Brachydactyly Type D and Type E linked to chromosome 7p in an ethnic group from eastern Nepal. K. D. Williams1, J. Blangero2, S. A. Czerwinski1, C. R. Cottom1, S. Lawrence1, J. Subedi3, B. Jha4, T. Dyer2, J. L. VandeBerg2, S. Williams-Blangero2, B. Towne1 1) Wright State University Boonshoft School of Medicine, Dayton, OH; 2) Southwest Foundation for Biomedical Research, San Antonio, TX; 3) Miami University, Oxford, OH; 4) Tribhuvan University Institute of Medicine, Kathmandu, Nepal.

   There is phenotypic overlap between Brachydactyly Type D (BDD) and Brachydactyly Type E (BDE) that suggests a possible common underlying etiology. BDD is characterized by a short, broad distal phalanx of the thumb, and BDE includes short 3rd, 4th, and/or 5th metacarpals and often the thumb. The Jirel ethnic group of eastern Nepal participates in various genetic epidemiological studies, including those of skeletal growth and development. As part of the Jiri Growth Study, a hand-wrist x-ray is taken annually for each child to assess skeletal maturation. Hand-wrist x-rays have also been taken for all adult relatives in order to study familial brachydactylies. For this study, a total of 2,308 individuals (1,381 children; 927 adults) in one large extended pedigree were examined for BDD and BDE. The prevalence of BDD and BDE in this sample is 3.94%. We used variance-components methods implemented in SOLAR (Almasy and Blangero, 1998) to conduct a genome-wide linkage scan for QTL influencing BDD- and/or BDE-affected status in a subsample of 1,722 individuals typed for ~400 STR markers. The additive genetic heritability was highly statistically significant in this sample (h2 SE = 0.78 0.11, p=210-12). Significant linkage was found for BDD and/or BDE to markers on chromosome 7p at 40 cM between 7p21-7p14 (LOD score = 3.74). Possible positional candidate genes in the one-lod support interval include TWIST1 and the HOXA1-A13 cluster. Mutations of TWIST1 and HOXA13 have been implicated in other limb development disorders. This is the first study to report significant linkage results for BDD and BDE using a large extended pedigree, and the first to suggest that TWIST1 and/or the HOXA1-A13 cluster may contribute to these specific skeletal anomalies. Supported by NIH grants F32HD053206, R01HD40377, R01AI37091, R01AI44406, and R37MH59490.