Neural tube defects are one of the most common congenital malformations. They have been included in the category of multifactorial-threshold inheritance and can be part of several chromosomal abnormality syndromes. Nonetheless, none of the gene loci conferring susceptibility to neural tube defects have been located. Studies identifying loci in quantitative inheritance suggest that a small number of loci cause most of the trait variation. Consequently, the present techniques of linkage mapping are likely to succeed in identifying susceptibility loci. We are using linkage mapping techniques to identify gene loci which contribute to the phenotype of neural tube defects. We have collected to date 65 families with more than one living case of neural tube defect (including 185 cases of myelomeningocele, 17 cases of sacral defect with anterior sacral meningocele, and 513 unaffected family members). There are 31 autosomal dominant families and a total of 176 affected pairs (including sib-pairs and affected relative pairs). One autosomal dominant family has 17 affected individuals in 5 generations. Blood lymphoblast lines have been prepared for 104 individuals so far in these families. We have identified candidate gene loci and are typing members of these families for highly informative polymorphisms at or near these loci using PCR polymorphisms (especially dinucleotide repeats), VNTRs and RFLPS. Data are analyzed by affected-pair methods for the sib-pairs and affected relative pairs and by the lod score method for the dominant families. We continue to collect families and blood samples. We estimate there are at least 300 such families in the United States. Identification of loci conferring susceptibility to neural tube defects is important because: a) Identification of genetically susceptible individuals in the population will facilitate identification of the environmental factors which interact to cause neural tube defects. b.) Knowledge of the genetic and environmental factors will lead to strategies for prevention in susceptible individuals. c.) Cloning the susceptibility genes will allow determination of their function and their mechanism of action. d.) Knowledge of genetic factors will aid in genetic counseling and prenatal diagnosis of these disorders.
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