Alakbarzade, V; (2016) Defining The Genetic Basis Of Three Hereditary Neurological Conditions In Families From The Indian Subcontinent. Doctoral thesis , UCL (University College London).

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Abstract

Neurogenetic studies have revolutionised our understanding of the genetic and molecular basis of inherited neurological disorders, primarily as a result of the identification of single disease-causing genes. The incidence of such disorders is increased amongst populations with common shared ancestry or a high rate of consanguinity. Hence, the investigation of inherited neurological conditions in genetic isolates provides a robust opportunity to define the molecular pathogenic basis of these conditions. Neurological and neurodevelopmental disorders present important public health issues in the developing countries in the Indian subcontinent. The global burden of these disorders is worsened by the lack of targeted research funding and relevant in-country research capacity. This project, undertaken as part of a wider research study investigating inherited disorders in the Indian subcontinent, aimed to define the molecular genetic bases of three extended families with distinct neurological and neurodevelopmental disorders. In the first family with multiple individuals affected by a severe autosomal recessive form of neurodevelopmental delay with microcephaly, genetic studies identified mutation in a gene (MFSD2A), not previously associated with inherited disease, which led to a reduction of fatty acid transportation in patients homozygous for the disease-causing mutation. In the second family, genotyping identified a complex chromosomal rearrangement associated with diverse clinical outcomes including Wolf Hirschorn-, 3p deletion-, and 4p duplication syndrome, among ten chromosomally-imbalanced affected individuals. In the third family, a duplication event on chromosome 15q24 encompassing the LINGO1 gene was identified as a likely cause of dystonic tremor in affected individuals. Together these molecular discoveries provide fundamentally important biological insight into the pathogenic basis of abnormal brain growth and control of movement with the potential diagnostic and treatment applications.

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