Early-Onset Aortic Dissection: Characterization of a New Pathogenic Splicing Variation in the MYH11 Gene with Several...

Area of Science:

• Genetics and Molecular Biology
• Cardiovascular Pathology

Background:

• Pathogenic variants in the MYH11 gene are linked to thoracic aortic aneurysms and dissections, typically as heterozygous missense variants or in-frame deletions.
• Understanding the physiopathological mechanisms of MYH11 gene alterations is crucial, as variants of unknown significance are common.
• Previous studies noted distinct phenotypes associated with different inheritance patterns (autosomal recessive for megacystis-microcolon-intestinal hypoperistalsis syndrome).

Purpose of the Study:

• To investigate the pathogenicity of a novel MYH11 gene variant identified in a young patient with aortic dissection.
• To elucidate the molecular consequences of a splice site variant in MYH11.
• To underscore the importance of detailed splicing analysis for MYH11 variants of unknown significance.

Main Methods:

• Identification of a variant affecting the consensus donor splice site of exon 29 in the MYH11 gene.
• Transcript analysis on cultured fibroblasts to identify abnormal transcripts.
• Familial screening to determine the inheritance pattern of the identified variant.

Main Results:

• A patient presenting with aortic type A dissection at age 23 carried a de novo variant in the MYH11 gene affecting the exon 29 splice site.
• Transcript analysis revealed abnormal splicing, including two in-frame transcripts: one with a deletion of 78 nucleotides from exon 29 and another with exon 29 skipping.
• The identified variant was classified as pathogenic based on the clinical presentation, molecular analysis, and familial screening.

Conclusions:

• This case confirms a novel pathogenic splice site variant in MYH11 associated with thoracic aortic dissection.
• The study highlights the critical role of splicing alterations in the pathogenesis of MYH11-related aortic diseases.
• Systematic investigation of splicing consequences is essential for accurate interpretation of MYH11 variants.