Elucidation of Molecular Genetic Basis of Schizophrenia and Primary Microcephaly in Pakistani Population

The high degree of consanguineous marriages, languages, and religion are important factors responsible for high frequency of diverse hereditary disorders in Pakistani population. High incidence of inherited disorders is an ideal substrate to initiate molecular studies in Pakistani population. In this thesis I have systematically identified, phenotyped and sampled complex disorder (Schizophrenia) and rare Mendelian disorder (Primary Microcephaly) in families of different ethnicities/regions in Pakistan. Schizophrenia is a chronic neuropsychiatric disease afflicting around 1.1% of the population worldwide. The symptoms appear in late adolescence or early adulthood, and mainly manifest as hallucination, delusions, cognitive deficit, abnormal moods and behavior. In this thesis 16 multiplex schizophrenia families were systematically identified, diagnosed and sampled from different ethnicities/regions of Pakistan, along with a second cohort of 508 unrelated Pakistani schizophrenia patients. Fifteen out of the sixteen families were excluded for the presence of pathogenic Copy Number Variations (CNVs) by genome wide array screening. While in one of the 16 families pathogenic rare novel duplication was detected on chromosome 5q14.1_q14.2 that truly segregated with the phenotype. Exome sequencing of schizophrenia families revealed three rare and eight common variants in two families. A set of top schizophrenia candidate genes (MIR137, CACNA1C, CSMD1, GRM3 and DRD2) was selected to evaluate their association with schizophrenia in Pakistani population. A case control association study revealed a significant difference in the genotype and allele frequencies of three SNPs between the patients and controls (p = 0.000). Autosomal Recessive Primary Microcephaly (MCPH) is a neurodevelopment defect, characterized by congenital reduction in Occipitofrontal Circumferance (OFC)/Head Circumference (HC) is at least 4 standard deviations (SD) below the ethnically matched, age and sex related mean. MCPH is associated with some degree of mental retardation which persists throughout their life without additional xx morphological or clinical symptoms. The prevalence of primary MCPH is 1 in 10,000 in Pakistani population. In this thesis six consanguineous MCPH families originating from different cities of Punjab were analyzed. Linkage analysis and exome sequencing revealed four novel and two known mutations in MCPH families. The findings in this study will help in understanding the disease mechanism and related pathways as well as annotating various entities of genome. This knowledge will help in efficient carrier screening, genetic counseling and prenatal diagnosis of affected families and ultimately to development of effective therapeutic approaches.