Parental mosaicism for a point mutation in a type III collagen (COI3AI) allele produces Ehlers-Danlos type IV (EDS4) in heterozygous offspring

Abstract

We describe a family with EDS type IV in which the clinically unaffected mother of two affected children is mosaic for the mutation in the COL3A1 gene. The proband, a 27 year old male, presented with a spontaneous retroperitoneal hemorrhage and multiple arterial pseudoaneurysms. At the age of 20, he had a spontaneous colonic perforation. His sister had a cerebral hemorrhage at 23, spontaneous splenic rupture at 26, recurrent paleuar dislocations and delayed wound healing. Skin fibroblasts from the proband secreted diminished amounts of type III collagen precursors and retained overmodified proα1(III) chains, consistent with a defect in one COL3A1 allele. SSCP screening and sequence analysis of cDNA identified a point mutation resulting in a substitution of Asp for Gly at amino acid 493 within the triple helical domain of the proα1(III) chain of type III collagen. The mutation eliminated an AvaII restriction site. Amplification and digestion of DNA from the proband's sister showed the identical mutation. Paternal mosaicism was initially suspected as the father had a history or spontaneous rupture of a pancreatic duct cyst. However, digestion of paternal white blood cell DNA with AvaII revealed a normal restriction pattern in the father, but evidence for the presence of the mutation in a population of cells in the mother. A small number of families have now been identified in which one asymptomatic parent was mosaic which indicates that this risk must be considered in counseling parents after the identification of an affected child.