The c.7409G>A (p.Cys2470Tyr) Variant of <b><i>FBN1</i></b>: Phenotypic Variability across Three Generations

Abstract

findings to date. These findings suggest that FBN1 C-terminal missense mutations may not confer the ophthalmological features of Marfan syndrome, but they also confer a more significant risk for cardiovascular pathology than that suggested by previous studies. Furthermore, clinical data from this family supports the previously reported association of dural ectasia with C-terminal mutations. Copyright © 2013 S. Karger AG, Basel Marfan syndrome is an autosomal dominant connective tissue disorder with an incidence of between 1 and 3 per 10,000 individuals [Gray et al., 1994;Ramirez et al., 2007]. The disease predominantly manifests in the cardiovascular, skeletal and ocular systems as well as in the dura mater. Prominent cardiovascular features include dilatation of the aorta and proximal pulmonary artery as well as prolapse of the mitral and tricuspid valves. Musculoskeletal manifestations include joint laxity, chest deformities and overgrowth of tubular bones. Myopia is common and lens displacement is thought to occur in over 60% of affected individuals throughout their lifetime [Maumenee, 1981;Dietz, 1993;Ammash et al., 2008;Datta Kanjilal and Datta, 2009]. The recently revised Ghent Key Words Cardiovascular phenotype · Diagnostic criteria · FBN1 · Marfan syndrome · Novel mutation Abstract Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the fibrillin gene FBN1 , which encodes an extracellular matrix glycoprotein. Major features of Marfan syndrome occur in the ocular, cardiovascular, and skeletal systems as well as in the dura mater. Approximately 60% of known disease-causing mutations are missense mutations of single amino acid residues. Effects on the cardiovascular system are classically associated with mutations in exons 24-32 of the 65 FBN1 exons and many, though not all, reports associate missense mutations in exons 59-65 with a mild cardiovascular phenotype. Here we present 5 related individuals among whom a c.7409G>A (p.Cys2470Tyr) missense variant in exon 59 of FBN1 is associated with significant cardiovascular features. The index case also had an apparently de novo 46,XX,del(5)(q33.1q33.3) deletion on chromosome 5. This family demonstrates skeletal, dermatological and neurological features consistent with Marfan syndrome but lacks significant ophthalmological

Generation of heterozygous fibrillin-1 mutant cloned pigs from genome-edited foetal fibroblasts

“…However, the cloned piglets did not exhibit a homogenous phenotype. The relationship between MFS genotype and the phenotype is extremely complex, and there are differences in pathology between patients of the same family lineage 30 . Moreover, heterozygous FBN1 knockout (KO) mice carrying the same mutation exhibit lineage-specific phenotypic differences, and the severity of disease correlates negatively with the level of FBN1 mRNA expression.…”

Scoliosis in Shprintzen–Goldberg Syndrome

“…Shprintzen–Goldberg syndrome is similar to Marfan syndrome, causing diverse symptoms due to systemic weakness in the connective tissues in the skeletal system, cardiovascular system, and eyes [ 1 , 2 ]. TGFBR2 missense mutation has been identified as the causative gene [ 3 – 7 ], and typical clinical symptoms include cardiac malformation, arachnodactyly, and craniosynostosis.…”

Next-generation sequencing identifies novel mutations in the FBN1 gene for two Chinese families with Marfan syndrome

“…Currently, the diagnosis of MFS remains predominantly based on clinical manifestation ( 1 ). The genetic dissection of this lethal disease helps to establish the diagnosis of familial FS and to predict neonatal patients and young children, even when the clinical manifestations are not yet evident ( 23 ). In the present study, a rapid and convenient measure for routine MFS genetic diagnosis has been described.…”