Ocular phenotypes of three genetic variants of Bardet–Biedl syndrome

Abstract

Bardet-Biedl syndrome is a genetically heterogeneous multisystem disorder that causes severe visual impairment. Retinitis pigmentosa (RP), hypogonadism, digit and renal anomalies, obesity, and a variable degree of mental retardation characterize the disorder. Eight different loci have been identified on 2q31(BBS5), 3p13 (BBS3), 4q27 (BBS7), 11q13 (BBS1), 14q32 (BBS8), 15q22.3 (BBS4), 16q21 (BBS2), and 20p12 (BBS6). The ocular manifestations of Bardet-Biedl syndrome include an early and severe rod-cone dystrophy causing legal blindness in the second decade. Features of systemic phenotypic variability were proposed to distinguish patients mapped to either the BBS2, BBS3, or BBS4 loci but no phenotype-genotype correlation has been established for the ocular phenotype. We studied the three original families used for the identification of BBS2, BBS3, and BBS4 loci to define the ocular phenotypes of patients (n = 34) and obligate carriers (n = 32) using clinical examination and electroretinography (ERG). RP was severe and early in all cases. Myopia was associated with BBS3 and BBS4, but not BBS2. One patient with Bardet-Biedl syndrome also had iris and chorioretinal colobomata, features suggestive of Biemond syndrome.

Bardet–Biedl syndrome

“…39,40 Genotype-phenotype correlation Genotype-phenotype correlations are poor, although one study suggests a milder phenotype associated with the common M390R mutation found in BBS1. 15 Other studies have suggested that specific ocular phenotypes 41,42 and more severe digital abnormalities 42 may be linked to BBS2, BBS3 and BBS4 mutations. Large-scale studies have not supported these findings, and predictions about correlation are further compounded by the significant interfamilial and intrafamilial phenotypic variability.…”

Bardet–Biedl syndrome: Is it only cilia dysfunction?

“…Having said that, thorough analyzes of different BBS patient cohorts and animal models are demonstrating subtle differences in disease presentation that are likely due to specific functions of different BBS proteins. For example, studies suggest that mutations in BBS2, BBS3 and BBS4 are associated with characteristic ocular phenotypes [15,16] and patients bearing mutations in BBS16/SDCCAG8 are characterized by highly penetrant renal disease but do not present with polydactyly [13]. Similarly, patients with mutations in BBS6, BBS10 or BBS12 present with a more severe renal phenotype [17].…”

Bardet-Biedl Syndrome

“…Furthermore, the mechanistic basis for the pathogenic impact of heterozygous mutations remains largely elusive. The existing statistics may be compromised by the fact that the majority of available studies put both protein-truncating and presumably pathogenic missense mutations in one basket, Nonsyndromic retinitis pigmentosa [Shevach et al, 2015] BBS3 (ARL6, RP55), 3q11.2 [Sheffield et al, 1994;Chiang et al, 2004;Fan et al, 2004] 0.4% higher frequency in India (18%) [Sathya Priya et al, 2014] Small GTPase, participates in BBSome assembly c.272T>C (p.I91T), India [Sathya Priya et al, 2014] Myopia was associated with BBS3 and BBS4, but not BBS2 mutations [Héon et al, 2005] Nonsyndromic retinitis pigmentosa [Aldahmesh et al, 2009] BBS4, 15q22.3q23 [Carmi et al, 1995;Mykytyn et al, 2001 or BBS12 genes had more severe renal disease [Imhoff et al, 2011] BBS11 (TRIM32, HT2A, LGMD2H, TATIP), 9q31q34.1 [Chiang et al, 2006] 0.1%…”