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.
- bardet-biedl syndrome
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Contributors AT and SajM were responsible for the concept and design of the study. EYB, SarM and UW generated and interpreted the data. SajM and MA contributed clinical data. AT, SajM, EYB and UW drafted the manuscript. All authors revised the manuscript.
Funding This research was supported by Boğaziçi University Research Fund (project 10860; to AT), the Scientific and Technological Research Council of Turkey (114Z829; to AT) and URF-QAU, Pakistan (to SajM). UW is supported by FONDECYT no. 1150743.
Competing interests None declared.
Patient consent Guardian consent obtained.
Ethics approval Informed consent was obtained from/for participants in accordance with the regulations of the Ethical Review Committee of Quaid-i-Azam University and Boğaziçi University Institutional Review Board for Research with Human Participants, both of which approved the study protocol.
Provenance and peer review Not commissioned; externally peer reviewed.