Submission Details

EMILIN1 was first reported in relation to autosomal recessive Arterial Tortuosity-Bone Fragility Syndrome in 2022 (Adamo et al., PMID: 36351433). Affected individuals are reported with disease onset in the neonatal period or early childhood. Disease hallmarks include arterial tortuosity and bone fragility which can include multiple fractures. Some patients had additional features including dysmorphic facial features, cutis laxa, joint hypermobility, congenital heart malformations, arterial stenosis, and aortic root dilatation.

Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found a difference in molecular mechanism, inheritance pattern and phenotype between patients with autosomal recessive Arterial Tortuosity-Bone Fragility Syndrome and those reported to have autosomal dominant neuronopathy, distal hereditary motor and/or autosomal dominant EMILIN1-related connective tissue disease. Therefore, autosomal recessive Arterial Tortuosity-Bone Fragility Syndrome (ClinGen term “EMILIN1-related arterial tortuosity syndrome”) will be curated separately from autosomal dominant forms of disease reported to be associated with this gene.

Seven variants (two nonsense, five frameshift) have been reported in five probands in two publications (PMIDs: 36351433, 40062121) and are included in this curation. The mechanism of pathogenicity is reported to be loss of function. To date, all reported cases in the literature have been male and all variants are reported to result in loss of function of the MANE transcript. There is a second transcript which has not been well characterized and to date, all patients have either one or both loss-of-function variants located upstream of the start site for this transcript.

This gene-disease relationship is also supported by experimental evidence including a mouse model, expression studies and functional data (PMIDs: 36351433, 14701737). These studies showed reduced EMILIN1 positive signals from elastic fibers in the skin and elastin core abnormalities. They also showed impaired EFEMP2 deposition and reduced LOX levels and enzyme activity. Knock-out mice recapitulated human phenotypes and had bone, collagen, and elastic fiber abnormalities (PMID:36351433).

In summary, there is definitive evidence supporting the relationship between the EMILIN1 gene and EMILIN1-related arterial tortuosity syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Heritable Thoracic Aortic Aneurysm and Dissection subgroup of the Hereditary Cardiovascular Disease GCEP on June 6, 2025 (SOP Version 11)