Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Ehlers-Danlos Syndrome vascular Type (EDS type IV) [Q79.6]

OMIM numbers: 130050, 120180 (COL3A1)

Dr. rer. nat. Karin Mayer

Scientific Background

A typical feature of the vascular EDS type IV, apart from easily bruising and translucent skin, is the high risk for arterial, uterine or organ rupture with fatal bleeding. Typical facial features can support clinical diagnosis. The pattern of inheritance is autosomal dominant, the prevalence is estimated to be 1:50,000. Mutations in the COL3A1 gene (α1 chain of type III collagen) are causative. So far more than 200 different mutations are known, more than 50% are de novo mutations. The mutational spectrum includes 60% missense mutations (predominantly glycine substitutions within the triple helix) and 30% splice mutations as well as frameshift mutations. Structural mutations generally affect the formation of homotrimers which, in the case of heterozygosity, causes 90% of the trimers to contain at least one mutated α1 chain and not being secreted. Translational stop mutations, what is known as null alleles, lead to haploinsufficiency. Genomic deletions and complex rearrangements that affect all or several exons make up about 5% of all described mutations in the COL3A1 gene.

With up to 45% type III collagen is an important component in the walls of arteries and inner organs which makes these tissues to be particularly affected in EDS type IV. The clinical diagnosis can be supported by the biochemical and electron-microscopical detection of structural defects in type III collagen and confirmed by the detection of a mutation in the COL3A1 gene. The mutation detection rate in patients that fulfill the major criteria of the Vilefranche classification is higher than 90%.

A clinical subtype of Loeys-Dietz syndrome (LDS II) is a differential diagnosis to EDS type IV. Like in EDS type IV, characteristic for LDS II are aneurysms and ruptures of the great vessels as well as translucent skin and propensity for hematoma formation without finding the typical abnormalities in the type III collagen or mutations in the COL3A1 gene. In this case, mutations in the genes for the transforming growth factor beta receptors 1 and 2  (TGFBR1 and TGFBR2) are causative.