Clinical and genetic characterization of Bardet–Biedl syndrome in Tunisia: defining a strategy for molecular diagnosis

Abstract

Bardet-Biedl syndrome (BBS, OMIM 209900) is a rare genetic disorder characterized by obesity, retinitis pigmentosa, post axial polydactyly, cognitive impairment, renal anomalies and hypogonadism. The aim of this study is to provide a comprehensive clinical and molecular analysis of a cohort of 11 Tunisian BBS consanguineous families in order to give insight into clinical and genetic spectrum and the genotype-phenotype correlations. Molecular analysis using combined sequence capture and high-throughput sequencing of 30 ciliopathies genes revealed 11 mutations in 11 studied families. Five mutations were novel and six were previously described. Novel mutations included c.1110G>A and c.39delA (p.G13fs*41) in BBS1, c.115+5G>A in BBS2, c.1272+1G>A in BBS6, c.1181_1182insGCATTTATACC in BBS10 (p.S396Lfs*6). Described mutations included c.436C>T (p.R146*) and c.1473+4A>G in BBS1, c.565C> (p.R189*) in BBS2, deletion of exons 4-6 in BBS4, c.149T>G (p.L50R) in BBS5, and c.459+1G>A in BBS8; most frequent mutations were described in BBS1 (4/11, 37%) and BBS2 (2/11, 18%) genes. No phenotype-genotype correlation was evidenced. This data expands the mutations profile of BBS genes in Tunisia and suggests a divergence of the genetic spectrum comparing Tunisian and other populations.

Meta‐analysis of genotype‐phenotype associations in Bardet‐Biedl syndrome uncovers differences among causative genes

“…The literature search was performed according to the protocol preregistered in Prospero (CRD42018096099) and it followed the PRISMA guidelines whenever applicable (Table S1 and Figure S1). In total, we identified 85 relevant studies (Abu Safieh et al, ; Agha et al, ; Ajmal et al, ; Al‐Hamed et al, ; Alazami et al, ; Aldahmesh et al, ; Azari et al, ; Badano, ; Baker et al, ; Bee, Chawla, & Zhao, ; Bennouna‐Greene et al, ; Billingsley et al, ; Billingsley, Vincent, Deveault, & Heon, ; Branfield Day et al, ; Braun et al, ; Bujakowska et al, ; Castro‐Sanchez et al, ; Chaki et al, ; Chul Yoon et al, ; Cox et al, ; Davies, ; Deveault et al, ; Ece Solmaz et al, ; Esposito et al, ; Estrada‐Cuzcano, Koenekoop, et al, ; Estrada‐Cuzcano, Neveling, et al, ; Fan et al, ; Fattahi et al, ; Fedick et al, ; Frank et al, ; Gerth, Zawadzki, Werner, & Heon, ; Ghadami et al, ; González‐del Pozo et al, ; Harville et al, ; Heon et al, ; Hjortshoj, Gronskov, Brondum‐Nielsen, & Rosenberg, ; Hjortshoj et al, ; Hulleman et al, ; Iannaccone et al, ; Innes et al, ; Iurian, Arts, Brunner, & Fintina, ; Janssen et al, ; Kamme, Mayer, Strom, Andréasson, & Weisschuh, ; Katsanis et al, ; Katsanis et al, ; Kerr, Bhan, & Héon, ; A. O. Khan, Decker, Bachmann, Bolz, & Bergmann, ; S. Khan et al, , S. A. Khan et al, ; Laurier et al, ; Leitch et al, ; Lim et al, ; Lindstrand et al, ; Lindstrand et al, ; M'Hamdi et al, ; Maria et al,…”

Genetics of human Bardet–Biedl syndrome, an updates

“…So far, 70 mutations have been reported including point mutations, deletions and splicing mutations (Table ) .…”

“…Thirty‐five mutations have been reported so far including missense/nonsense mutations, splicing, insertion and deletion mutations (Table ) .…”

Genetics and genomic medicine in Tunisia

“…Bardet‐Biedl syndrome (BBS) is relatively rare, with an estimated prevalence of 1 in 156,000 (M'hamdi, Ouertani, Maazoul, & Chaabouni, ). Mutations were frequently found in BBS1 (37%) and BBS2 (18%) (M'hamdi et al., ), and founder mutations identified in both BBS2 and BBS8 (p.R189X and c.459 + 1G>A, respectively) (Smaoui et al., ).…”