Triallelic Inheritance in Bardet-Biedl Syndrome, a Mendelian Recessive Disorder

TLDR

Bardet‑Biedl syndrome is a genetically heterogeneous autosomal recessive disorder presenting with retinal dystrophy, polydactyly, obesity, developmental delay, and renal defects, and recent cloning has identified BBS2 and BBS6 as implicated genes. The study proposes that Bardet‑Biedl syndrome may be a triallelic disease requiring three mutant alleles for manifestation. The authors screened 163 BBS families for BBS2 and BBS6 mutations, finding three mutant alleles in affected individuals across four pedigrees. The study identified unaffected carriers with two BBS2 mutations but no BBS6 mutation and concluded that a triallelic inheritance model may be crucial for understanding both Mendelian and multifactorial disorders.

Abstract

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized by multiple clinical features that include pigmentary retinal dystrophy, polydactyly, obesity, developmental delay, and renal defects. BBS is considered an autosomal recessive disorder, and recent positional cloning efforts have identified two BBS genes (BBS2 and BBS6). We screened our cohort of 163 BBS families for mutations in both BBS2 and BBS6 and report the presence of three mutant alleles in affected individuals in four pedigrees. In addition, we detected unaffected individuals in two pedigrees who carry two BBS2 mutations but not a BBS6 mutation. We therefore propose that BBS may not be a single-gene recessive disease but a complex trait requiring three mutant alleles to manifest the phenotype. This triallelic model of disease transmission may be important in the study of both Mendelian and multifactorial disorders.