Molecular Genetics of Inherited Neurodevelopmental and Neurodegenerative Brain Disorders in Pakistan: Genomic Landscape, Genotype–Phenotype Correlations, Diagnostic Challenges and Precision Medicine Perspectives

Abstract

Neurological disorders with inherited causes encompass a diverse range of conditions, including intellectual disability, autism spectrum disorders, epilepsy, hereditary spastic paraplegia, and progressive neurodegenerative disorders. In Pakistan, factors such as high rates of consanguineous marriages, large multi-generational families, geographical isolation and unique population structures have intensified the prevalence of autosomal recessive neurological disorders, leading to an accumulation of rare homozygous pathogenic variants. This review consolidates contemporary insights into the genetic architecture, genotype-phenotype correlations, and clinical challenges related to inherited brain disorders in Pakistani families. A strong emphasis is placed on advanced techniques such as homozygosity mapping, targeted gene panels, and various sequencing methods including whole-exome and whole-genome sequencing, alongside copy-number-variation analysis and functional validation. These genomic approaches have identified pathogenic variants in genes involved in neuronal processes, including migration, cortical development, synaptic signaling and mitochondrial metabolism. Despite extensive research in neurological genetics globally, Pakistan faces significant obstacles to translating genomic discoveries clinically. These challenges include a lack of diagnostic facilities, high sequencing costs, insufficient trained genetic professionals, limited bioinformatics resources and the absence of population-specific genomic databases and national rare disease registers. To overcome these hurdles, it is essential to integrate genomics with advancements in Artificial Intelligence, multi-omics technologies, detailed clinical phenotyping, functional studies and culturally sensitive genetic counseling. The implementation of national genomic initiatives, establishment of multidisciplinary precision-neurology centers and provision of equitable diagnostic services stand to enhance early diagnosis, variant interpretation, reproductive counseling and the development of personalized therapeutic strategies for inherited neurological disorders in Pakistan.