THSD4

Inheritance Pattern: AD

Disease ID:MONDO:0019625

Submitter: ClinGen

The THSD4 gene encodes for ADAMTS-like protein 6 (ADAMTSL6), an extracellular matrix protein known to promote fibrillin-1 matrix assembly. *THSD4* was first reported in relation to autosomal dominant familial thoracic aortic aneurysm and aortic dissection (FTAAD) in 2021 by Elbitar et. al. (PMID 32855533). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Six THSD4 (NM_024817) variants (one frameshift, two nonsense, two missense variants, and one in-frame duplication) that have been reported in six probands are included in this curation (PMID 32855533, 41999216). One in-frame duplication, *THSD4*:c.137_145dup (p.Asp46_Gly48dup), one frameshift variant, *THSD4*:c.1402del (p.Ala468GlnfsX45), and one nonsense variant *THSD4*:c.740del (p.Leu247Ter), were shown to segregate with disease in families (PMIDs 32855533); however, there were insufficient number of segregations to qualify as scorable evidence as per the ClinGen Gene-Disease Validity Standard Operating Procedures (version 12). The evidentiary value of the variants, *THSD4*:c.2258G>A (p.Gly753Asp) and *THSD4*c.2341C>T (p.Arg781Trp) were reduced due to high minor allele frequency. Functional studies completed for the two PTC variants and the two missense variants demonstrated haploinsufficiency or impaired assembly (disorganization of the aortic media) of fibrillin-1 microfibrils (PMID 32855533). An additional nonsense variant, *THSD4*:c.1862G>A (p.Trp621Ter), has been reported in a 61 year old male with a history of annuloaortic ectasia and bicuspid aortic valve and is predicted to result in loss of function through premature termination, consistent with the *THSD4* haploinsufficiency mechanism which has been proposed for *THSD4* in heritable thoracic aortic disease (PMID 41999216). This gene-disease relationship is further supported by experimental data in the form of tissue expression, biochemical/functional assays, and mouse models. Bulk tissue gene expression data from the GTEx Portal indicates *THSD4* is expressed in arteries/aorta (PMID: 23715323). Protein interaction studies demonstrate ADAMTSL-6 is a novel microfibril-associated protein that binds directly to fibrillin-1 and promotes assembly of fibrillin-1 microfibrils (PMID 19940141). Thsd4+/− mouse models revealed typical medial degeneration and diffuse disruption of extracellular matrix in aortic samples (PMID 32855533). Although the total evidence score is 9.6 points, the ClinGen Heritable Thoracic Aortic Aneurysm and Dissection subgroup of the Hereditary Cardiovascular Gene Curation Expert Panel opted to downgrade the classification from Moderate to Limited on the basis of recent unpublished data showing multiple observations of nonpenetrance of an aortic disease phenotype among families with the TSHD4 variant and, even more importantly, non-segregation of the familial TSHD4 variant in family members with thoracic aortic aneurysm/dissection. These observations question the monogenic character of *THSD4* in relation to FTAAD (Mèlanie H.A.M. Perik, 2024, University of Antwerp, manuscript in preparation for publication and PhD thesis, https://hdl.handle.net/10067/2079210151162165141). In summary, there is limited evidence to support this gene-disease relationship. This classification was approved by the ClinGen Heritable Thoracic Aortic Aneurysm and Dissection subgroup of the Hereditary Cardiovascular Gene Curation Expert Panel on the meeting date September 4, 2026 (SOP Version 12).

Inheritance Pattern: AD

Disease ID:MONDO:0019625

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0030731

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0019625

Submitter: Franklin by Genoox

As part of Thoracic aortic aneurysm and dissection study conducted in France, two unrelated probands were found to carry THSD4 heterozygote mutation which were considered causative. https://doi.org/10.1038/s41436-020-00947-4