In search of triallelism in Bardet-Biedl syndrome

• Published in: European journal of human genetics : EJHG Vol. 20; no. 4; pp. 420 - 427
• Main Authors: ABU-SAFIEH, Leen, AL-ANAZI, Shamsa, AL-SALEM, Ahmad, ALRASHED, May, FAQEIH, Eissa, SOFTAH, Ameen, AL-HASHEM, Amal, WALI, Sami, RAHBEENI, Zuhair, ALSAYED, Moeen, KHAN, Arif O, AL-GAZALI, Lihadh, AL-ABDI, Lama, TASCHNER, Peter Em, AL-HAZZAA, Selwa, ALKURAYA, Fowzan S, HASHEM, Mais, ALKURAYA, Hisham, ALAMR, Mushari, SIRELKHATIM, Mugtaba O, AL-HASSNAN, Zuhair, ALKURAYA, Basim, MOHAMED, Jawahir Y
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.04.2012
• Subjects: Alleles; Bardet-Biedl syndrome; Bardet-Biedl Syndrome - genetics; BBS gene; Biological and medical sciences; Cell Cycle Proteins - genetics; Cohort Studies; Disease; Family; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genes, Modifier; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genotypes; Heredity; Hospitals; Humans; Male; Medical genetics; Medical sciences; Metabolic diseases; Molecular and cellular biology; Mutation; Obesity; Pediatrics; Phenotypes; Polygenic inheritance; Research centers; Retinitis; Retinitis pigmentosa; Saudi Arabia; Riyadh Saudi Arabia; Endocrinopathy; Obesity; Laurence-Moon-Bardet-Biedl syndrome; Nervous system diseases; Diseases of the osteoarticular system; Nutrition disorder; penetrance; Epistasis; modifiers; Genetic disease; Genital diseases; oligogenic; Eye disease; Malformation; Gene penetrance; Genetics; Complex syndrome; Nutritional status
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2011.205

Bardet-Biedl syndrome (BBS) is a model disease for ciliopathy in humans. The remarkable genetic heterogeneity that characterizes this disease is consistent with accumulating data on the interaction between the proteins encoded by the 14 BBS genes identified to date. Previous reports suggested that such interaction may also extend to instances of oligogenic inheritance in the form of triallelism which defies the long held view of BBS as an autosomal recessive disease. In order to investigate the magnitude of triallelism in BBS, we conducted a comprehensive analysis of all 14 BBS genes as well as the CCDC28B-modifier gene in a cohort of 29 BBS families, most of which are multiplex. Two in trans mutations in a BBS gene were identified in each of these families for a total of 20 mutations including 12 that are novel. In no instance did we observe two mutations in unaffected members of a given family, or observe the presence of a third allele that convincingly acted as a modifier of penetrance and supported the triallelic model of BBS. In addition to presenting a comprehensive genotype/phenotype overview of a large set of BBS mutations, including the occurrence of nonsyndromic retinitis pigmentosa in a family with a novel BBS9 mutation, our study argues in favor of straightforward autosomal recessive BBS in most cases.