COL3A1 haploinsufficiency results in a variety of Ehlers-Danlos syndrome type IV with delayed onset of complications and longer life expectancy.
Purpose: To characterize the clinical outcome of heterozygosity for COL3A1 null mutations in Ehlers-Danlos syndrome type IV, the vascular type. Methods: We identified mutations that produced premature termination codons and resulted in nonsense-mediated messenger RNA decay in 19 families. We reviewed the clinical and family histories and medical complications in 54 individuals from these families with COL3A1 null mutations. Results: Compared with individuals with missense or exon-skipping mutations, we found that life span was extended, the age of first complication was delayed by almost 15 years, and major complications were limited to vascular events. The families were ascertained after a complication in a single individual, but only 28% of relatives, some of whom had reached their seventies or eighties without incidents, had a complication and only 30% had minor clinical features of Ehlers-Danlos syndrome type IV Conclusion: Null mutations have reduced penetrance compared with missense and splicing mutations, and the phenotype seems to be limited almost entirely to vascular events.