Biallelic COL3A1 mutations result in a clinical spectrum of specific structural brain anomalies and connective tissue...

Vascular Ehlers-Danlos syndrome (type IV) is an autosomal dominant disorder caused by heterozygous variants of COL3A1. We identified biallelic COL3A1 variants in two unrelated families. In a 3-year-old female with developmental delay the nonsense variant c.1282C>T, p.(Arg428*) was detected in combination the c.2057delC, p.(Pro686Leufs*105) frame shift variant. Both compound heterozygous variants were novel. This patient was born with bilateral clubfoot, joint laxity, and dysmorphic facial features. At the age of 2 years she developed an aneurysmal brain hemorrhage. Cerebral MRI showed a peculiar pattern of profound cerebral abnormalities including bilateral frontoparietal polymicrogyria of the cobblestone variant. In the second family, the two affected siblings were homozygous for the missense variant c.145C