Report of five novel and one recurrent COL2A1 mutations with analysis of genotype-phenotype correlation in patients with a lethal type II collagen disorder

Achondrogenesis II-hypochondrogenesis and severe spondyloepiphyseal dysplas ia congenita (SEDC) are lethal forms of dwarfism caused by dominant mutatio ns in the type II collagen gene (COL2A1). To identify the underlying defect in seven cases with this group of conditions, we used the combined strateg y of cartilage protein analysis and COL2A1 mutation analysis. Overmodified type II collagen and the presence of type I collagen was found in the carti lage matrix of all seven cases. Five patients were heterozygous for a nucle otide change that predicted a glycine substitution in the triple helical do main (G313S, G517V, G571A, G910C, G943S). In an five cases, analysis of car tilage type II collagen suggested incorporation of the abnormal al(II) chai n in the extracellular collagen trimers. The G943S mutation has been report ed previously in another unrelated patient with a strikingly similar phenot ype, illustrating the possible specific effect of the mutation. The radiogr aphically less severely affected patient was heterozygous for a 4 bp deleti on in the splice donor site of intron 35, likely to result in aberrant spli cing. One case was shown to be heterozygous for a single nucleotide change predicted to result in a T1191N substitution in the carboxy-propeptide of t he proal(II) collagen chain. Study of the clinical, radiographic, and morph ological features of the seven cases supports evidence for a phenotypic con tinuum between achondrogenesis II-hypochondrogenesis and lethal SEDC and su ggests a relationship between the amount of type I collagen in the cartilag e and the severity of the phenotype.