Homozygous mutation in CEP19, a gene mutated in morbid obesity, in Bardet-Biedl syndrome with predominant postaxial polydactyly. Issue 3 (10th November 2017)

• Record Type: Journal Article
• Authors: Yıldız Bölükbaşı, Esra; Mumtaz, Sara; Afzal, Muhammad; Woehlbier, Ute; Malik, Sajid; Tolun, Aslıhan
• Is Part Of: Journal of medical genetics. Volume 55:Issue 3(2018)
• Page Start: 189
• Page End: 197
• Publication Date: 2017-11-10
• Subjects: bardet-biedl syndrome -- cep19 -- gli1 -- ccdc28b -- modifier; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2017-104758
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: Bardet-Biedl syndrome (BBS) is a ciliopathy with extensive phenotypic variability and genetic heterogeneity. We aimed to discover the gene mutated in a consanguineous kindred with multiple cases of a BBS phenotype. Methods: SNP genotype data were used for linkage analysis and exome sequencing to identify mutations. Modelling and in silico analysis were performed to predict mutation severity. Results: Patients had postaxial polydactyly plus variable other clinical features including rod-cone dystrophy, obesity, intellectual disability, renal malformation, developmental delay, dental anomalies, speech disorder and enlarged fatty liver. The 4.57 Mb disease locus harboured homozygous, truncating CEP19 c.194_195insA (p.Tyr65*) mutation. We also found glioma-associated oncogene homolog 1( GLI1 ) c.820G>C (p.Gly274Arg) in the homozygous state in most patients. In silico modelling strongly suggests that it is damaging. Also, different combinations of four possible modifier alleles in BBS-related genes were detected. Two are known modifier alleles for BBS, splicing variant CCDC28B c.330C>T and missense MKKS/BBS6 p.Ile339Val, and the others are C8ORF37/BBS21 p.Ala178Val and TMEM67 / BBS14 modifier p.Asp799Asp. Some patients carry all those five known/possible modifier alleles. Such variants are highly significantly more abundant in our patients than in a control group. Conclusion: CEP19 encodes a centrosomal and ciliary protein, as all BBS genes do. Another truncating mutation p.Arg82* has been reported as responsible for morbid obesity in a family; however, in the family we present, not all homozygotes are obese, although some are severely obese. The variant in GLI1, encoding a transcription factor that localises to the primary cilium and nucleus and is a mediator of the sonic hedgehog pathway, possibly exacerbates disease severity when in the homozygous state.