Marfan syndrome resulting from a rare pathogenic FBN1 variant, ascertained through a proband with IgG4-related arteriopathy

Eric A. Haan*, Francois H. Chamalaun, S.A.J. Chamuleau, Leonard F. Arnolda, John P. Slavotinek, Nadia C. Wise, Dimuth N. Gunawardane, Ulrike Schwarze, Peter H. Byers, Genevieve M. Gabb

*Corresponding author for this work

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A 57-year-old man with a family history of aortic aneurysm was found, during assessment of unexplained fever, to have an infrarenal aortic aneurysm requiring immediate repair. Dilatation of popliteal and iliac arteries was also present. Progressive aortic root dilatation with aortic regurgitation was documented from 70 years leading to valve-sparing aortic root replacement at 77 years, at which time genetic studies identified a likely pathogenic FBN1 missense variant c.6916C > T (p.Arg2306Cys) in exon 56. The proband's lenses were normally positioned and the Marfan syndrome (MFS) systemic score was 0/20. Cascade genetic testing identified 15 other family members with the FBN1 variant, several of whom had unsuspected aortic root dilatation; none had ectopia lentis or MFS systemic score ≥ 7. Segregation analysis resulted in reclassification of the FBN1 variant as pathogenic. The combination of thoracic aortic aneurysm and dissection (TAAD) and a pathogenic FBN1 variant in multiple family members allowed a diagnosis of MFS using the revised Ghent criteria. At 82 years, the proband's presenting abdominal aortic aneurysm was diagnosed retrospectively to have resulted from IgG4-related inflammatory aortopathy.
Original languageEnglish
Pages (from-to)2180-2189
JournalAmerican Journal of Medical Genetics, Part A
Issue number7
Publication statusPublished - 1 Jul 2021
Externally publishedYes

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