title: Decreased frequency of FBN1 missense variants in Ghent criteria-positive Marfan syndrome and characterization of novel FBN1 variants.
abstract: The diagnosis of Marfan syndrome (MFS) remains challenging despite the 2010 revision to Ghent nosology criteria, and there is a lack of published information regarding FBN1 genotype associations in patients since the update in Ghent criteria. Applying revised Ghent criteria, we reviewed consecutive proband cases (n=292) submitted for FBN1 sequencing. Testing yielded 207 pathogenic or likely pathogenic FBN1 variants, with 114/207 (55%) missense, 67/207 (32%) non-sense or frameshift, and 28/207 (13%) splicing. There were 130 novel FBN1 variants predicted as pathogenic or likely pathogenic (n=109) or variant of undetermined significance (n=21). Of the 104 patients who met 2010 revised Ghent criteria, 87/104 (82%) had a pathogenic or likely pathogenic variant. There was a significantly lower frequency of missense variants (41 vs 89%; P<0.0001) observed in the Ghent-positive (vs Ghent-negative) patients, and this association held true in age-based groupings. Previously described genotype associations with ectopia lentis and early onset/'neonatal' MFS were confirmed in our cohort. Overall, our study points to the imperfect nature of relying solely on clinical criteria to diagnose MFS as well as the potential importance of truncating/splicing variants in Ghent-positive cases. Furthermore, the description of numerous novel variants and associated clinical findings may be useful for future clinical interpretation of FBN1 genotype in patients with suspected MFS.
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors: Linnea M
authors: LM
authors: Baudhuin
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors: Katrina E
authors: KE
authors: Kotzer
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors: Susan A
authors: SA
authors: Lagerstedt
mesh_terms: D000293:Adolescent; D004252:DNA Mutational Analysis; D000071838:Fibrillin-1; D000071837:Fibrillins; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics*; D020125:Mutation, Missense; D022821:RNA Splice Sites; D055815:Young Adult; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D022821:RNA Splice Sites; C000605722:FBN1 protein, human; D054392:Adipokines
references: Hum Mutat. 2007 Sep;28(9):928
references: 17657824
references: Eur J Hum Genet. 2001 Jan;9(1):13-21
references: 11175294
references: Hum Mol Genet. 1995;4 Spec No:1799-809
references: 8541880
references: Eur J Med Genet. 2013 Jul;56(7):356-60
references: 23684891
references: Hum Mutat. 2010 Jan;31(1):E1021-42
references: 19802897
references: Clin Genet. 1999 Feb;55(2):110-7
references: 10189088
references: Hum Mutat. 2005 Nov;26(5):494
references: 16222657
references: Cell. 1996 May 17;85(4):597-605
references: 8653794
references: Am J Med Genet A. 2008 Dec 15;146A(24):3157-66
references: 19012347
references: Am J Med Genet A. 2007 Sep 1;143A(17 ):1968-77
references: 17663468
references: Am J Hum Genet. 2007 Sep;81(3):454-66
references: 17701892
references: Lancet. 2005 Dec 3;366(9501):1965-76
references: 16325700
references: Am J Hum Genet. 1999 Oct;65(4):1007-20
references: 10486319
references: Am J Med Genet A. 2009 Feb;149A(2):161-70
references: 19161152
references: J Med Genet. 2010 Jul;47(7):476-85
references: 20591885
references: Clin Genet. 2012 Sep;82(3):240-7
references: 21883168
references: Arch Intern Med. 2001 Nov 12;161(20):2447-54
references: 11700157
references: Am J Med Genet A. 2012 May;158A(5):989-95
references: 22162372
references: Hum Mutat. 2004 Jan;23 (1):99
references: 14695540
references: Hum Mutat. 2005 Dec;26(6):529-39
references: 16220557
references: Am J Med Genet A. 2012 May;158A(5):982-8
references: 22461464
references: Br J Ophthalmol. 2002 Dec;86(12 ):1359-62
references: 12446365
references: Hum Mutat. 2002 Sep;20(3):153-61
references: 12203987
references: J Med Genet. 1994 Jan;31(1):51-4
references: 8151638
references: Genet Med. 2015 Mar;17 (3):177-87
references: 25101912