Refinement of 2q and 7p loci in a large multiplex NTD family

BACKGROUND: NTDs are considered complex disorders that arise from an interaction between genetic and environmental factors. NTD family 8776 is a large multigenerational Caucasian family that provides a unique resource for the genetic analysis of NTDs. Previous linkage analysis using a genome-wide SNP screen in family 8776 with multipoint nonparametric mapping methods identified maximum LOD* scores of similar to 3.0 mapping to 2q33.1-q35 and 7p21.1-pter. METHODS: We ascertained an additional nuclear branch of 8776 and conducted additional linkage analysis, fine mapping, and haplotyping. Expression data from lymphoblast cell lines were used to prioritize candidate genes within the minimum candidate intervals. Genomic copy number changes were evaluated using BAC tiling arrays and subtelomeric fluorescent in situ hybridization probes. RESULTS: Increased evidence for linkage was observed with LOD* scores of similar to 3.3 for both regions. Haplotype analyses narrowed the minimum candidate intervals to a 20.3 Mb region in 2q33.1-q35 between markers rs1050347 and D2S434, and an 8.3 Mb region in 7p21.1-21.3 between a novel marker 7M0547 and rs28177. Within these candidate regions, 16 genes were screened for mutations; however, no obvious causative NTD mutation was identified. Evaluation of chromosomal aberrations using comparative genomic hybridization arrays, subtelomeric fluorescent in situ hybridization, and copy number variant detection techniques within the 2q and 7p regions did not detect any chromosomal abnormalities. CONCLUSIONS: This large NTD family has identified two genomic regions that may harbor NTD susceptibility genes. Ascertainment of another branch of family 8776 and additional fine mapping permitted a 9.1 Mb reduction of the NTD candidate interval on chromosome 7 and 37.3 Mb on chromosome 2 from previously published data. Identification of one or more NTD susceptibility genes in this family could provide insight into genes that may affect other NTD families.