TY - JOUR
T1 - Homozygosity mapping reveals novel and known mutations in Pakistani families with inherited retinal dystrophies
AU - Saqib, Muhammad Arif Nadeem
AU - Nikopoulos, Konstantinos
AU - Ullah, Ehsan
AU - Sher Khan, Falak
AU - Iqbal, Jamila
AU - Bibi, Rabia
AU - Jarral, Afeefa
AU - Sajid, Sundus
AU - Nishiguchi, Koji M.
AU - Venturini, Giulia
AU - Ansar, Muhammad
AU - Rivolta, Carlo
N1 - Funding Information:
This work was funded in part by the University Research Fund of Quaid-I-Azam University, Islamabad, Pakistan and the Swiss National Science Foundation, Switzerland (Grant 310030_138346). Muhammad Arif Nadeem Saqib was supported by the Indigenous Fellowships and the International Research Support Program (IRSIP) from the Higher Education Commission (HEC) of Pakistan. We would like to thank the iGE3 Genomics Platform at University of Geneva, and in particular all members of the families that participated in this study for their invaluable participation and cooperation.
PY - 2015/5/6
Y1 - 2015/5/6
N2 - 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.
AB - 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.
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U2 - 10.1038/srep09965
DO - 10.1038/srep09965
M3 - Article
C2 - 25943428
AN - SCOPUS:84928981044
VL - 5
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 9965
ER -