An FBN1 pseudoexon mutation in a patient with Marfan syndrome: confirmation of cryptic mutations leading to disease

• Published in: Journal of human genetics Vol. 53; no. 11-12; pp. 1007 - 1011
• Main Authors: Guo, Dong-Chuan, Gupta, Prateek, Tran-Fadulu, Van, Guidry, Tera V, Leduc, Magalie S, Schaefer, Frederick V, Milewicz, Dianna M
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.12.2008
• Subjects: Adult; Base Sequence; Child; Deoxyribonucleic acid; DNA; DNA Mutational Analysis - methods; DNA sequencing; Exons; Exons - genetics; Female; Fibrillin-1; Fibrillins; Fibroblasts; Genetic analysis; Genetic Predisposition to Disease; Humans; Insertion; Introns - genetics; Male; Marfan syndrome; Marfan Syndrome - genetics; Microfilament Proteins - genetics; Middle Aged; Molecular Sequence Data; Mutation; Mutation - genetics; Point mutation; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism
• ISSN: 1434-5161; 1435-232X
• DOI: 10.1007/s10038-008-0334-7

Marfan syndrome (MFS) results from heterozygous mutations in FBN1. However, genetic analyses of deoxyribonucleic acid (DNA) from approximately 10-30% of MFS patients who meet diagnostic criteria do not reveal an identifiable FBN1 mutation. In a patient who met the diagnostic criteria for MFS, bidirectional DNA sequencing of exons and intron-exon boundaries of FBN1 failed to reveal a mutation. Assessment of the FBN1 message in dermal fibroblasts from the patient revealed insertion of a pseudoexon between exons 63 and 64. Sequencing of intron 63 identified a point mutation, IVS63+373, located near the middle of intron 63 of FBN1 that created a donor splice site in intron 63, leading to inclusion of a 93-bp fragment of intronic sequence in the FBN1 message. Identification of a novel pseudoexon mutation in FBN1, in association with a clinical diagnosis of MFS, confirms that cryptic mutations that are missed by the current DNA-based diagnostic methods have a causative role.