardet-Biedl syndrome

Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive ciliopathy characterized by pleiotropic clinical manifestations including retinal degeneration, obesity, polydactyly, intellectual disability, renal abnormalities, and hypogenitalism. Significant genetic heterogeneity exists, with over 20 genes implicated in its pathogenesis. This study provides a comprehensive overview of the genetic mutations identified in a cohort of Iranian patients with BBS.

A total of 26 unrelated Iranian patients clinically suspected of BBS were enrolled. Whole-exome sequencing (WES) was performed on an Illumina HiSeq4000 platform.

Causative or potentially causative variants were identified in all 26 probands across 13 distinct genes. The most frequently mutated gene was BBS10 (n = 3), followed by BBS2 (n = 3), BBS5 (n = 3), BBS12 (n = 3), and CEP290 (n = 3). Other affected genes included BBS1 (n = 2), SDCCAG8 (n = 2), and single cases involving BBIP1, BBS7, TTC8, MKS1, IFT172, TRIM32, and GRID2. All identified variants followed an autosomal recessive pattern, with 15 variants classified as pathogenic, 5 as likely pathogenic, and 7 as variants of uncertain significance (VUS). Consanguinity was present in 88.4% of families, consistent with the high rate of homozygous mutations observed. One patient (Case 5) exhibited a dual diagnosis with a homozygous pathogenic variant in GJB2 associated with autosomal recessive deafness.

This study expands the mutational spectrum of BBS in the Iranian population, highlighting the predominance of BBS2, BBS5 and BBS10 pathogenic/likely pathogenic variants. WES can provide a high diagnostic yield and represent an effective first-line or early diagnostic approach in clinically suspected genetically heterogeneous BBS/ciliopathy cases, particularly where appropriate CNV analysis is included. The high rate of consanguinity underscores the importance of homozygous variant detection. These findings facilitate accurate genetic counseling, enable carrier screening in at-risk families, and support the development of targeted molecular diagnostic strategies for BBS in Iran.