The clinical spectrum of complete FBN1 allele deletions

• Published in: European journal of human genetics : EJHG Vol. 19; no. 3; pp. 247 - 252
• Main Authors: HILHORST-HOFSTEE, Yvonne, HAMEL, Ben Cj, MOLL, Henriette A, BREUNING, Martijn H, PALS, Gerard, VERHEIJ, Joke Bgm, RIJLAARSDAM, Marry Eb, MANCINI, Grazia Ms, COBBEN, Jan M, GIROTH, Cindy, RUIVENKAMP, Claudia Al, HANSSON, Kerstin Bm, TIMMERMANS, Janneke
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.03.2011
• Subjects: Adolescent; Adult; Age; Alleles; Aorta; Biological and medical sciences; Bone diseases; Cardiology; Child; Child, Preschool; Chromosomes; Clonal deletion; Congenital diseases; Cysteine; Cysteine - metabolism; Ectopia Lentis - genetics; Ectopia Lentis - pathology; Female; Fibrillin; Fibrillin-1; Fibrillins; Frameshift mutation; Fundamental and applied biological sciences. Psychology; Gene deletion; General aspects. Genetic counseling; Genes; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Glaucoma; Haploinsufficiency; Humans; Hypotheses; Male; Marfan syndrome; Marfan Syndrome - genetics; Marfan's syndrome; Medical genetics; Medical sciences; Microfilament Proteins - genetics; Missense mutation; Mitral valve; Mitral Valve Prolapse - genetics; Molecular and cellular biology; Mutation; Pathogenesis; Patients; Phenotype; Phenotypes; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Scoliosis; Sequence Deletion; Surgery; Young Adult; Netherlands; Chromosomal aberration; Connective tissue disease; Skin disease; Elastic tissue disease; fibrillin-1; Marfan syndrome; Genetic disease; Symptomatology; Allele; Phenotype; haploinsufficiency; Systemic disease; Deletion; Genetics; FBN1
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2010.174

The most common mutations found in FBN1 are missense mutations (56%), mainly substituting or creating a cysteine in a cbEGF domain. Other mutations are frameshift, splice and nonsense mutations. There are only a few reports of patients with marfanoid features and a molecularly proven complete deletion of a FBN1 allele. We describe the clinical features of 10 patients with a complete FBN1 gene deletion. Seven patients fulfilled the Ghent criteria for Marfan syndrome (MFS). The other three patients were examined at a young age and did not (yet) present the full clinical picture of MFS yet. Ectopia lentis was present in at least two patients. Aortic root dilatation was present in 6 of the 10 patients. In three patients, the aortic root diameter was on the 95th percentile and in one patient, the diameter of the aortic root was normal, the cross-section, however, had a cloverleaf appearance. Two patients underwent aortic root surgery at a relatively young age (27 and 34 years). Mitral valve prolapse was present in 4 of the 10 patients, and billowing of the mitral valve in 1. All patients had facial and skeletal features of MFS. Two patients with a large deletion extending beyond the FBN1 gene had an extended phenotype. We conclude that complete loss of one FBN1 allele does not predict a mild phenotype, and these findings support the hypothesis that true haploinsufficiency can lead to the classical phenotype of Marfan syndrome.