title: Exome sequencing identifies a novel and a recurrent BBS1 mutation in Pakistani families with Bardet-Biedl syndrome.
abstract: OBJECTIVE
  To determine the genetic cause of Bardet-Biedl syndrome (BBS) in two consanguineous Pakistani families.
  
  
  METHODS
  Clinical characterization of the affected individuals in both families was performed with ophthalmic examination, electroretinography, electrocardiography, and liver and renal profiling. Seventeen genes are known to be associated with BBS, so exome sequencing was preferred over candidate gene sequencing. One affected individual from both families was selected for exome sequencing. Segregation of the identified variants was confirmed with Sanger sequencing.
  
  
  RESULTS
  Retinitis pigmentosa, obesity, and learning difficulties were present in the affected individuals in both families. In family A, a sixth finger (polydactyly) of the proband's sister was removed by a surgical operation leaving a scar on the little finger. Polydactyly was also present in both affected individuals from family B. All diagnostic symptoms were characteristic of BBS in both families. In both affected individuals from family A, exome sequencing identified a novel homozygous mutation (c.47+1G>T) in BBS1 that inactivates the splice donor site at the end of exon 1. In family B, a previously reported mutation, c.442G>A; p.(Asp148Asn), was detected.
  
  
  CONCLUSIONS
  Exome sequencing is an efficient and cost-effective technique for identifying mutations in genetically heterogeneous diseases. In addition, intrafamilial phenotypic variability in family A argues for the modifying effect of other still unknown modifier alleles.
authors.affiliation: Department of Biosciences, Faculty of Science, COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ajmal
authors.forename: Muhammad Imran
authors.initials: MI
authors.lastname: Khan
authors.forename: Kornelia
authors.initials: K
authors.lastname: Neveling
authors.forename: Ali
authors.initials: A
authors.lastname: Tayyab
authors.forename: Sulman
authors.initials: S
authors.lastname: Jaffar
authors.forename: Ahmed
authors.initials: A
authors.lastname: Sadeque
authors.forename: Humaira
authors.initials: H
authors.lastname: Ayub
authors.forename: Nasir Mahmood
authors.initials: NM
authors.lastname: Abbasi
authors.forename: Moeen
authors.initials: M
authors.lastname: Riaz
authors.forename: Shazia
authors.initials: S
authors.lastname: Micheal
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Syeda Hafiza Benish
authors.initials: SH
authors.lastname: Ali
authors.forename: Maleeha
authors.initials: M
authors.lastname: Azam
authors.forename: Rob W J
authors.initials: RW
authors.lastname: Collin
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.forename: Raheel
authors.initials: R
authors.lastname: Qamar
mesh_terms: D000328:Adult; D020788:Bardet-Biedl Syndrome / Q000235:genetics* / Q000503:physiopathology; D001483:Base Sequence; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D055724:Electrophysiological Phenomena; D059472:Exome / Q000235:genetics*; D005190:Family; D005260:Female; D005654:Fundus Oculi; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010154:Pakistan; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C464790:Bbs1 protein, human; D008869:Microtubule-Associated Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger
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