RESUMO
Van der Woude syndrome (VWS) is an autosomal dominant craniofacial disorder with high penetrance and variable expression. Its clinical features are variably expressed, but include cleft lip and/or cleft palate, lip pits and hypodontia. All VWS families studied to date map the disease gene to a < 2 cM region of chromosome 1q32, with no evidence of locus heterogeneity. The aim of this study is to refine the localization of the VWS gene and to further assess possible heterogeneity. We analyzed four multiplex VWS families. All available members were clinically assessed and genotyped for 19 short tandem repeat markers on chromosome 1 in the VWS candidate gene region. We performed two-point and multipoint limit of detection (LOD) score analyses using a high penetrance autosomal dominant model. All families showed positive LOD scores without any recombination in the candidate region. The largest two-point LOD score was 5.87. Our assay method for short tandem repeat (STR) markers provided highly accurate size estimation of marker allele fragment sizes, and therefore enabled us to determine the specific alleles segregating with the VWS gene in each of our four families. We observed a striking pattern of STR allele sharing at several closely linked loci among our four Caucasian VWS families recruited at three different locations in the US. These results suggest the possibility of a unique origin for a mutation responsible for many or most cases of VWS.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 1/genética , Fenda Labial/genética , Fissura Palatina/genética , Repetições de Microssatélites/genética , Alelos , Efeito Fundador , Humanos , Escore Lod , Mutação , Linhagem , Penetrância , SíndromeAssuntos
Cromossomos Humanos Par 6/genética , Desequilíbrio de Ligação , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Esquizofrenia/genética , Repetições de Trinucleotídeos/genética , Ataxina-1 , Ataxinas , Simulação por Computador , Feminino , Ligação Genética , Humanos , Masculino , Modelos GenéticosRESUMO
We have performed linkage analysis in 186 multiplex families to search for genes that predispose to schizophrenia. Under a model with partially dominant inheritance, moderately broad disease definition and assuming locus homogeneity, a lod score of 3.2 was obtained for D6S260 on chromosome 6p23. A multipoint lod score of 3.9 (P = 2.3 x 10(-5)) was achieved when the F13A1 and D6S260 loci were analysed, allowing for locus heterogeneity. Adjusted for testing of multiple models, the multipoint lod score of 3.9 under heterogeneity has a genome wide significance of between 5-8%. The nonparametric affected pedigree member test provided results (P = 3 x 10(-4)) also supporting this finding. Our findings provide supportive evidence for a susceptibility locus for schizophrenia on distal chromosome 6p, and support a model of locus heterogeneity.
