Purpose ABCA4 retinopathies are a group of ABCA4 gene-associated disorders with phenotypic heterogeneity and variable disease severity. The genotype-phenotype correlation is a great challenge for exact disease diagnosis because of symptom variations even within the same family members and the same gene variants giving altered disease phenotypes. This study describes the molecular epidemiology of 10 Pakistani families segregating pathogenic variants of the ABCA4 gene and summarizes ABCA4-associated genetic findings from Pakistani families reported until October 2024. Methods We enrolled consanguineous Pakistani families having at least one child affected with retinal dystrophy. DNA was extracted from blood samples. Probands were analyzed using capture panel sequencing of 344 known genes for retinal dystrophies. Sanger sequencing was used to perform family segregation testing. To review previously published ABCA4 disease-causing variants from Pakistan, data were extracted by retrieving articles through online sources—specifically, PubMed and Google Scholar. Results Out of 72 families, 10 revealed a total of five reported (c. 6658CT, c. 214GA, c. 6088CT, c. 6729+5₆729+19del, and c. 6218GC) and two novel (c. 2790CA and c. 1099+5GA) variants in the ABCA4 gene were segregating in each respective family. Furthermore, one of the novel variants, c. 1099+5GA, was segregating in a compound heterozygous manner along with a c. 6658CT stop-gain variant of the ABCA4 gene in one family. All identified ABCA4 variants were segregated in an autosomal recessive manner. Conclusions The variant c. 6658CT was detected in 50% of families analyzed in this study, but previous reports from Pakistan highlight the c. 214GA variant as a frequent ABCA4 mutation in cases of Pakistani decent. Identification of two novel pathogenic variants in the present study reaffirms the allelic and genetic heterogeneity of ABCA4 retinopathies in Pakistani patients. The clinical variability or discordance among individuals carrying the same pathogenic variant may be due to other factors influencing the phenotype, including variables such as sex of the individual or role of modifiers that have yet to be identified.
Akhtar et al. (Sun,) studied this question.