A systematic review of hereditary neurological disorders diagnosed by whole exome sequencing in Pakistani population: updates from 2014 to November 2024.

Hereditary neurological disorders (HNDs) are a group of heterogeneous disorders characterized by significant genetic and clinical variability. HNDs are caused by dysfunction of the central or peripheral nervous system due to aberrant electrical impulses. More than 600 types of HNDs have been documented, and overall, these are the second leading cause of death worldwide. This systematic review is based on a retrospective analysis of research articles reporting HNDs diagnosed using whole exome sequencing in Pakistani families from 2014 to November 2024. Original research articles were retrieved through online surveys, notably Google Scholar, PubMed, and the Web of Science. Based on stringent selection criteria, 89 research articles and 188 variants published around 10 years were considered. Variants and research articles were cross-checked and further validated in different online databases/resources to confirm their genomic nomenclature and pathogenicity according to the ACMG guidelines. A total of 188 variants in 143 distinct genes in Pakistani families identified through whole exome sequencing have been reported to date that caused genetic and clinically heterogeneous HNDs. Consanguineous parentage was found in around 90% of cases, and approximately 91% of causative alleles were reported in homozygous state showing a predominant burden of HNDs because of blood-related marriages. The most frequent type of pathogenic variants were single nucleotide substitutions (92 missense and 39 nonsense). Among 188 variants, 76 variants were reported in 2024 and 44 variants were observed in 2023. Pakistan is the fifth most populous country in the world having an extreme prevalence of consanguinity resulting in the expression of pathogenic variants due to homozygosity. Therefore, there is a prevalence of genetic disorders particularly rare monogenic or Mendelian disorders. Next-generation sequencing approach is strongly recommended for diagnosis, early therapeutic intervention and genetic counselling.