ADAM17

Inheritance Pattern: AR

Disease ID:MONDO:0013693

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0013693

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0013693

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013693

Submitter: ClinGen

*ADAM17* (also known as TACE, TNF-α converting enzyme) was first reported in relation to autosomal recessive inflammatory skin and bowel disease, neonatal, 1 in 2011 by Blaydon et al. (PMID: 22010916). NISBD1 is a severe multisystem disorder characterized by neonatal- or infantile-onset inflammatory skin disease, including erythroderma, pustular dermatitis, perioral and perianal erythema, together with chronic diarrhea/enteropathy, recurrent cutaneous and systemic infections, failure to thrive, and variable abnormalities of hair, nails, and immune function. *ADAM17* encodes a membrane-bound metalloprotease that mediates ectodomain shedding of numerous cell-surface proteins, including TNF-α, IL-6 receptor, and epidermal growth factor receptor (EGFR) ligands, thereby regulating epithelial barrier homeostasis, tissue repair, and inflammatory signaling. At least nine unique *ADAM17* variants have been reported in seven probands across seven publications (PMIDs: 22010916, 25804906, 32447396, 33953303, 34993966, 40968583, 42015567). The reported variant spectrum includes frameshift variants, a multi-exon deletion, a canonical splice-site variant, a synonymous splice-disrupting variant, and multiple missense variants. Several variants have direct functional evidence demonstrating impaired *ADAM17* activity, which abolish ectodomain shedding activity in cell-based assays. No clinical manifestations have been reported in heterozygous carriers from families with NISBD1-associated *ADAM17* variants. This gene-disease relationship is further supported by experimental evidence including biochemical function studies, expression analyses, functional alteration studies, and animal models. *ADAM17* expression is demonstrated in disease-relevant tissues including skin and intestine, and affected patient tissues show markedly reduced or absent *ADAM17* protein expression (PMID: 22010916). Patient-derived peripheral blood mononuclear cells exhibit defective TNF-α release despite preserved or increased production of other inflammatory cytokines, consistent with loss of *ADAM17* sheddase activity (PMID: 22010916). Mouse models with reduced or absent adam17 function recapitulate major components of the human phenotype, including epithelial abnormalities, hair defects, impaired intestinal homeostasis, defective epithelial regeneration, and increased susceptibility to colitis (PMIDs: 22236242, 26283731, 9812885, 20603312). In summary, there is definitive evidence supporting the relationship between *ADAM17* and autosomal recessive inflammatory skin and bowel disease, neonatal, 1. This relationship has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Primary Immune Regulatory Disorders Gene Curation Expert Panel (SOP Version 12). Of note, a single family with autosomal dominant hypotrichosis associated with a heterozygous *ADAM17* variant has been reported (PMID: 38771644); however, there is currently insufficient evidence to determine whether this represents a distinct disease entity or a milder allelic manifestation of *ADAM17* deficiency, and therefore this assertion was not included in the present curation.

Inheritance Pattern: AR

Disease ID:MONDO:0017411

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*ADAM17* (formerly known as *TACE*) was FIRST reported in relation to autosomal dominant congenital heart disease in 2016 (Priest et al., PMID: 27058611). For this curation, variants in *ADAM17* have been reported in individuals with the following phenotypes: Tetralogy of Fallot and atrioventricular septal defect. Of note, this gene has also been implicated in neonatal inflammatory skin and bowel disease (OMIM:614328). This will be assessed separately. At least six unique missense variants have been reported in humans with congenital heart disease; however, three of them were too frequent to cause disease. Evidence supporting this gene-disease relationship includes case-level data. Variants in this gene have been reported in at least five probands in two publications (PMIDs: 27058611, 30610007). This gene-disease relationship is supported by animal models and expression studies (PMIDs: 9812885, 12773386, 14499647, 15936750, 33957124). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 08/14/2023 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0013693

Submitter: PanelApp Australia