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Degenerative and developmental eye disorders, including inherited retinal dystrophies (IRDs), anophthalmia, and congenital cataracts arise from genetic mutations, causing progressive vision loss or congenital structural abnormalities. IRDs include a group of rare, genetically, and clinically heterogeneous retinal diseases. It is caused by variations in at least 324 genes, affecting numerous retinal regions. In addition to IRDs, other developmental eye disorders such as anophthalmia and congenital cataracts also have a strong genetic basis. Autosomal recessive IRDs, anophthalmia, and congenital cataracts are common in consanguineous populations. In many endogamous populations, including those in Pakistan, a significant proportion of IRD and anophthalmia cases remain genetically undiagnosed. The present study investigated the variations in IRDs, anophthalmia, and congenital cataracts genes in 50 affected families. These unrelated consanguineous families were recruited from the different provinces of Pakistan including Punjab, Khyber Pakhtoon Khwa, Sindh, Gilgit Baltistan, and Azad Kashmir. Whole exome sequencing (WES) was conducted for the proband of each family. An in-house customized pipeline examined the data, and bioinformatics analysis predicted the pathogenic effects of identified variants. The relevant identified DNA variants of selected families were assessed in parents and healthy siblings via Sanger sequencing. WES identified 12 novel variants across 10 known IRD-associated genes. The four most frequently implicated genes were CRB1 (14.3%), GUCY2D (9.5%), AIPL1 (9.5%), and CERKL (7.1%) that together accounted for 40.4% of all molecularly diagnosed cases. Additionally, 25 reported variants in 19 known IRDs, anophthalmia, and congenital cataracts-associated genes were found. Among the identified variants, p. Trp278X, a stop–gain mutation in the AIPL1 (NM_014336) gene, was the most common causative variant detected. The most frequently observed phenotype was retinitis pigmentosa (46.5%) followed by Leber congenital amaurosis (18.6%). Furthermore, 98% of pedigrees (49 out of 50) were affected by autosomal recessive IRDs, anophthalmia and congenital cataracts. The discovery of 12 novel likely pathogenic variants in 10 IRD genes, 25 reported variants in 19 known IRDs, anophthalmia and congenital cataracts genes, atypical phenotypes, and inter and intra-familial variability underscores the genetic and phenotypic heterogeneity of developmental and degenerative eye disorders in the Pakistani population and further expands the mutational spectrum of genes associated with these ocular disorders. Full article

The core objective of forensic DNA typing is developing DNA profiles from biological evidence for personal identification. The present study was designed to check the validation of the IrisPlex system and the Prevalence of eye colour in the Pakhtoon population residing within the Malakand Division. Methods: Eye colour digital photographs and buccal swab samples of 893 individuals of different age groups were collected. Multiplexed SNaPshot single base extension chemistry was used, and the genotypic results were analysed. Snapshot data were used for eye colour prediction through the IrisPlex and FROG-kb tool. Results: The results of the present study found brown eye colour to be the most prevalent eye colour in comparison to intermediate and blue coloured. Overall, individuals with brown-coloured eyes possess CT (46.84%) and TT (53.16%) genotypes. Blue eye-coloured individuals are solely of the CC genotype, while individuals of intermediate eye colour carry CT (45.15%) and CC (53.85%) genotypes in rs12913832 SNP in the HERC2 gene. It was also revealed that brown-coloured eyes individuals were dominant among all age groups followed by intermediate and blue. Statistical analysis between particular variables and eye colour showed a significant p-value (<0.05) for rs16891982 SNP in SLC45A2 gene, rs12913832 SNP in HERC2 gene, rs1393350 SNP in SLC45A2, districts and gender. The rest of the SNPs were non-significant with eye colour, respectively. The rs12896399 SNP and SNP rs1800407 were found significant with rs16891982 SNP. The result also demonstrated that the study group differs from the world population based on eye colour. The two eye colour prediction results were compared, and it was discovered that IrisPlex and FROG-Kb had similar higher prediction ratios for Brown and Blue eye colour. Conclusions: The results of the current study revealed brown eye colour to be the most prevalent amongst members of the local population of Pakhtoon ethnicity in the Malakand Division of northern Pakistan. A set of contemporary human DNA samples with known phenotypes are used in this research to evaluate the custom panel’s prediction accuracy. With the aid of this forensic test, DNA typing can be supplemented with details about the appearance of the person from whom the sample was taken in cases involving missing persons, ancient human remains, and trace samples. This study may be helpful for future population genetics and forensics studies. Full article