In our database, we discovered two families with hitherto unreported co-occurrence of FBN1/FBN2 variants causing phenotypes with mixed or modified MFS/CCA clinical features.
The presence of fibrillin 2 in the murine zonule and an intact zonule in Fbn1-knockout mice may limit the utility of rodent models for studying ectopia lentis in MFS.
Their physiological importance is underscored by the complex spectrum of clinical manifestations associated with mutations of fibrillin-1 and fibrillin-2 in Marfan syndrome (MFS) and congenital contractural arachnodactyly, respectively.
The incidence of CCA is unknown and its prevalence is difficult to estimate considering the overlap in phenotype with MFS; the number of patients reported has increased following the identification of FBN2 mutation.
In order to evaluate the contribution of FBN1, FBN2, TGFBR1, and TGFBR2 mutations to the Marfan syndrome (MFS) phenotype, the four genes were analyzed by direct sequencing in 49 patients with MFS or suspected MFS as a cohort study.
All the identified CCA mutations in FBN2 cluster in a limited region similar to where severe MFS mutations cluster in FBN1, specifically between exons 23 and 34.
Impaired assembly potentially plays a role in the molecular pathogenesis of genetic disorders caused by mutations in fibrillin-1 (Marfan syndrome) and fibrillin-2 (congenital contractural arachnodactyly).
Previous studies have mapped the human genes for two fibrillins to chromosome bands 15q21 (FBN1) and 5q23-q31 (FBN2) and have demonstrated that FBN1 mutations are associated with Marfan syndrome, while FBN2 is linked to the gene for congenital contractural arachnodactyly.