title: Homozygosity mapping identified a novel protein truncating mutation (p.Ser100Leufs*24) of the BBS9 gene in a consanguineous Pakistani family with Bardet Biedl syndrome.
abstract: BACKGROUND
  Bardet Biedl Syndrome (BBS) is a rare condition of multi-organ dysfunction with characteristic clinical features of retinal degeneration, truncal obesity, postaxial polydactyly, genital anomaly, intellectual disability and renal dysfunction. It is a hetero-genetic disorder and nineteen BBS genes have been discovered so far.
  
  
  METHODS
  Whole genome SNP genotyping was performed by using CytoScan® 750 K array (Affymetrix). Subsequently, the segregation of the disease locus in the whole family was carried out by genotyping STS markers within the homozygous interval. Finally, the mutation analysis was performed by Sanger DNA sequencing.
  
  
  RESULTS
  In the present molecular study a consanguineous Pakistani family, with autosomal recessive BBS, was analyzed. The clinical analysis of affected individuals presented with synpolydactyly, obesity, intellectual disability, renal abnormality and retinitis pigmentosa. The presented phenotype was consistent with the major features of BBS syndrome. Homozygosity mapping identified a common homozygous interval within the known BBS9 locus. Sequence analysis of BBS9/PTHB1 gene revealed a single base deletion of c.299delC (p.Ser100Leufs*24) in exon 4. This frame-shift mutation presumably leads to a 122 amino acid truncated protein with complete loss of its C-terminal PTHB1 domain in combination with a partial loss of the N-terminal PTHB1 domain as well. BBS9/PTHB1 gene mutations have been shown to be associated with BBS syndrome and to the best of our knowledge this study reports the first Pakistani family linked to the BBS9 gene.
  
  
  CONCLUSIONS
  Our molecular findings expand the mutational spectrum of BBS9 gene and also explain the genetic heterogeneity of Pakistan families with BBS syndrome. The growing number of mutations in BBS genes in combination with a detailed phenotypical description of patients will be helpful for genotype-phenotype correlation, targeted genetic diagnosis, prenatal screening and carrier testing of familial and non-familial BBS patients.
authors: Gomal Centre of Biochemistry and Biotechnology, Gomal University Dera Ismail Khan, Khyber-Pakhtoonkhwa, Khyber-Pakhtoonkhwa, 29050, Pakistan. muzammil.gandapur@hotmail.com.|Interim Translational Research Institute, Genomic Core Facility, Academic Health System, Hamad Medical Corporation, Doha, 3050, Qatar. muzammil.gandapur@hotmail.com.
authors: Muzammil Ahmad
authors: MA
authors: Khan
authors: Institute of Human Genetics, Medical University of Graz, Graz, 8010, Austria. Sumitra.Mohan@cruk.manchester.ac.uk.
authors: Sumitra
authors: S
authors: Mohan
authors: Gomal Centre of Biochemistry and Biotechnology, Gomal University Dera Ismail Khan, Khyber-Pakhtoonkhwa, Khyber-Pakhtoonkhwa, 29050, Pakistan. muhammad.zubair0913@gmail.com.
authors: Muhammad
authors: M
authors: Zubair
authors: Institute of Human Genetics, Medical University of Graz, Graz, 8010, Austria. christian.windpassinger@medunigraz.at.
authors: Christian
authors: C
authors: Windpassinger
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D020788:Bardet-Biedl Syndrome / Q000175:diagnosis / Q000235:genetics*; D002874:Chromosome Mapping; D003241:Consanguinity; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D060005:Genotyping Techniques; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D010154:Pakistan; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C472639:BBS9 protein, human; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins