Abstract
Marfan syndrome (MFS) is an autosomal dominant genetic disorder of the connective tissue, typically characteristic of cardiovascular manifestations, valve prolapse, left ventricle enlargement, and cardiac failure. Fibrillin-1 (FBN1) is the causative gene in the pathogenesis of MFS. Patients with different FBN1 mutations often present more considerable phenotypic variation. In the present study, three affected MFS pedigrees were collected for genetic analysis. Using next-generation sequencing (NGS) technologies, 3 novel frameshift pathogenic mutations which are cosegregated with affected subjects in 3 pedigrees were identified. These novel mutations provide important diagnostic and therapeutic insights for precision medicine in MFS, especially regarding the lethal cardiovascular events.
Highlights
Marfan syndrome (MFS; OMIM 154700) is a common autosomal dominant connective tissue disorder; the incidence rate was estimated to be at least 1 per 10,000 individuals without any racial, geographical, or occupational predilection
MFS was caused by fibrillin-1 (FBN1) gene mutations (NM_000138), which is located on chromosome 15q21.1 and had 65 exons
About 3000 mutations [3] have been detected in FBN1 and mainly classified into 3 types including missense mutations, inframe deletions, and nonsense mutations due to frameshift leading to premature termination codons (PTC) [4, 5], even though progresses had been made for the detection of causal mutations in MFS
Summary
Marfan syndrome (MFS; OMIM 154700) is a common autosomal dominant connective tissue disorder; the incidence rate was estimated to be at least 1 per 10,000 individuals without any racial, geographical, or occupational predilection. This disorder affects cardiovascular, ocular, and skeletal systems, as well as skin, lung, and central nervous systems. Fibrillin-1, a kind of extracellular matrix glycoprotein, was reported as an important calcium-binding microfibrillar structural molecule and a regulator of TGF-β signaling [2]. About 3000 mutations [3] have been detected in FBN1 and mainly classified into 3 types including missense mutations, inframe deletions, and nonsense mutations due to frameshift leading to premature termination codons (PTC) [4, 5], even though progresses had been made for the detection of causal mutations in MFS
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