| Title: | Utility of genome sequencing and group-enrichment to support splice variant interpretation in Marfan syndrome |
| Journal: | Genetics in Medicine |
| Published: | 2 Jun 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40476350/ |
| DOI: | https://doi.org/10.1016/j.gim.2025.101477 |
| URL: | https://www.gimjournal.org/action/showPdf?pii=S1098360025001248 |
Publication 15097
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Abstract
PURPOSE: To quantify the impact of noncanonical FBN1 splice site variants in undiagnosed Marfan syndrome (MFS), a connective tissue disorder associated with skeletal abnormalities and familial thoracic aortic aneurysm disease (FTAAD).</p>
METHODS: A systematic analysis of ultrarare FBN1 variants was performed using genome sequencing data from the 100,000 Genomes Project. Variants were annotated with SpliceAI and the significance of enrichment among individuals with FTAAD was assessed using Fisher's exact test. Experimental validation used RNA sequencing, reverse transcriptase polymerase chain reaction, minigene constructs, and replication analysis was with data from UK Biobank.</p>
RESULTS: Using aggregate data for 78,195 individuals, we identified 13,864 singleton single-nucleotide variants in FBN1 of which 21 were predicted to affect splicing (SpliceAI > 0.5). Incidence of candidate splice variants in individuals recruited with FTAAD (9/703) was significantly elevated compared with that seen in non-FTAAD participants (12/77,492; odds ratio = 84, P = 9.7 × 10-14). Additional analysis uncovered a further 14 families harboring 11 different FBN1 splice variants. A total of 20 candidate splice variants in 23 families were identified, of which 70% lay beyond the ±8 splice regions. RNA testing confirmed the predicted splice aberration in 16 of 20 and for 9 of 20, pseudoexonization was the likely splicing anomaly.</p>
CONCLUSION: Our findings indicate that noncanonical splice variants may account for approximately 3% of families with undiagnosed FTAAD, highlighting the importance of incorporating analysis of introns and confirmatory RNA testing into genetic testing for Marfan syndrome.</p>
13 Keywords
- Adipokines
- Adult
- Aortic Aneurysm, Thoracic
- Female
- Fibrillin-1
- Genetic Predisposition to Disease
- Humans
- Male
- Marfan Syndrome
- Polymorphism, Single Nucleotide
- RNA Splice Sites
- RNA Splicing
- Whole Genome Sequencing
47 Authors
- Susan Walker
- David J Bunyan
- Huw B Thomas
- Yesim Kesim
- Christopher J Kershaw
- John Holloway
- Htoo Wai
- Michael Day
- Cassandra L Smith
- Gareth Hawkes
- Andrew R Wood
- Michael N Weedon
- Ed Blair
- Stephanie L Curtis
- Catherine Fielden
- Julie Evans
- Rebecca Whittington
- Sarah F Smithson
- Helen Cox
- Paul Clift
- Meriel McEntagart
- Matina Prapa
- Suzanne Alsters
- Deborah Morris-Rosendahl
- John Dean
- Patrick J Morrison
- Abhijit Dixit
- Ajoy Sarkar
- Katrina Prescott
- Leila Amel Riazat Kesh
- Riya Tharakan
- Claire Turner
- Sian Ellard
- Charles Shaw-Smith
- James Fasham
- Virginia Clowes
- Simon Holden
- Suresh Somarathi
- Catherine Mercer
- Ian Berry
- Raymond T O'Keefe
- Siddharth Banka
- Diana Baralle
- N Simon Thomas
- Emma L Baple
- Jenny C Taylor
- Alistair T Pagnamenta
1 Application
| Application ID | Title |
|---|---|
| 103356 | Understanding the role of rare and common genetic variation in human phenotypes |
Enabling scientific discoveries that improve human health