A +3 variant at a donor splice site leads to a skipping of the MYH11 exon 32, a recurrent RNA defect causing Heritable Thoracic Aortic Aneurysm and Dissection and/or Patent Ductus Arteriosus
Abstract Background Pathogenic variants in MYH11 are associated with either heritable thoracic aortic aneurysm and dissection (HTAAD), patent ductus arteriosus (PDA) syndrome, or megacystis‐microcolon‐intestinal hypoperistalsis syndrome (MMIHS). Methods and Results We report a family referred for mo...
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Wiley
2021
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oai:doaj.org-article:7dfbe9dc055d409dac473c9c0a3607fc2021-11-21T19:38:53ZA +3 variant at a donor splice site leads to a skipping of the MYH11 exon 32, a recurrent RNA defect causing Heritable Thoracic Aortic Aneurysm and Dissection and/or Patent Ductus Arteriosus2324-926910.1002/mgg3.1814https://doaj.org/article/7dfbe9dc055d409dac473c9c0a3607fc2021-11-01T00:00:00Zhttps://doi.org/10.1002/mgg3.1814https://doaj.org/toc/2324-9269Abstract Background Pathogenic variants in MYH11 are associated with either heritable thoracic aortic aneurysm and dissection (HTAAD), patent ductus arteriosus (PDA) syndrome, or megacystis‐microcolon‐intestinal hypoperistalsis syndrome (MMIHS). Methods and Results We report a family referred for molecular diagnosis with HTAAD/PDA phenotype in which we found a variant at a non‐conserved position of the 5’ donor splice site of intron 32 of MYH11 potentially altering splicing (NM_002474.3:c.4578+3A>C). Although its cosegregation with disease was observed, it remained of unknown significance. Later, aortic surgery in the proband gave us the opportunity to perform a transcript analysis. This showed a skipping of the exon 32, an RNA defect previously reported to be translated to an in‐frame loss of 71 amino acids and a dominant‐negative effect in the smooth muscle myosin rod. This RNA defect is also reported in 3 other HTAAD/PDA pedigrees. Conclusion This report confirms that among rare variants in MYH11, skipping of exon 32 is recurrent. This finding is of particular interest to establish complex genotype–phenotype correlations where some alleles are associated with autosomal dominant HTAAD/PDA, while others result in recessive or dominant visceral myopathies.Bertrand ChesneauAurélie PlanckeGuillaume RollandBertrand MarcheixYves DulacThomas EdouardJulie PlaisanciéMarion Aubert‐MuccaSophie JuliaMaud LangeoisThierry Lavabre‐BertrandPhilippe Khau Van KienWileyarticlegenotype–phenotype correlationheritable aortic aneurysm syndromeMYH11patent ductus arteriosussplicingGeneticsQH426-470ENMolecular Genetics & Genomic Medicine, Vol 9, Iss 11, Pp n/a-n/a (2021) |
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genotype–phenotype correlation heritable aortic aneurysm syndrome MYH11 patent ductus arteriosus splicing Genetics QH426-470 |
| spellingShingle |
genotype–phenotype correlation heritable aortic aneurysm syndrome MYH11 patent ductus arteriosus splicing Genetics QH426-470 Bertrand Chesneau Aurélie Plancke Guillaume Rolland Bertrand Marcheix Yves Dulac Thomas Edouard Julie Plaisancié Marion Aubert‐Mucca Sophie Julia Maud Langeois Thierry Lavabre‐Bertrand Philippe Khau Van Kien A +3 variant at a donor splice site leads to a skipping of the MYH11 exon 32, a recurrent RNA defect causing Heritable Thoracic Aortic Aneurysm and Dissection and/or Patent Ductus Arteriosus |
| description |
Abstract Background Pathogenic variants in MYH11 are associated with either heritable thoracic aortic aneurysm and dissection (HTAAD), patent ductus arteriosus (PDA) syndrome, or megacystis‐microcolon‐intestinal hypoperistalsis syndrome (MMIHS). Methods and Results We report a family referred for molecular diagnosis with HTAAD/PDA phenotype in which we found a variant at a non‐conserved position of the 5’ donor splice site of intron 32 of MYH11 potentially altering splicing (NM_002474.3:c.4578+3A>C). Although its cosegregation with disease was observed, it remained of unknown significance. Later, aortic surgery in the proband gave us the opportunity to perform a transcript analysis. This showed a skipping of the exon 32, an RNA defect previously reported to be translated to an in‐frame loss of 71 amino acids and a dominant‐negative effect in the smooth muscle myosin rod. This RNA defect is also reported in 3 other HTAAD/PDA pedigrees. Conclusion This report confirms that among rare variants in MYH11, skipping of exon 32 is recurrent. This finding is of particular interest to establish complex genotype–phenotype correlations where some alleles are associated with autosomal dominant HTAAD/PDA, while others result in recessive or dominant visceral myopathies. |
| format |
article |
| author |
Bertrand Chesneau Aurélie Plancke Guillaume Rolland Bertrand Marcheix Yves Dulac Thomas Edouard Julie Plaisancié Marion Aubert‐Mucca Sophie Julia Maud Langeois Thierry Lavabre‐Bertrand Philippe Khau Van Kien |
| author_facet |
Bertrand Chesneau Aurélie Plancke Guillaume Rolland Bertrand Marcheix Yves Dulac Thomas Edouard Julie Plaisancié Marion Aubert‐Mucca Sophie Julia Maud Langeois Thierry Lavabre‐Bertrand Philippe Khau Van Kien |
| author_sort |
Bertrand Chesneau |
| title |
A +3 variant at a donor splice site leads to a skipping of the MYH11 exon 32, a recurrent RNA defect causing Heritable Thoracic Aortic Aneurysm and Dissection and/or Patent Ductus Arteriosus |
| title_short |
A +3 variant at a donor splice site leads to a skipping of the MYH11 exon 32, a recurrent RNA defect causing Heritable Thoracic Aortic Aneurysm and Dissection and/or Patent Ductus Arteriosus |
| title_full |
A +3 variant at a donor splice site leads to a skipping of the MYH11 exon 32, a recurrent RNA defect causing Heritable Thoracic Aortic Aneurysm and Dissection and/or Patent Ductus Arteriosus |
| title_fullStr |
A +3 variant at a donor splice site leads to a skipping of the MYH11 exon 32, a recurrent RNA defect causing Heritable Thoracic Aortic Aneurysm and Dissection and/or Patent Ductus Arteriosus |
| title_full_unstemmed |
A +3 variant at a donor splice site leads to a skipping of the MYH11 exon 32, a recurrent RNA defect causing Heritable Thoracic Aortic Aneurysm and Dissection and/or Patent Ductus Arteriosus |
| title_sort |
+3 variant at a donor splice site leads to a skipping of the myh11 exon 32, a recurrent rna defect causing heritable thoracic aortic aneurysm and dissection and/or patent ductus arteriosus |
| publisher |
Wiley |
| publishDate |
2021 |
| url |
https://doaj.org/article/7dfbe9dc055d409dac473c9c0a3607fc |
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