This variant, formerly titled MARFAN SYNDROME, ATYPICAL or MARFAN SYNDROME VARIANT, has been reclassified based on the findings of Forlino et al. (1998) and Vomund et al. (2004).
Byers et al. (1981) found 2 species of the alpha-2 chain of type I collagen in 1 of 11 Marfan patients studied; one of the alpha-2 chains was normal whereas the other contained a 20-amino acid insertion in the amino-terminal propeptide. This alteration in chain size probably accounted for the 5- to 10-fold increase in collagen extraction into nondenaturing solvents from this patient's skin compared to controls. The patient of Byers et al. (1981) was a 39-year-old woman who had unaffected parents and 2 unaffected sibs. Features were equinovarus deformities of both feet at birth; arachnodactyly first noted at age 9 and lumbar scoliosis and heart murmur first noted at age 10. Aortic and mitral regurgitation with dilated root of the aorta prompted surgical replacement of the aortic valve and a portion of the ascending aorta at age 37. Her height was 164.5 cm, span 178 cm, upper segment to lower segment ratio 0.80. No lens dislocation was detected. She showed bluish-gray sclerae and mild myopia. Mild pectus carinatum was present, as well as long slender limbs with increased mobility in all joints except the fourth and fifth fingers which bilaterally showed marked camptodactyly. Henke et al. (1985) suggested that there was a 38-basepair insertion in the COL1A2 gene that caused the Marfan syndrome. Dalgleish et al. (1986) found, however, that this is a common polymorphism of the COL1A2 gene. Among 28 normal persons, 12 were homozygous for the large oligo, 12 were heterozygous, and 4 were homozygous for the small oligo. Phillips et al. (1990) further studied the patient and demonstrated a single base change, resulting in substitution of arginine-618 by glutamine at the Y position of a Gly-X-Y repeat. Family studies indicated that the substitution was inherited from the patient's father who also produced abnormally migrating pro-alpha-2(I) collagen chains and shared some of the abnormal skeletal features. The single base change at nucleotide 2258 resulted in a new Bsu36I (SauI, MstII) restriction site detectable in genomic DNA by Southern blot analysis when probed with a COL1A2 fragment. Analyses of 103 chromosomes in 52 controlled individuals were negative for the new site, indicating that the substitution is not a common polymorphism.
Forlino et al. (1998) identified the R618Q variant and a gly421-to-asp mutation (G421D; 120160.0053) in cis in a patient with lethal osteogenesis imperfecta (166210). The patient's unaffected father also carried the R618Q variant. Forlino et al. (1998) determined that the R618Q variant resulted in only mild electrophoretic delay. They suggested that G421D was the causative mutation and that R618Q is a rare variant.
Vomund et al. (2004) analyzed the helical stability and fibrillar assembly of type I collagen from cultured dermal fibroblasts of controls and 2 unrelated individuals heterozygous for the R618Q variant. They found that the thermal stability of the R618Q-containing collagen molecules did not differ statistically from control molecules, but that the diameter of assembled R618Q-containing collagen fibrils was approximately 20% of control collagen fibrils. Vomund et al. (2004) suggested that while the R618Q variant does not impact triple-helical stability, it does impact collagen fibril assembly and may therefore have a role as a modifier in disease pathogenesis.
