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Original research
A systematic study and literature review of parental somatic mosaicism of FBN1 pathogenic variants in Marfan syndrome
  1. Paula Fernández-Álvarez1,2,
  2. Marta Codina-Sola1,2,
  3. Irene Valenzuela1,2,
  4. Gisela Teixidó-Turá3,
  5. Anna Cueto-González1,2,
  6. Ida Paramonov1,2,
  7. María Antolín1,2,
  8. Fermina López-Grondona1,2,
  9. Teresa Vendrell1,2,
  10. Artur Evangelista3,
  11. Elena García-Arumí1,4,
  12. Eduardo F Tizzano1,2
  1. 1Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Barcelona, Spain
  2. 2Medicine Genetics Group, Vall d’Hebron Institut de Recerca, Barcelona, Spain
  3. 3Department of Cardiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain
  4. 4Departament de Patologia Neuromuscular i Mitocondrial, Biomedical Network Research Centre on Rare Diseases (CIBERER), Vall d’Hebron Institut de Recerca, Barcelona, Spain
  1. Correspondence to Dr Eduardo F Tizzano, Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Barcelona, Barcelona, Spain; etizzano{at}vhebron.net

Abstract

Background A proportion of de novo variants in patients affected by genetic disorders, particularly those with autosomal dominant (AD) inheritance, could be the consequence of somatic mosaicism in one of the progenitors. There is growing evidence that germline and somatic mosaicism are more common and play a greater role in genetic disorders than previously acknowledged. In Marfan syndrome (MFS), caused by pathogenic variants in the fibrillin-1 gene (FBN1) gene, approximately 25% of the disease-causing variants are reported as de novo. Only a few cases of parental mosaicism have been reported in MFS.

Methods Employing an amplicon-based deep sequencing (ADS) method, we carried out a systematic analysis of 60 parents of 30 FBN1 positive, consecutive patients with MFS with an apparently de novo pathogenic variant.

Results Out of the 60 parents studied (30 families), the majority (n=51, 85%) had a systemic score of 0, seven had a score of 1 and two a score of 2, all due to minor criteria common in the normal population. We detected two families with somatic mosaicism in one of the progenitors, with a rate of 6.6% (2/30) of apparently de novo cases.

Conclusions The search for parental somatic mosaicism should be routinely implemented in de novo cases of MFS, to offer appropriate genetic and reproductive counselling as well as to reveal masked, isolated clinical signs of MFS in progenitors that may require specific follow-up.

  • genetic testing
  • cardiology
  • genetic counseling
  • aneurysm
  • genetics

Data availability statement

Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

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Footnotes

  • EG-A and EFT are joint senior authors.

  • Contributors PF-A, EG-A and EFT designed the study. PF-A, MA carried out the molecular genetic studies. IP performed the bioinformatic analysis. MC-S, IV, GT-T, AC-G, FLG, TV and AE contributed to clinical data collection and critical reading of the manuscript. PF-A performed the literature review and wrote the paper. EG-A and EFT wrote the paper and supervised the project. All authors approved the final version.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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