title: Genetic and clinical characterization of Pakistani families with Bardet-Biedl syndrome extends the genetic and phenotypic spectrum.
abstract: Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder that is both genetically and clinically heterogeneous. To date 19 genes have been associated with BBS, which encode proteins active at the primary cilium, an antenna-like organelle that acts as the cell's signaling hub. In the current study, a combination of mutation screening, targeted sequencing of ciliopathy genes associated with BBS, and whole-exome sequencing was used for the genetic characterization of five families including four with classic BBS symptoms and one BBS-like syndrome. This resulted in the identification of novel mutations in BBS genes ARL6 and BBS5, and recurrent mutations in BBS9 and CEP164. In the case of CEP164, this is the first report of two siblings with a BBS-like syndrome with mutations in this gene. Mutations in this gene were previously associated with nephronophthisis 15, thus the current results expand the CEP164-associated phenotypic spectrum. The clinical and genetic spectrum of BBS and BBS-like phenotypes is not fully defined in Pakistan. Therefore, genetic studies are needed to gain insights into genotype-phenotype correlations, which will in turn improve the clinician's ability to make an early and accurate diagnosis, and facilitate genetic counseling, leading to directly benefiting families with affected individuals.
authors.affiliation: Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.|Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Maleeha
authors.initials: M
authors.lastname: Maria
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands.
authors.forename: Ideke J C
authors.initials: IJ
authors.lastname: Lamers
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands.|Genetics and Genomic Medicine, UCL Institute of Child Health, 30 Guilford Street, London, UK.|Center for Pediatrics and Adolescent Medicine, Pediatric Genetics Division, University Hospital Freiburg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Schmidts
authors.affiliation: Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ajmal
authors.affiliation: Shifa International Hospital, Islamabad, Pakistan.
authors.forename: Sulman
authors.initials: S
authors.lastname: Jaffar
authors.affiliation: School of Applied Sciences, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand.|Auckland City Hospital, Auckland District Health Board, Auckland, New Zealand.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Ullah
authors.affiliation: Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Bilal
authors.initials: B
authors.lastname: Mustafa
authors.affiliation: Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Shakeel
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, 30 Guilford Street, London, UK.
authors.forename: Katia
authors.initials: K
authors.lastname: Nazmutdinova
authors.affiliation: North East Thames Regional Genetics Service, Hospital for Children, London, UK.
authors.forename: Bethan
authors.initials: B
authors.lastname: Hoskins
authors.affiliation: Department of Otorhinolaryngology, Radboud University Medical Centre, Nijmegen, the Netherlands.|Donders Center for Neurosciences, Radboud University Nijmegen, the Netherlands.
authors.forename: Erwin
authors.initials: E
authors.lastname: van Wijk
authors.affiliation: Department of Pediatric Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Linda
authors.initials: L
authors.lastname: Koster-Kamphuis
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Muhammad Imran
authors.initials: MI
authors.lastname: Khan
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, 30 Guilford Street, London, UK.|Centre for Translational Omics-GOSgene, Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Phil L
authors.initials: PL
authors.lastname: Beales
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.|Donders Center for Neurosciences, Radboud University Nijmegen, the Netherlands.
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.affiliation: Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Maleeha
authors.initials: M
authors.lastname: Azam
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.|Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands.|Department of Biochemistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Heleen H
authors.initials: HH
authors.lastname: Arts
authors.affiliation: Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.|Department of Biochemistry, Al-Nafees Medical College &Hospital, Isra University, Islamabad, Pakistan.|Pakistan Academy of Sciences, Constitution Avenue, Islamabad, Pakistan.
authors.forename: Raheel
authors.initials: R
authors.lastname: Qamar
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D020788:Bardet-Biedl Syndrome / Q000235:genetics*; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D008868:Microtubule Proteins / Q000235:genetics*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D010154:Pakistan; D010375:Pedigree; D028044:Phosphate-Binding Proteins; D011506:Proteins / Q000235:genetics*; D000073359:Exome Sequencing / Q000379:methods; D055815:Young Adult
chemical_list: C487434:BBS5 protein, human; C472639:BBS9 protein, human; C524694:CEP164 protein, human; D003598:Cytoskeletal Proteins; D008868:Microtubule Proteins; D009363:Neoplasm Proteins; D028044:Phosphate-Binding Proteins; D011506:Proteins; C491435:ARL6 protein, human; D020727:ADP-Ribosylation Factors