Exome sequencing in a Romanian Bardet‐Biedl syndrome cohort revealed an overabundance of causal BBS12 variants
Bardet‐Biedl syndrome (BBS), is an emblematic ciliopathy hallmarked by pleiotropy, phenotype variability, and extensive genetic heterogeneity. BBS is a rare (~1/140,000 to ~1/160,000 in Europe) autosomal recessive pediatric disorder characterized by retinal degeneration, truncal obesity, polydactyly...
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Published in | American journal of medical genetics. Part A Vol. 191; no. 9; pp. 2376 - 2391 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Hoboken, USA
John Wiley & Sons, Inc
01.09.2023
Wiley Subscription Services, Inc |
Subjects | |
Online Access | Get full text |
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Summary: | Bardet‐Biedl syndrome (BBS), is an emblematic ciliopathy hallmarked by pleiotropy, phenotype variability, and extensive genetic heterogeneity. BBS is a rare (~1/140,000 to ~1/160,000 in Europe) autosomal recessive pediatric disorder characterized by retinal degeneration, truncal obesity, polydactyly, cognitive impairment, renal dysfunction, and hypogonadism. Twenty‐eight genes involved in ciliary structure or function have been implicated in BBS, and explain the molecular basis for ~75%–80% of individuals. To investigate the mutational spectrum of BBS in Romania, we ascertained a cohort of 24 individuals in 23 families. Following informed consent, we performed proband exome sequencing (ES). We detected 17 different putative disease‐causing single nucleotide variants or small insertion–deletions and two pathogenic exon disruptive copy number variants in known BBS genes in 17 pedigrees. The most frequently impacted genes were BBS12 (35%), followed by BBS4, BBS7, and BBS10 (9% each) and BBS1, BBS2, and BBS5 (4% each). Homozygous BBS12 p.Arg355* variants were present in seven pedigrees of both Eastern European and Romani origin. Our data show that although the diagnostic rate of BBS in Romania is likely consistent with other worldwide cohorts (74%), we observed a unique distribution of causal BBS genes, including overrepresentation of BBS12 due to a recurrent nonsense variant, that has implications for regional diagnostics. |
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Bibliography: | Sheraz Khan and Ina Ofelia Focșa contributed equally to this study. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authors Contributions SK performed genetic data analysis/interpretation, variant validation and segregation analysis, manuscript first draft, review and editing of the manuscript; IOF collected the cases and performed clinical assessment; MB, CS, FN, LB, LC, LBu, MP, CR, CJ, AEC, CB, MBa performed clinical assessment; AS assisted with organization of clinical samples and data; WA and SMB reviewed and edited the manuscript; EED conceptualized and designed the study, reviewed genomic variants, reviewed and edited the manuscript (with input and approval from all authors) and acquired funding. All authors contributed to the manuscript and approved for the final submission. |
ISSN: | 1552-4825 1552-4833 1552-4833 |
DOI: | 10.1002/ajmg.a.63322 |