ADAMTS9

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

*ADAMTS9* gene is located on chromosome 3 at 3p14.1 and encodes ADAMTS family the DAM Metallopeptidase With Thrombospondin Type 1 Motif 9, an enzyme belonging to the ADAMTS family. The secreted metalloprotease that plays a role in ciliogenesis by localizing to the base of the cilium. Bi-allelic variants in *ADAMTS9* are associated with a nephronophthisis-related ciliopathy disease in humans. This gene-disease pair was first proposed in 2019 (Choi et al., 2019; PMID: 30609407). Patients in this study shared common phenotypes including proteinuria, end stage renal disease, gross morphological defects in the kidneys and extra-renal features including deafness, and short stature. In contrast, another study (PMID: 34750010) describes bi-allelic variants in *ADAMTS9* being associated with Joubert syndrome-like presentation (complete with the neurological and ocular features) without the renal manifestations. In total, five unrelated individuals harboring bi-allelic variants in *ADAMTS9* have been reported in the literature presenting with renal and/or extra-renal symptoms (PMID: 30609407, 37035301,37230223, 34750010). To date, eight unique variants have been described associated with disease and were scored in the curation (six missense, one nonsense, one frameshift). This gene-disease relationship is also supported by experimental data. ADAMTS9 knockout kidney organoids demonstrated abnormal cilia, and ciliogenesis that is not rescued by ADAMTS9 variants (PMID: 37035301). ADAMTS9 is shown to be expressed in podocytes and proximal tubules, influences the Wnt/PCP pathway, regulates the localization of junction proteins (PMID: 37035301). Biochemical assays further demonstrate the ADAMTS9-mediated cleavage that separates TMEM67 into a C-terminal portion for ciliary transition zone assembly and a full-length form for Wnt signaling (PMID: 40436881). A novel mouse model in preprint demonstrates the loss of ADAMTS9 disrupts ciliogenesis and collagen homeostasis resulting in nephronophthisis-like polycystic kidneys (PMID: 41542618). Functional studies performed with transgenic animal models have investigated the role of ADAMTS9 in development, particularly in the context of the cardiac, cartilage, bone development (PMID: 20096780). The first study linking ADAMTS9 to disease (PMID: 30609407) performed functional studies using patient-derived fibroblasts. These studies demonstrated that patient fibroblasts have reduced primary cilia, suggesting a role for ADAMTS9 in cilia formation (PMID: 30609407). A morpholino-mediated knockdown of ADAMTS9 in zebrafish that caused curved body axis, hydrocephalus, and pronephric cysts (PMID: 33290818). In summary, there is definitive evidence supporting the relationship between *ADAMTS9* and autosomal recessive ciliopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The curation was originally evaluated by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 05/11/2022 (SOP Version 8). It was re-evaluated on 04/22/2026 (SOP version 12). As a result, the classification increased from Limited to Definitive with the addition of two case reports (PMIDs: 37230223, 37035301) and several functional studies (PMIDs: 37035301, 40436881, 41542618).

Inheritance Pattern: AR

Disease ID:MONDO:0022409

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0019005

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009728

Submitter: Orphanet