Early-Onset Aortic Dissection: Characterization of a New Pathogenic Splicing Variation in the MYH11 Gene with Several In-Frame Abnormal Transcripts

Author:

Arnaud Pauline12ORCID,Cadenet Margaux1,Mougin Zakaria2,Le Goff Carine2,Perbet Sébastien3,Francois Mathilde4,Dupuis-Girod Sophie4,Boileau Catherine12,Hanna Nadine12ORCID

Affiliation:

1. Département de Génétique, AP-HP, Hôpital Bichat, F-75018 Paris, France

2. Université Paris Cité, Inserm, LVTS U1148, F-75018 Paris, France

3. Pôle de Médecine Péri-Opératoire, CHU Clermont-Ferrand, F-63000 Clermont-Ferrand, France

4. Service de Génétique, Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, F-69500 Bron, France

Abstract

Rare pathogenic variants in the MYH11 gene are responsible for thoracic aortic aneurysms and dissections. They are usually heterozygous missense variants or in-frame deletions of several amino acids without alteration of the reading frame and mainly affect the coiled-coil domain of the protein. Variants leading to a premature stop codon have been described in patients with another phenotype, megacystis-microcolon-intestinal hypoperistalsis syndrome, with an autosomal recessive inheritance. The physiopathological mechanisms arising from the different genetic alterations affecting the MYH11 gene are still poorly understood. Consequently, variants of unknown significance are relatively frequent in this gene. We have identified a variant affecting the consensus donor splice site of exon 29 in the MYH11 gene in a patient who suddenly died from an aortic type A dissection at the age of 23 years old. A transcript analysis on cultured fibroblasts has highlighted several abnormal transcripts including two in-frame transcripts. The first one is a deletion of the last 78 nucleotides of exon 29, corresponding to the use of a cryptic alternative donor splice site; the second one corresponds to an exon 29 skipping. Familial screening has revealed that this molecular event occurred de novo in the proband. Taken together, these experiments allowed us to classify this variant as pathogenic. This case underlines the challenging aspect of the discovery of variations in the MYH11 gene for which the consequences on splicing should be systematically studied in detail.

Funder

2020-Call for Proposals from French Rare Disease Network FAVA-Multi

Publisher

Hindawi Limited

Subject

Genetics (clinical),Genetics

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