NDLI: Good performance of the criteria of American College of Medical Genetics and Genomics/Association for Molecular Pathology in prediction of pathogenicity of genetic variants causing thoracic aortic aneurysms and dissections

Content Provider	Springer Nature : BioMed Central
Author	Ponińska, Joanna Kinga Bilińska, Zofia Teresa Truszkowska, Grażyna Michalak, Ewa Podgórska, Anna Stępień-Wojno, Małgorzata Chmielewski, Przemysław Lutyńska, Anna Płoski, Rafał
Abstract	Background The identification of pathogenic variant in patients with thoracic aortic aneurysms and dissections (TAAD) was previously found to be a significant indicator pointing to earlier need for surgical intervention. In order to evaluate available methods for classifying identified genetic variants we have compared the event-free survival in a cohort of TAAD patients classified as genotype-positive versus genotype-negative by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) criteria or by ClinVar database. Methods We analyzed previously unreported cohort of 132 patients tested in the routine clinical setting for genetic variants in a custom panel of 30 genes associated with TAAD or the TruSight Cardio commercial panel of 174 genes associated with cardiac disease. The identified variants were classified using VarSome platform. Kaplan–Meier survival curves were constructed to compare the event-free survival between probands defined as ‘genotype-positive’ and ‘genotype-negative’ using different classifications in order to compare their performance. Results Out of 107 rare variants found, 12 were classified as pathogenic/likely pathogenic by ClinVar, 38 were predicted to be pathogenic/likely pathogenic by ACMG. Variant pathogenicity as assessed by ACMG criteria was a strong predictor of event free survival (event free survival at 50 years 83% vs. 50%, for genotype positive patients vs. reference, respectively, p = 0.00096). The performance of ACMG criteria was similar to that of ClinVar (event free survival at 50 years 87% vs. 50%, for genotype positive patients vs. reference, respectively p = 0.023) but independent from it as shown by analysing variants with no ClinVar record (event free survival at 50 years 80% vs. 50%, p = 0.0039). Variants classified as VUS by ACMG criteria or ClinVar did not affect event-free survival. TAAD specific custom gene panel performed similar to the larger universal cardiac panel. Conclusions In our cohort of unrelated TAAD patients ACMG classification tool available at VarSome was useful in assessing pathogenicity of novel genetic variants. Gene panel containing the established genes associated with the highest risk of hereditary TAAD (ACTA1, COL3A1, FBN1, MYH11, SMAD3, TGFB2, TGFBR1, TGFBR2, MYLK) was sufficient to identify prevailing majority of variants most likely to be causative of the disease.
Related Links	https://translational-medicine.biomedcentral.com/counter/pdf/10.1186/s12967-022-03251-8.pdf
Ending Page	10
Page Count	10
Starting Page	1
File Format	HTM / HTML
ISSN	14795876
DOI	10.1186/s12967-022-03251-8
Journal	Journal of Translational Medicine
Issue Number	1
Volume Number	20
Language	English
Publisher	BioMed Central
Publisher Date	2022-01-25
Access Restriction	Open
Subject Keyword	Biomedicine Medicine Public Health Thoracic aortic aneurysm and dissections Next-generation sequencing Genetic variant classification Medicine/Public Health
Content Type	Text
Resource Type	Article
Subject	Biochemistry, Genetics and Molecular Biology Medicine
Journal Impact Factor	6.1/2023
5-Year Journal Impact Factor	6.3/2023

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