Submission Details

Bi-allelic variants in ADAMTS9 are associated with a nephronophthisis-related ciliopathy disease in humans. This is a recent association, first proposed in 2019 (Choi et al., 2019; PMID: 30609407) and currently does not have an official OMIM disease association. 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, three unrelated individuals harboring bi-allelic variants (missense as well as loss of function) in ADAMTS9 have been reported in the literature (consisting of the above two studies) presenting with renal and/or extra-renal symptoms. To date, four unique variants have been described associated with disease and were scored in the curation. However, these variants were not all assigned the default points owing to verified consanguinity, population frequency of the variants in databases such as gnomAD, or in silico predictions indicating the variant’s impact on the protein to be likely benign. Taken together, ADAMTS9 currently has limited genetic case-level data to establish a clear gene-disease relationship. Functional studies performed with transgenic animal models (reviewed but not scored in the curation) have investigated the role of Adamts9 in development, particularly in the context of the cardiac, cartilage, bone development. However, there are currently no studies that have explored the role of this gene in the renal system. 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. Further lines of evidence in mouse epithelial cells indicate a dysfunction in signaling pathways, such as Shh signaling, and impaired spheroid formation. However, these phenotypes have not been directly implicated in the human disease and such findings have also not been demonstrated in a relevant cell line of human origin, although it should be noted that overexpression of human ADAMTS9 was demonstrated to rescue spheroid formation, strongly suggesting a direct involvement of the protein in this process. In addition, a study (PMID: 30814516) has explored the role of Adamts9 in ciliary trafficking using mice models, but the genetic background of this model is not consistent with the human disease context. Therefore, in keeping with the gene curation SOP guidelines, this evidence has been either only reviewed or scored with reduced points. Default points were given to the morpholino-mediated knockdown of Adamts9 in zebrafish that caused curved body axis, hydrocephalus, and pronephric cysts (PMID: 30609407). In summary, due to the limited genetic evidence as well as the absence of renal-specific experimental evidence, the causal relationship between the bi-allelic variants in ADAMTS9 and its associated disease ciliopathy cannot be unequivocally determined at this time. Therefore, this gene-disease relationship, based on our scoring of currently available information has been determined as limited. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 05/11/22 (SOP Version 8).