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Identification and functional studies of genetic variants causing neurodevelopmental disorders in the Pakistani population

  • Date: 2022-2026
  • Project leader: Waqas Ahmad

Neurodevelopmental disorders (NDDs) are clinically and genetically heterogeneous group of disorders, which includes primary microcephaly, autism spectrum disorder, intellectual disability, cerebral palsy, leukodystrophy and other congenital neural anomalies. They are associated with a broad range of symptoms, such as deficits in language, behavioural and other motor functions. Consanguinity increases the probability of a rare recessive disease variant to manifest in offspring in homozygous state leading to an abnormal phenotype. In Pakistan around 70% of the local population is practicing such unions, making it one of the most inbred populations in the world. Identification of the underlying mutations is the first step towards any disease prevention. Cutting-edge sequencing techniques such as Illumina Global Screening Array coupled with homozygosity mapping will be used to identify causative variants in affected individuals. Comparative genomic analysis will be performed to characterize the novel variants and determine their possible involvement in neurodevelopmental pathways. This study combined sequencing with functional testing approaches which are based to established functional role of each defective protein. we will use Zebrafish as a model organism to investigate novel disease loci by establishing mutant stable lines. Structural and functional deficits associated with NDD will be identified by dysfunction of candidate gene. Several cellular characterization techniques (qPCR, RNAseq, and in-situ hybridization) will be used to detect and visualize cell proliferation, apoptosis, and neuronal structures. The ability to visualize neuronal cell types and migration is a key strength of this model system. Together this work expands the genetically heterogenous mutational landscape and mechanistic understanding of central nervous system

Project in collaboration with Professor Richard Nichols