Exome Sequencing Identified a Novel FBN2 Mutation in a Chinese Family with Congenital Contractural Arachnodactyly.

Guoling You,Yunlan Xu,Bailing Zu,Bo Wang,Zhigang Wang,Qihua Fu

doi:10.3390/ijms18040626

Abstract

Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder of connective tissue. CCA is characterized by arachnodactyly, camptodactyly, contrature of major joints, scoliosis, pectus deformities, and crumpled ears. The present study aimed to identify the genetic cause of a three-generation Chinese family with CCA. We successfully identified a novel missense mutation p.G1145D in the fibrillin-2 (FBN2) gene as the pathogenic mutation by whole exome sequencing (WES). The p.G1145D mutation occurs in the 12th calcium-binding epidermal growth factor-like (cbEGF) domain. The p.G1145D mutation caused a hydrophobic to hydrophilic substitution, altering the amino acid property from neutral to acidic. Three-dimensional structural analysis showed that this mutation could alter the conformation of the residue side chain, thereby producing steric clashes with spatially adjacent residues, disrupting the formation of H bonds and causing folding destabilization. Therefore, this amino acid appears to play an important role in the structure and function of FBN2. Our results may also provide new insights into the cause and diagnosis of CCA and may have implications for genetic counseling and clinical management.

Highlights

Congenital contractural arachnodactyly (CCA, Online Mendelian Inheritance in Man (OMIM), 121050), known as Beals–Hecht syndrome, is an autosomal dominant connective tissue disorder [1], with extremely rare incidence [2]
The structure of fibrillin-2 calcium-binding epidermal growth factor-like (cbEGF) pairs should be further investigated by a solution–nuclear magnetic resonance (NMR) method
The reasons for the phenotypic heterogeneity caused by FBN2 mutations are still unknown, and more studies should be further conducted to investigate the mechanism of FBN2 mutations for CCA

Summary

Introduction

Congenital contractural arachnodactyly (CCA, Online Mendelian Inheritance in Man (OMIM), 121050), known as Beals–Hecht syndrome, is an autosomal dominant connective tissue disorder [1], with extremely rare incidence [2]. The incidence of CCA is unknown, but appears to be lower than that of the Marfan syndrome (MFS). The prevalence of CCA is difficult to estimate considering the overlap in phenotype with MFS. CCA can be divided into classical CCA and severe/lethal CCA [3]. Classical CCA is characterized by arachnodactyly, camptodactyly, contracture of major joints (hips, knees, ankles, or elbows), scoliosis, pectus deformities, and crumpled ears [4]. Severe/lethal CCA is a rare form of CCA that is characterized by multiple cardiovascular (aortic root dilatation) and gastrointestinal anomalies in addition to the typical skeletal features [5]. CCA, which appears to be fully penetrant, exhibits no specific geographic or ethnic predilection; germline mosaicism has been observed [6]

Methods

Results

Conclusion