Keywords: Molecular Basis of Mendelian Disorders, KW037 - DYSMORPHOLOGY, KW068 - GENOTYPE-PHENOTYPE CORRELATIONS, KW099 - NATURAL HISTORY, KW110 - PHENOTYPE, KW015 - CHARACTERIZATION OF DISORDERS

Genotype/Phenotype Correlations in Vascular Ehlers-Danlos Syndrome. J. Yang¹, B.F. Griswold¹, W. Chen¹, C.A. Francomano², N.B. McDonnell¹ 1) LCI, NIA/NIH, Baltimore, MD; 2) GBMC, Baltimore, MD.

   Vascular Ehlers-Danlos syndrome is a hereditary disorder of connective tissue caused by mutations in COL3A1, encoding procollagen III. The clinical features include skin fragility, easy bruising and bleeding, joint hypermobility, bowel or uterine rupture, arterial dissections and aneurysms. The life expectancy is significantly reduced. Analysis of phenotype/genotype correlations with COL3A1 mutations can be helpful for anticipatory guidance and counseling for affected families. Thirteen affected families were identified at the National Institutes of Health, and COL3A1 gene was sequenced. The mutations identified included substitution mutations leading to the critical glycine residues in the collagen helix, splice site mutations, small deletions that disrupt the alignment of collagen trimers, as well as premature termination codons that lead to haploinsufficiency. The exon skipping mutations were associated with severe skin features and scarring, while the haploinsufficency mutations were found to lead to a relatively milder phenotype with later age of onset of complications. Glycine substitution mutations were associated with a higher incidence of aneurysms and variable skin features. Maternal death due to uterine rupture had not occurred in the probands or affected family members in our cohort.