Homozygosity Mapping and Genetic Analysis of Autosomal Recessive Retinal Dystrophies in 144 Consanguineous Pakistani Families

Abstract

PurposeThe Pakistan Punjab population has been a rich source for identifying genes causing or contributing to autosomal recessive retinal degenerations (arRD). This study was carried out to delineate the genetic architecture of arRD in the Pakistani population.MethodsThe genetic origin of arRD in a total of 144 families selected only for having consanguineous marriages and multiple members affected with arRD was examined. Of these, causative mutations had been identified in 62 families while only the locus had been identified for an additional 15. The remaining 67 families were subjected to homozygosity exclusion mapping by screening of closely flanking microsatellite markers at 180 known candidate genes/loci followed by sequencing of the candidate gene for pathogenic changes.ResultsOf these 67 families subjected to homozygosity mapping, 38 showed homozygosity for at least one of the 180 regions, and sequencing of the corresponding genes showed homozygous cosegregating mutations in 27 families. Overall, mutations were detected in approximately 61.8 % (89/144) of arRD families tested, with another 10.4% (15/144) being mapped to a locus but without a gene identified.ConclusionsThese results suggest the involvement of unmapped novel genes in the remaining 27.8% (40/144) of families. In addition, this study demonstrates that homozygosity mapping remains a powerful tool for identifying the genetic defect underlying genetically heterogeneous arRD disorders in consanguineous marriages for both research and clinical applications.

Identification of the genetic determinants responsible for retinal degeneration in families of Mexican descent

“…However, in the Mexican population, approximately 15–20% of RP cases are autosomal dominant, 20–25% are autosomal recessive, 10–15% are X-linked recessive, and 40–55% are considered to have “simplex” inheritance (8). Higher incidence of recessive IRDs has been reported in subpopulations with high consanguinity (13). Inbreeding has been reported in certain regions of southern Mexico including the Yucatan peninsula; IRD in these populations have not been studied extensively.…”

Combined CNV, haplotyping and whole exome sequencing enable identification of two distinct novel EYS mutations causing RP in a single inbred tribe

“…Despite the first impression of the disease being inherited in a dominant mode, as implied by the pedigree (Figure ), the high inbreeding rate in the Bedouin community studied here raised the possibility of recessive, pseudo‐dominant inheritance of the disease. Homozygosity mapping has played a critical role in finding the cause for monogenic diseases, highlighting variants that otherwise could be missed (Alkuraya, ; Li et al, ; Zelinger et al, ). That being said, our findings of two different deleterious mutations in the same gene inherited in a single inbred kindred, highlight again the limitations of homozygosity mapping in disease‐gene identification, even in inbred cohorts (Abu‐safieh et al, ; Mcmillin et al, ; Miano et al, ; Pannain et al, )., and mark again the importance of CNV analysis and of combining different tools and methods.…”

“…Homozygosity mapping and genome‐wide linkage analysis are common tools applied to the study of consanguineous families (Alkuraya, ; Li et al, ; Zelinger et al, ). Both play a critical role in minimizing the number of candidate variants emerging from sequencing data, by focusing on mutations occurring only within relevant loci.…”

Whole exome sequencing identified mutations causing hearing loss in five consanguineous Pakistani families

“…Consanguineous pedigrees represent a suitable natural model to study recessive disorders [13]. In Pakistan, there are numerous consanguineous pedigrees because of their customs, and these pedigrees may provide more opportunities to study and recognize such disorders [14,15].…”