The genetic heterogeneity of severe von Willebrand disease (vWd) type III was estimated by analysing extended haplotypes of eleven intragenic restriction fragment length polymorphisms and one variable number of tandem repeat polymorphism in 32 patients from 28 families from Germany or of German origin. All patients were screened for gross deletions and for mutations at potential "hot spot" regions of the von Willebrand factor (vWf) gene. Disease-associated haplotypes were established in 24 families. Only a few, apparently unrelated families shared common haplotypes suggesting a considerable genetic heterogeneity in the German population of vWd type III patients. Defects causing vWd type III were identified on 14 out of 56 chromosomes (25%). Gross deletions were detected in two families. A complete homozygous deletion of the vWf gene was displayed in one patient. Another patient was compound heterozygous for a large deletion of at least 100 kb of the vWf gene with an additional, as yet unidentified, defect. One homozygous missense mutation was detected in exon 10, and two nonsense mutations were detected in exon 8 and exon 45 of the vWf gene, respectively. A frameshift mutation (delta C) in exon 18 was identified in five families and an additional frameshift mutation (delta G) was found in exon 28 in one family. It appears that delta C is the most common molecular defect in German patients with vWd type III. Its association with a number of different haplotypes suggests repeated de novo mutations at a mutation "hot spot". Evidence is presented that particular molecular defects causing vWd type III are associated with different patterns of inheritance, depending on their location within the vWf gene. Complete deletions of the gene and nonsense mutations in the pro-sequence are correlated with recessive inheritance, whereas frameshift and nonsense mutations in the gene sequence corresponding to the mature vWf subunit tend to be inherited in a dominant fashion.
Five sets of monozygotic (MZ) twins with Williams-Beuren syndrome (WBS) have been reported so far. We report on an additional pair of mz twins concordant for WBS but variable expression for the syndrome. Although both faces look different monozygosity of the twins was proven by DNA fingerprint analysis, HLA, and blood group pattern. Both girls had the typical facial appearance with strabismus. Both had developmental delay, mild supravalvular aortic stenosis (SVAS), hypoplasia of both pulmonary arteries and multiple peripheral pulmonary stenoses, and inguinal hernia. Unilateral renal agenesis was seen in one of the twins. In addition the pedigree pointed to a second disorder with probably autosomal dominant inheritance. Both twins had a cleft palate, but their father had cleft lip and the grandfather as well as the greatgrandfather had cleft lip/palate. Findings of linkage analysis in pedigrees with nonsyndromic oral facial cleft were taken to suggest that a major locus for nonsyndromal oral facial cleft is located on the distal portion of chromosome 6. Linkage studies could serve as a starting point to examine a locus associated with WBS. Our observation and reports on the literature support the hypothesis that WBS is a genetic disorder.
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