Thoracic Aortic Disease in Genetic Syndromes Beyond Established Aortopathy Genes

De novo pathogenic variants in syndromic genes of chromatin regulation and RAS/MAPK signalling, associated with an aortic phenotype beyond established aortopathy genes

Heritable thoracic aortic aneurysms and dissections are attributed to up to 42 genes, yet many patients remain genetically unsolved. The authors queried a clinical exome and genome sequencing database for individuals with de novo pathogenic or likely pathogenic variants and aortic HPO terms. Of 250 individuals, 32 (12.8%) carried variants in genes already on commercial aortopathy panels and were excluded; the remaining 218 spanned 144 genes, 16 of which were found in three or more unrelated individuals. Combining rare-variant burden analyses in the UK Biobank and All of Us, independent thoracic aortic disease cohorts and published reports, the strongest evidence was for DNMT3A, NF1, PTPN11, PPP1CB, NSD1, ANKRD11, ADNP and ABL1, with significant rare-variant burden associations for three of them; aortic phenotypes also occurred across several BAF-complex (Coffin-Siris) genes.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The practical consequence is not about working up isolated aortopathy but about syndrome follow-up: for a child carrying a de novo variant in one of these genes, requesting a baseline aortic ultrasound becomes defensible, although almost no surveillance protocol mentions it. Ascertainment bias is substantial — a laboratory database, with phenotypes coded as HPO terms by ordering clinicians — and this is a non-peer-reviewed preprint. The predominance of chromatin regulation and RAS/MAPK genes remains consistent with the aortic involvement already described in RASopathies.

Analysis by Dr Thibaut Benquey