Significant number out of 2.2 billion vision impairments in the world can be attributed to genetics. The current study is aimed to decipher the genetic basis of Leber congenital Amaurosis (LCA), Anterior Segment dysgenesis (ASD), and Retinitis Pigmentosa (RP), segregating in four large consanguineous Pakistani families. The exome sequencing followed by segregation analysis via Sanger sequencing revealed the LCA phenotypes segregating in families GCUF01 and GCUF04 can be attributed to c.465G>T (p.(Gln155His)) missense and novel c.139_140delinsA p.(Pro47Trhfster38) frameshift variant of AIPL1 and GUCY2D, respectively. The c.1843A>T (p.(Lys615*) truncating allele of MERTK is homozygous in all the affected individuals, presumably suffering with RP, of the GCUF02 family. Meanwhile, co-segregation of the ASD phenotype and the c.289A>G (p.(Ile97Val)) variant of FOXE3 was found in the GCUF06 family. All the identified variants were either absent or present in very low frequencies in the control databases. Our in-silico analyses and 3D molecular modeling support the deleterious impact of these variants on the encoded proteins. Variants identified in MERTK, GUCY2D, and FOXE3 were categorized as “pathogenic” or “likely pathogenic”, while the missense variant found in AIPL1 was deemed to have “uncertain significance” based upon the variant pathogenicity guidelines from the American College of Medical Genetics and Genomics (ACMG). This paper highlights the genetic diversity of vision disorders in the Pakistani population and reports the identification of four novel mutations in families who segregate clinically heterogeneous eye diseases. Our results give insight into the genotype-phenotype correlations of AIPL1, FOXE3, MERTK, and GUCY2D variants.

世界上22亿视力障碍中有很大一部分可归因于遗传学。当前的研究旨在破译Leber先天性黑斑病（LCA），前节发育不全（ASD）和视网膜色素变性（RP）的遗传基础，这些遗传基础分布在四个大型近亲巴基斯坦家庭中。外显子组测序以及随后通过Sanger测序进行的分离分析表明，在GCUF01和GCUF04家族中分离的LCA表型可归因于c.465G> T（p。（Gln155His））错义和新型c.139_140delinsA p。（Pro47Trhfster38）移码变体AIPL1和GUCY2D分别。c.1843A> T（p。（Lys615 *）截短的MERTK等位基因在GCUF02家族的所有受影响个体中，可能是患有RP的纯合子。同时，在GCUF06家族中发现了ASD表型与FOXE3的c.289A> G（p。（Ile97Val））变体的共分离。在对照数据库中，所有鉴定出的变体都不存在或以极低的频率出现。我们的计算机分析和3D分子建模支持了这些变体对编码蛋白的有害影响。在MERTK，GUCY2D和FOXE3中鉴定的变体被归类为“致病性”或“可能是致病性”，而AIPL1中发现的错义变体根据美国医学遗传学和基因组学学院（ACMG）的变异致病性指南，被认为具有“不确定的意义”。本文重点介绍了巴基斯坦人口视力障碍的遗传多样性，并报告了在临床上将异类眼病隔离的家庭中的四个新突变的鉴定。我们的结果深入了解了AIPL1，FOXE3，MERTK和GUCY2D变体的基因型与表型的相关性。