Genetic Analysis of Complex Neurodevelopmental Disorders: A Model for the genetic etiology of autism and the related pervasive develomental disorders and Mapping of a gene responsible for X-linked mental retardation
Date of Award
Doctor of Philosophy (PhD)
Professor Bradley N. White
The genetic factors underlying many of the major neuropsychiatric disorders have so far escaped elucidation, due to their complex segregation patterns and confounding influences such as heterogeneity and non-genetic influences. Approaches which are specifically suited to these types of problems have been developed, and are currently being applied to the genetic analysis of complex disorders. Two examples of such approaches are described here: the identification of genes involved in the etiology of autism and the pervasive developmental disorders (autism/PDD) using affected sib pair and allelic association methods, and the linkage analysis of X-linked mental retardation in an extended pedigree. The excess of males in the autistic/PDD population suggests the involvement of a locus on the X chromosome in the etiology of this group of disorders. In thirty-two pairs of affected brothers (male multiplex sibships), no evidence of increased sharing of maternal alleles was found at any of 16 highly polymorphic loci distributed along the X chromosome. However, at loci in the monoamine oxidase A gene in Xp11.23-11.4, the mothers of these affected sib pairs showed decreased heterozygosity. A haplotype consisting of the B2 and 122 bp alleles at two polymorphisms in the gene was found to be significantly more frequent in mothers of male multiplex sibships than in controls (x²=16.22, 14 df, p<0.05). As the affected siblings were not concordant for this haplotype more often than expected by chance, these data suggest that maternal genotype plays a role in the etiology of autism/PDD, i.e. that altered maternal MAOA activity results in the exposure of the fetus to abnormal monoamine neurotransmitter levels at a critical point in development, leading to autism/PDD. In the same set of male multiplex sibships, evidence was found for increased concordance near the serotonin transporter in 17q11.2-q21 (x²=7.11,1 df, p<0.01) and the dopamine transporter in 5p13.3 (x²=5.24, 1 df, p<0.025). Concordance was significantly increased for maternal, but not paternal, alleles at these loci. No significant increase in concordance was found for a locus linked to the norepinephrine transporter gene in 16q12.2. These findings suggest roles for the serotonin and dopamine transporters in the etiology of autism/PDD in these families. On the basis of these results in male multiplex families and other evidence from the literature, a model for the etiology of autism/PDD is proposed, in which the disorder arises from exposure of the fetus at a critical stage of development to abnormal monoamine neurotransmitter levels from maternal serum, due to a combination of maternal and fetal genotypes,and influenced by environmental factors. This model explains most of the unusual genetic features of autism/PDD. Two-point linkage analysis was used to map the locus responsible for X-linked mental retardation with macrocephaly and seizures (MRX38) in a single family with five affected males, to Xp21.1-p22.13, with a peak lod score 2.71 with no recombination. The region of localization is bounded by recombination events with DXS1226 distally and DXS1238 proximally, defining a genetic interval of approximately 14cM. The MRX38 locus maps to a region overlapping several other MRX localizations, but appears to represent a novel X-linked mental retardation entity.
Schutz, Christopher Kevin, "Genetic Analysis of Complex Neurodevelopmental Disorders: A Model for the genetic etiology of autism and the related pervasive develomental disorders and Mapping of a gene responsible for X-linked mental retardation" (1998). Open Access Dissertations and Theses. Paper 1082.