Genetic diversity and pathogenic variants as possible predictors of severity in a French sample of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD)

• Published in: Genetics in medicine Vol. 21; no. 9; pp. 2015 - 2024
• Main Authors: Arnaud, Pauline, Hanna, Nadine, Benarroch, Louise, Aubart, Mélodie, Bal, Laurence, Bouvagnet, Patrice, Busa, Tiffany, Dulac, Yves, Dupuis-Girod, Sophie, Edouard, Thomas, Faivre, Laurence, Gouya, Laurent, Lacombe, Didier, Langeois, Maud, Leheup, Bruno, Milleron, Olivier, Naudion, Sophie, Odent, Sylvie, Tchitchinadze, Maria, Ropers, Jacques, Jondeau, Guillaume, Boileau, Catherine
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2019; Elsevier Limited; Nature Publishing Group
• Subjects: Adolescent; Adult; Aged; Aneurysm, Dissecting - diagnosis; Aneurysm, Dissecting - genetics; Aneurysm, Dissecting - physiopathology; Aneurysms; Aortic Aneurysm, Thoracic - diagnosis; Aortic Aneurysm, Thoracic - genetics; Aortic aneurysms; Aortic dissection; Child; class 4 and 5 variants; Codon, Nonsense - genetics; FBN1 gene; Female; Fibrillin-1 - genetics; Genes; Genetic Predisposition to Disease; Genetic Testing - methods; High-Throughput Nucleotide Sequencing; Human health and pathology; Humans; Infectious diseases; Life Sciences; Male; Middle Aged; Mutation; NGS; Pathology, Molecular - methods; Pedigree; SMAD3 gene; Smad3 Protein - genetics; thoracic aortic aneurysms and dissections; Young Adult; thoracic aortic aneurysms and dissections; class 4 and 5 variants; NGS; FBN1 gene; SMAD3 gene
• ISSN: 1098-3600; 1530-0366
• DOI: 10.1038/s41436-019-0444-y

Heritable thoracic aortic aneurysms and dissections (hTAAD) are life-threatening complications of well-known syndromic diseases or underdiagnosed nonsyndromic heritable forms (nshTAAD). Both have an autosomal dominant transmission and are genetically heterogeneous. Our objective was to describe the relevance of molecular diagnosis in these patients and the contribution of each gene in nshTAAD. Two hundred twenty-six consecutive nshTAAD probands, either young (<45 years) sporadic or familial cases were included. A next-generation sequencing capture panel comprising 23 known disease-causing genes was performed. Class 4 or 5 variants were identified in 18% of the nshTAAD probands, while class 3 variants were found in 10% of them. The yield in familial cases was greater than in sporadic cases. SMAD3 and FBN1 genes were the major disease-causing genes. Unexpectedly, no premature termination codon variant was identified in the FBN1 gene. Furthermore, we report for the first time that aortic dissection or surgery occurred significantly more often and earlier in probands with a class 4 or 5 pathogenic variant. This study indicates that genetic screening using NGS is efficient in young and familial nshTAAD. The presence of a pathogenic variant has a possible predictive value, which needs to be further investigated because it may influence care.