An enormous Italian pedigree of Marfan syndrome with a novel mutation in the FBN1 gene

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Abstract

We characterize a large Italian family presenting with Marfan syndrome (MFS), where the same NM_000138.4:c.6872‐1G > T splice site mutation in the FBN1 gene was detected in 37 affected individuals with different pathological phenotypes. Further studies on such a large pedigree could identify other genetic factors that influence MFS manifestation.

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Revised diagnostic criteria for the Marfan syndrome.

A. De Paepe, R Devereux, H Dietz … (1996)

In 1986, the diagnosis of the Marfan syndrome was codified on the basis of clinical criteria in the Berlin nosology [Beighton et al., 1988]. Over time, weaknesses have emerged in these criteria, a problem accentuated by the advent of molecular testing. In this paper, we propose a revision of diagnostic criteria for Marfan syndrome and related conditions. Most notable are: more stringent requirements for diagnosis of the Marfan syndrome in relatives of an unequivocally affected individual; skeletal involvement as a major criterion if at least 4 of 8 typical skeletal manifestations are present; potential contribution of molecular analysis to the diagnosis of Marfan syndrome; and delineation of initial criteria for diagnosis of other heritable conditions with partially overlapping phenotypes.

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The Marfan syndrome.

R E Pyeritz (1999)

The Marfan syndrome (MFS), initially described just over 100 years ago, was among the first conditions classified as a heritable disorder of connective tissue. MFS lies at one end of a phenotypic continuum, with people in the general population who have one or another of the features of MFS at the other end, and those with a variety of other conditions in between. Diagnosis of MFS and these other conditions remains based on clinical features. Mutations in FBN1, the gene that encodes fibrillin-1, are responsible for MFS and (in a few patients) other disorders in the continuum. In addition to skeletal, ocular, and cardiovascular features, patients with MFS have involvement of the skin, integument, lungs, and muscle tissue. Over the past 30 years, evolution of aggressive medical and surgical management of the cardiovascular problems, especially mitral valve prolapse, aortic dilatation, and aortic dissection, has resulted in considerable improvement in life expectancy.

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Association of modifiers and other genetic factors explain Marfan syndrome clinical variability

Catherine Boileau, Guillaume Jondeau, Jean-François Deleuze … (2018)

Marfan syndrome (MFS) is a rare autosomal dominant connective tissue disorder related to variants in the FBN1 gene. Prognosis is related to aortic risk of dissection following aneurysm. MFS clinical variability is notable, for age of onset as well as severity and number of clinical manifestations. To identify genetic modifiers, we combined genome-wide approaches in 1070 clinically well-characterized FBN1 disease-causing variant carriers: (1) an FBN1 eQTL analysis in 80 fibroblasts of FBN1 stop variant carriers, (2) a linkage analysis, (3) a kinship matrix association study in 14 clinically concordant and discordant sib-pairs, (4) a genome-wide association study and (5) a whole exome sequencing in 98 extreme phenotype samples. Three genetic mechanisms of variability were found. A new genotype/phenotype correlation with an excess of loss-of-cysteine variants ( P = 0.004) in severely affected subjects. A second pathogenic event in another thoracic aortic aneurysm gene or the COL4A1 gene (known to be involved in cerebral aneurysm) was found in nine individuals. A polygenic model involving at least nine modifier loci (named gMod-M1-9) was observed through cross-mapping of results. Notably, gMod-M2 which co-localizes with PRKG1 , in which activating variants have already been described in thoracic aortic aneurysm, and gMod-M3 co-localized with a metalloprotease (proteins of extra-cellular matrix regulation) cluster. Our results represent a major advance in understanding the complex genetic architecture of MFS and provide the first steps toward prediction of clinical evolution.

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Author and article information

Contributors

Omid Daneshjoo:

ORCID: https://orcid.org/0000-0003-1026-1047

omid.daneshjoo@uniroma1.it

Leila B. Salehi: leilab.salehi@ptvonline.it

Journal

Journal ID (nlm-ta): Clin Case Rep

Journal ID (iso-abbrev): Clin Case Rep

Journal ID (doi): 10.1002/(ISSN)2050-0904

Journal ID (publisher-id): CCR3

Title: Clinical Case Reports

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Electronic): 2050-0904

Publication date (Electronic): 02 June 2020

Publication date Collection: August 2020

Volume: 8

Issue: 8 ( doiID: 10.1002/ccr3.v8.8 )

Pages: 1445-1451

Affiliations

[ ¹ ] Medical Genetics Group Department of Experimental Medicine “Sapienza’’ University of Rome Rome Italy

[ ² ] U.O.C. of Medical Genetics Policlinic of Tor Vergata Rome Italy

[ ³ ] Rare Diseases Centre for Marfan Syndrome and Related Disorders Policlinico Tor Vergata Rome Italy

[ ⁴ ] Department of Biomedicine and Prevention University of Rome “Tor Vergata’’ Italy

Author notes

[*] [* ] Correspondence

Omid Daneshjoo and Leila B. Salehi, U.O.C. of Medical Genetics, Policlinic of Tor Vergata, Rome, Italy.

Emails: omid.daneshjoo@ 123456uniroma1.it (O. M.); leilab.salehi@ 123456ptvonline.it (L. B. S)

Author information

Omid Daneshjoo https://orcid.org/0000-0003-1026-1047

Antonio Pizzuti http://orcid.org/0000-0003-3245-1925

Giuseppe Novelli https://orcid.org/0000-0002-7781-602X

Federica Sangiuolo http://orcid.org/0000-0002-6227-4248

Article

Publisher ID: CCR32881

DOI: 10.1002/ccr3.2881

PMC ID: 7455403

SO-VID: 3563cc46-2419-43fa-8286-784f04e01f22

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date received : 31 October 2019

Date revision received : 26 March 2020

Date accepted : 28 March 2020

Page count

Figures: 3, Tables: 1, Pages: 7, Words: 3864

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source-schema-version-number 2.0

cover-date August 2020

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.8 mode:remove_FC converted:28.08.2020

An enormous Italian pedigree of Marfan syndrome with a novel mutation in the FBN1 gene

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Most cited references 21

Revised diagnostic criteria for the Marfan syndrome.

The Marfan syndrome.

Association of modifiers and other genetic factors explain Marfan syndrome clinical variability

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