Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome

Abstract

Bardet-Biedl syndrome (BBS) is a defining ciliopathy, notable for extensive allelic and genetic heterogeneity, almost all of which has been identified through sequencing. Recent data have suggested that copy-number variants (CNVs) also contribute to BBS. We used a custom oligonucleotide array comparative genomic hybridization (aCGH) covering 20 genes that encode intraflagellar transport (IFT) components and 74 ciliopathy loci to screen 92 unrelated individuals with BBS, irrespective of their known mutational burden. We identified 17 individuals with exon-disruptive CNVs (18.5%), including 13 different deletions in eight BBS genes (BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, BBS7, BBS9, and NPHP1) and a deletion and a duplication in other ciliopathy-associated genes (ALMS1 and NPHP4, respectively). By contrast, we found a single heterozygous exon-disruptive event in a BBS-associated gene (BBS9) in 229 control subjects. Superimposing these data with resequencing revealed CNVs to (1) be sufficient to cause disease, (2) Mendelize heterozygous deleterious alleles, and (3) contribute oligogenic alleles by combining point mutations and exonic CNVs in multiple genes. Finally, we report a deletion and a splice site mutation in IFT74, inherited under a recessive paradigm, defining a candidate BBS locus. Our data suggest that CNVs contribute pathogenic alleles to a substantial fraction of BBS-affected individuals and highlight how either deletions or point mutations in discrete splice isoforms can induce hypomorphic mutations in genes otherwise intolerant to deleterious variation. Our data also suggest that CNV analyses and resequencing studies unbiased for previous mutational burden is necessary to delineate the complexity of disease architecture.

Retrotransposon insertion as a novel mutational event in Bardet‐Biedl syndrome

“…Recently, two cases affected with nonBBS ciliopathy phenotypes were associated with retrotransposon insertions; a L1 in exon 7 of CC2D2A and an Alu in exon 16 of ALMS1 (Takenouchi et al, ; Taschner et al, ). A recent study of BBS cases also found that 40% (6 out of 15) of the CNV deletions detected in their cohort (in BBS1 , BBS4 , BBS5 , and IFT74 ) were mediated by Alu – Alu recombination (Lindstrand et al, ).…”

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,…”

Combining targeted panel-based resequencing and copy-number variation analysis for the diagnosis of inherited syndromic retinopathies and associated ciliopathies

“…Structural variants also represent an underestimated mutational burden that contributes to missing heritability and oligogenic mechanisms, not only in non-syndromic RD, but also in BBS and Joubert syndrome 20,24–26,51,52 . Here, we report novel heterozygous multi-exon structural variants for BBS1 and RPGRIP1 that were identified by targeted comparative read-depth analysis.…”