**Background:** Inherited retinal dystrophies (IRDs) are a group of rare genetic disorders affecting the retina, with a global prevalence ranging from 1 in 2000 to 1 in 4000. They can be non-syndromic (e.g., retinitis pigmentosa, Leber congenital amaurosis) or syndromic (e.g., Bardet-Biedl syndrome, Usher syndrome). Pakistan has a high rate of consanguineous marriages, which increases the likelihood of recessive genetic disorders. This systematic review aimed to comprehensively analyze the genetic and clinical landscape of IRDs in Pakistani families based on published literature from 1999 to April 2023.
**Methods:** A systematic literature search was conducted in PubMed, Google Scholar, and Web of Science following PRISMA guidelines. Inclusion criteria were studies on Pakistani families with syndromic or non-syndromic IRDs published between 1999 and April 2023. A total of 126 articles (1 case series, 34 case reports, 91 cohort studies) were included. Data on demographics, clinical features, and genetic variants were extracted. Genomic nomenclature was validated using VariantValidator, and pathogenicity was assessed per ACMG guidelines using Varsome, ClinVar, and in-silico tools (CADD, DANN, LRT, Mutation Assessor, Mutation Taster, Mutpred, PolyPhen-2, PROVEAN, SIFT).
**Key Results:** A total of 277 unique sequence variants in 87 known IRD-associated genes were identified. Parental consanguinity was reported in 70.03% of cases, and 88.81% of variants were homozygous. Over 95% of IRDs were recessively inherited. Missense variants were most common (41.88%), followed by indels/frameshift (26.35%), nonsense (19.13%), splice site (12.27%), and synonymous (0.36%). Non-syndromic IRDs accounted for 77.32% of cases, with retinitis pigmentosa (RP) being the most frequent (41%), followed by Leber congenital amaurosis (LCA) (14%). The most frequently mutated gene was PDE6A (5.32%), followed by TULP1 (4.76%), RP1 (4.48%), and RPE65 (4.48%). Among syndromic IRDs, Bardet-Biedl syndrome and Usher syndrome each accounted for 8% of cases. A recurrent frameshift mutation in LCA5 (c.1151delC) was reported seven times, and a missense variant in TULP1 (c.1138A>G) was reported five times. ACMG classification of all variants showed 71.48% as pathogenic/likely pathogenic, 19.49% as variants of uncertain significance, and 2.89% as benign/likely benign.
**Clinical Implications:** This review underscores the unique genetic architecture of IRDs in Pakistan, driven by high consanguinity, leading to a predominance of recessive, homozygous mutations. The identification of PDE6A as the leading cause of IRDs in this population contrasts with global trends where ABCA4 and USH2A are more common. These findings have direct implications for genetic counseling, carrier screening, and the development of targeted therapies. The high rate of consanguinity also facilitates the discovery of novel disease genes, as evidenced by at least 12 IRD-associated genes first identified in Pakistani families. The study highlights the need for comprehensive genetic testing and public health strategies to address the burden of IRDs in Pakistan.