Genetic investigation of both complex and Mendelian disorders: neural tube defects and Native American myopathy

This dissertation seeks to map genes for two disorders: one complex and one Mendelian. The first project investigated the genetic basis of neural tube defects (NTDs) in one large multiplex family (8776). NTDs are among the most common debilitating birth defects occurring in ~1/1000 live births in the U.S. and are considered complex disorders with both genetic and environmental factors implicated. Linkage analysis using a genomewide single-nucleotide polymorphism (SNP) screen in family 8776 identified maximum LOD* scores of ~3.0 mapping to 2q33.1- q35 and 7p21.1-pter. Ascertainment of another branch of this family further supported linkage at these two loci providing a ~3.3 LOD* score, and decreased the linkage interval for 7p by 7.8 Mb. Further haplotype analyses narrowed the minimum candidate intervals, with the new regions mapping to 2q33.1-q35 (20.3 Mb) and to 7p21.1-21.3 (8.3 Mb). Within these regions, sequencing of exons in eighteen candidate genes did not identify a causative mutation and chromosomal abnormalities were undetected. Identification of an NTD iii gene in this family may aid in a directed search for a disease gene for more typical NTD families. The second project studied Native American myopathy (NAM), a rare congenital disorder observed in the Lumbee population. In this dissertation, shared clinical features are described among 14 individuals of Lumbee Indian descent with Native American myopathy. Notably, in these 14 subjects, we observed a 36% mortality rate and 29% had MH episodes. The Lumbee population is relatively isolated with evidence of consanguinity suggesting that homozygosity mapping methods may be employed for identifying the NAM disease locus. To this end, we conducted a genomewide SNP screen which demonstrated five regions of shared homozygosity (≥ 3 contiguous SNPs) in individuals with NAM. Genotyping microsatellites in these five regions lead to only one 5.6 Mb region of shared homozygosity amongst the NAM patients mapping to 12q13.13 to 12q14.1. Sequencing of four genes within this region did not identify a functional mutation. Ultimately, the goal of these projects was to identify disease loci for NTD family 8776, and for NAM, to facilitate a targeted search of candidate genes for these debilitating congenital disorders