Ten novel<i>FBN2</i>mutations in congenital contractural arachnodactyly: Delineation of the molecular pathogenesis and clinical phenotype

TLDR

Congenital contractural arachnodactyly is an autosomal dominant disorder with skeletal features similar to Marfan syndrome but lacking its ocular and cardiovascular complications, caused by mutations in FBN2 that cluster between exons 23 and 34, mirroring the mutation hotspots of FBN1 in Marfan syndrome. The study screened exons 22–36 of FBN2 in 13 classic CCA patients using SSCP followed by direct sequencing. Ten novel FBN2 mutations were identified in the critical region, yielding a 75 % detection rate; none affected the calcium‑binding consensus sequence unlike many FBN1 mutations, and clinical analysis showed aortic root dilatation but generally no congenital heart disease, underscoring implications for molecular understanding, diagnosis, and genetic counseling of CCA. Hum Mutat 19:39–48, 2002; © 2001 Wiley‑Liss, Inc.

Abstract

Congenital contractural arachnodactyly (CCA) is an autosomal dominant condition that shares skeletal features with Marfan syndrome (MFS), but does not have the ocular and cardiovascular complications that characterize MFS. CCA and MFS result from mutations in highly similar genes, FBN2 and FBN1, respectively. 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. We screened exons 22 through 36 of FBN2 for mutations in 13 patients with classic CCA by single stranded conformational polymorphism analysis (SSCP) and then by direct sequencing. We successfully identified 10 novel mutations in this critical region of FBN2 in these patients, indicating a mutation detection rate of 75% in this limited region. Interestingly, none of these identified FBN2 mutations alter amino acids in the calcium binding consensus sequence in the EGF-like domains, whereas many of the FBN1 mutations alter the consensus sequence. Furthermore, analysis of the clinical data of the CCA patients with characterized FBN2 mutation indicate that CCA patients have aortic root dilatation and the vast majority lack evidence of congenital heart disease. These studies have implications for our understanding of the molecular basis of CCA, along with the diagnosis and genetic counseling of CCA patients. Hum Mutat 19:39–48, 2002. © 2001 Wiley-Liss, Inc.