Exploring the Genetic Landscape of Retinal Diseases in North-Western Pakistan Reveals a High Degree of Autozygosity and a Prevalent Founder Mutation in ABCA4
| Autor: | Virginie G. Peter, Andrea Superti-Furga, Mathieu Quinodoz, Carlo Rivolta, Atta Ur Rehman, Abdur Rashid, Syed Akhtar Khan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Proband Candidate gene Population Consanguinity hereditary retinal diseases Biology Compound heterozygosity 03 medical and health sciences symbols.namesake 0302 clinical medicine consanguinity Genetics Pakistan education Genotyping Genetics (clinical) Sanger sequencing education.field_of_study 3. Good health 030104 developmental biology ATP-Binding Cassette Transporters/genetics 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 autozygosity mapping 030221 ophthalmology & optometry symbols Founder effect |
| Zdroj: | Genes Volume 11 Issue 1 Genes, vol. 11, no. 1 |
| ISSN: | 2073-4425 |
| DOI: | 10.3390/genes11010012 |
| Popis: | 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 &ge 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> 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 &ldquo generic&rdquo variants and the prevalence of founder mutations. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|