title: Large genomic fibrillin-1 (FBN1) gene deletions provide evidence for true haploinsufficiency in Marfan syndrome.
abstract: Mutations in the FBN1 gene are the major cause of Marfan syndrome (MFS), an autosomal dominant connective tissue disorder, which displays variable manifestations in the cardiovascular, ocular, and skeletal systems. Current molecular genetic testing of FBN1 may miss mutations in the promoter region or in other noncoding sequences as well as partial or complete gene deletions and duplications. In this study, we tested for copy number variations by successively applying multiplex ligation-dependent probe amplification (MLPA) and the Affymetrix Human Mapping 500 K Array Set, which contains probes for approximately 500,000 single-nucleotide polymorphisms (SNPs) across the genome. By analyzing genomic DNA of 101 unrelated individuals with MFS or related phenotypes in whom standard genetic testing detected no mutation, we identified FBN1 deletions in two patients with MFS. Our high-resolution approach narrowed down the deletion breakpoints. Subsequent sequencing of the junctional fragments revealed the deletion sizes of 26,887 and 302,580 bp, respectively. Surprisingly, both deletions affect the putative regulatory and promoter region of the FBN1 gene, strongly indicating that they abolish transcription of the deleted allele. This expectation of complete loss of function of one allele, i.e. true haploinsufficiency, was confirmed by transcript analyses. Our findings not only emphasize the importance of screening for large genomic rearrangements in comprehensive genetic testing of FBN1 but, importantly, also extend the molecular etiology of MFS by providing hitherto unreported evidence that true haploinsufficiency is sufficient to cause MFS.
authors.affiliation: Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schorenstrasse 16, 8603, Schwerzenbach, Zurich, Switzerland. matyas@medgen.unizh.ch
authors.forename: Gábor
authors.initials: G
authors.lastname: Mátyás
authors.forename: Sira
authors.initials: S
authors.lastname: Alonso
authors.forename: Andrea
authors.initials: A
authors.lastname: Patrignani
authors.forename: Myriam
authors.initials: M
authors.lastname: Marti
authors.forename: Eliane
authors.initials: E
authors.lastname: Arnold
authors.forename: István
authors.initials: I
authors.lastname: Magyar
authors.forename: Caroline
authors.initials: C
authors.lastname: Henggeler
authors.forename: Thierry
authors.initials: T
authors.lastname: Carrel
authors.forename: Beat
authors.initials: B
authors.lastname: Steinmann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Berger
mesh_terms: D001483:Base Sequence; D019457:Chromosome Breakage; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods; D000071838:Fibrillin-1; D000071837:Fibrillins; D017353:Gene Deletion; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D019656:Loss of Heterozygosity; D008382:Marfan Syndrome / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000032:analysis; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D012333:RNA, Messenger; C000605722:FBN1 protein, human; D054392:Adipokines