Abstract
<title>Abstract</title> <p> Neurodevelopmental disorders (NDDs) are among the leading causes of lifelong disability worldwide. The risk of autosomal recessive NDDs is increased in endogamous populations like Pakistan. However, limited population-specific genetic data continue to hinder accurate molecular diagnosis in Pakistan. A retrospective systematic review was conducted to identify research articles reporting genetic findings in Pakistani families affected by NDDs between 2006 and 2024. Articles retrieved from PubMed, Google Scholar, and Web of Science were screened according to predefined eligibility criteria. Extracted data included demographic and clinical characteristics, implicated genes, and detailed variant annotations. Reported variants were cross-checked against ClinVar and evaluated using ACMG/AMP-based classification criteria. A total of 145 studies involving 537 families were included. Consanguinity was reported in 85% of the pedigrees, and whole-exome sequencing was the predominant molecular approach, accounting for approximately 85% of the studies. Overall, 424 unique genetic variants were identified across 289 NDD-associated genes. Almost 80% of the genes were reported in only one family, and 91% of the variants were non-recurrent. Autosomal recessive mode of inheritance accounted for approximately 86% of the total reported conditions, and 92% of the variants were identified in the homozygous state. Missense variants were the leading cause of NDDs (51%), followed by frameshift variants (22%), nonsense variants (18%), and splice-site or in-frame deletion variants (9%). Syndromic NDDs were more frequently reported than non-syndromic NDDs (79% versus 21%). Isolated intellectual disability was the most reported clinical phenotype, while <italic>ASPM</italic> , <italic>WDR62</italic> , and <italic>TRAPPC9</italic> were among the most frequently implicated genes. Most published families with available geographic information were recruited from Punjab and/or Khyber Pakhtunkhwa province. ClinVar annotations and ACMG/AMP-based assessments indicated that a substantial proportion of the reported variants were classified as pathogenic or likely pathogenic. This review provides a nationwide overview of published genetic findings associated with NDDs in Pakistani families over an 18-year period. The marked predominance of autosomal recessive inheritance and homozygous variants reflects the important contribution of consanguinity to the genetic burden of NDDs in Pakistan. Whole-exome sequencing was the principal molecular diagnostic and gene-discovery approach. The identification of 424 variants across 289 genes highlights the extensive genetic and allelic heterogeneity of NDDs in Pakistan. </p>