title: Homozygosity mapping reveals novel and known mutations in Pakistani families with inherited retinal dystrophies.
abstract: Inherited retinal dystrophies are phenotypically and genetically heterogeneous. This extensive heterogeneity poses a challenge when performing molecular diagnosis of patients, especially in developing countries. In this study, we applied homozygosity mapping as a tool to reduce the complexity given by genetic heterogeneity and identify disease-causing variants in consanguineous Pakistani pedigrees. DNA samples from eight families with autosomal recessive retinal dystrophies were subjected to genome wide homozygosity mapping (seven by SNP arrays and one by STR markers) and genes comprised within the detected homozygous regions were analyzed by Sanger sequencing. All families displayed consistent autozygous genomic regions. Sequence analysis of candidate genes identified four previously-reported mutations in CNGB3, CNGA3, RHO, and PDE6A, as well as three novel mutations: c.2656C > T (p.L886F) in RPGRIP1, c.991G > C (p.G331R) in CNGA3, and c.413-1G > A (IVS6-1G > A) in CNGB1. This latter mutation impacted pre-mRNA splicing of CNGB1 by creating a -1 frameshift leading to a premature termination codon. In addition to better delineating the genetic landscape of inherited retinal dystrophies in Pakistan, our data confirm that combining homozygosity mapping and candidate gene sequencing is a powerful approach for mutation identification in populations where consanguineous unions are common.
authors.affiliation: 1] Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan [2] Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland [3] Pakistan Medical Research Council, Islamabad, 44000, Pakistan.
authors.forename: Muhammad Arif Nadeem
authors.initials: MA
authors.lastname: Saqib
authors.affiliation: Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Nikopoulos
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Ullah
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
authors.forename: Falak
authors.initials: F
authors.lastname: Sher Khan
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
authors.forename: Jamila
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
authors.forename: Rabia
authors.initials: R
authors.lastname: Bibi
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
authors.forename: Afeefa
authors.initials: A
authors.lastname: Jarral
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
authors.forename: Sundus
authors.initials: S
authors.lastname: Sajid
authors.affiliation: Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.
authors.forename: Koji M
authors.initials: KM
authors.lastname: Nishiguchi
authors.affiliation: Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland.
authors.forename: Giulia
authors.initials: G
authors.lastname: Venturini
authors.affiliation: 1] Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan [2] Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.affiliation: Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rivolta
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002874:Chromosome Mapping / Q000379:methods*; D003241:Consanguinity; D005190:Family; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D010154:Pakistan; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015792:Retinal Dysplasia / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D055815:Young Adult
chemical_list: D005819:Genetic Markers