Exploring the Genetic Landscape of Retinal Diseases in North-Western Pakistan Reveals a High Degree of Autozygosity and a Prevalent Founder Mutation in ABCA4.

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License: CC BY 4.0
Serval ID
serval:BIB_2FF63BD2181F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Exploring the Genetic Landscape of Retinal Diseases in North-Western Pakistan Reveals a High Degree of Autozygosity and a Prevalent Founder Mutation in ABCA4.
Journal
Genes
Author(s)
Rehman A.U., Peter V.G., Quinodoz M., Rashid A., Khan S.A., Superti-Furga A., Rivolta C.
ISSN
2073-4425 (Electronic)
ISSN-L
2073-4425
Publication state
Published
Issued date
21/12/2019
Peer-reviewed
Oui
Volume
11
Number
1
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
Variants in more than 271 different genes have been linked to hereditary retinal diseases, making comprehensive genomic approaches mandatory for accurate diagnosis. We explored the genetic landscape of retinal disorders in consanguineous families from North-Western Pakistan, harboring a population of approximately 35 million inhabitants that remains relatively isolated and highly inbred (~50% consanguinity). We leveraged on the high degree of consanguinity by applying genome-wide high-density single-nucleotide polymorphism (SNP) genotyping followed by targeted Sanger sequencing of candidate gene(s) lying inside autozygous intervals. In addition, we performed whole-exome sequencing (WES) on at least one proband per family. We identified 7 known and 4 novel variants in a total of 10 genes (ABCA4, BBS2, CNGA1, CNGA3, CNGB3, MKKS, NMNAT1, PDE6B, RPE65, and TULP1) previously known to cause inherited retinal diseases. In spite of all families being consanguineous, compound heterozygosity was detected in one family. All homozygous pathogenic variants resided in autozygous intervals ≥2.0 Mb in size. Putative founder variants were observed in the ABCA4 (NM_000350.2:c.214G>A; p.Gly72Arg; ten families) and NMNAT1 genes (NM_022787.3:c.25G>A; p.Val9Met; two families). We conclude that geographic isolation and sociocultural tradition of intrafamilial mating in North-Western Pakistan favor both the clinical manifestation of rare "generic" variants and the prevalence of founder mutations.
Keywords
ATP-Binding Cassette Transporters/genetics, Consanguinity, DNA Mutational Analysis, Female, Founder Effect, Humans, Male, Mutation, Nicotinamide-Nucleotide Adenylyltransferase/genetics, Pakistan/epidemiology, Pedigree, Prevalence, Retinal Diseases/epidemiology, Retinal Diseases/genetics, Sequence Analysis, DNA, Whole Exome Sequencing/methods, Pakistan, autozygosity mapping, consanguinity, hereditary retinal diseases
Pubmed
Web of science
Open Access
Yes
Create date
03/01/2020 21:51
Last modification date
30/04/2021 6:09
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