2. Academic Validation
  3. Homozygous mutation in CEP19, a gene mutated in morbid obesity, in Bardet-Biedl syndrome with predominant postaxial polydactyly

Homozygous mutation in CEP19, a gene mutated in morbid obesity, in Bardet-Biedl syndrome with predominant postaxial polydactyly

  • J Med Genet. 2018 Mar;55(3):189-197. doi: 10.1136/jmedgenet-2017-104758.
Esra Yıldız Bölükbaşı 1,  Sara Mumtaz 2,  Muhammad Afzal 2,  Ute Woehlbier 3,  Sajid Malik 2,  Aslıhan Tolun 1
Affiliations

Affiliations

  • 1 Department of Molecular Biology and Genetics, Boğaziçi University, Istanbul, Turkey.
  • 2 Human Genetics Program, Department of Animal Sciences, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
  • 3 Center for Integrative Biology, Faculty of Science, Universidad Mayor, Santiago, Chile.
PMID: 29127258 DOI: 10.1136/jmedgenet-2017-104758
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.

Keywords

bardet-biedl syndrome; ccdc28b; cep19; gli1; modifier.

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