Identification of Novel FBN2 Variants in a Cohort of Congenital Contractural Arachnodactyly

Abstract

Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant disorder of connective tissue characterized by crumpled ears, arachnodactyly, camptodactyly, large joint contracture, and kyphoscoliosis. The nature course of CCA has not been well-described. We aim to decipher the genetic and phenotypic spectrum of CCA. The cohort was enrolled in Beijing Jishuitan Hospital and Peking Union Medical College Hospital, Beijing, China, based on Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study (http://www.discostudy.org/). Exome sequencing was performed on patients’ blood DNA. A recent published CCA scoring system was validated in our cohort. Seven novel variants and three previously reported FBN2 variants were identified through exome sequencing. Two variants outside of the neonatal region of FBN2 gene were found. The phenotypes were comparable between patients in our cohort and previous literature, with arachnodactyly, camptodactyly and large joints contractures found in almost all patients. All patients eligible for analysis were successfully classified into likely CCA based on the CCA scoring system. Furthermore, we found a double disease-causing heterozygous variant of FBN2 and ANKRD11 in a patient with blended phenotypes consisting of CCA and KBG syndrome. The identification of seven novel variants broadens the mutational and phenotypic spectrum of CCA and may provide implications for genetic counseling and clinical management.

Case report: Identification of novel fibrillin-2 variants impacting disulfide bond and causing congenital contractural arachnodactyly

“…In contrast with MFS, most individuals with CCA have crumpled ears, flexion contractures, muscular hypoplasia, and no ocular and cardiovascular complications (Lavillaureix et al, 2017). Initially, the F1 proband was admitted to our hospital for contractures of her bilateral fifth fingers, and then we noticed her classical marfanoid appearance, that is, arachnodactyly, camptodactyly, and tall slender build (Sun et al, 2022). Given that the proband exhibited crumpled ears, without a family medical history of typical MFS-related cardiovascular diseases, we made a presumptive diagnosis of CCA.…”

“…CCA is a connective tissue disease. People with CCA share many distinguishing features, such as arachnodactyly, camptodactyly, crumpled ears, scoliosis, pectus deformities, flexion contractures of multiple joints (especially, fingers, elbows, and knee joints), and muscular hypoplasia (Qiu et al, 2021;Sun et al, 2022). CCA has phenotypic heterogeneity, the phenotypes of which can vary within and between families.…”

Importancia de la genómica en el diagnóstico de nuevas variantes asociadas a trastornos del tejido conectivo con solapamiento fenotípico

“…El pronóstico físico no es malo, a menos que haya complicaciones cardiovasculares graves. Su vida es normal sin evidencia que sea más corta, pero se determina de acuerdo con las complicaciones cardiovasculares o la severidad de las deformidades a nivel de columna vertebral [2,10,13].…”

High-Throughput Genomics Identify Novel FBN1/2 Variants in Severe Neonatal Marfan Syndrome and Congenital Heart Defects

“…The pathogenic variant causes a decrease in the amount of FBN-2 protein available to form microfibrils; hence, low levels of microfibril present reduce the elasticity of fibers, resulting in the symptoms exhibited by CCA patients [14,16,40]. Currently, only 91 pathogenic variants in the FBN2 gene linked with CCA are reported in the literature, as recorded in the Human Genome Mutation Database (HGMD) [41]. In addition, there are no known genotype-phenotype correlations for FBN2 and congenital cardiac defects such as dextro-transposition of the great arteries (D-TGA) at the time of publication.…”