Mendeliome
Gene: ADAMTS9 Amber List (moderate evidence)I don't know
CLINGEN assessed as LIMITED (2022)
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.Created: 25 Nov 2022, 1:38 a.m. | Last Modified: 25 Nov 2022, 1:38 a.m.
Panel Version: 1.481
Green List (high evidence)
Two families reported with functional evidence
Sources: LiteratureCreated: 16 Jan 2020, 11:30 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Nephronophthisis-Related Ciliopathy
Publications
Phenotypes for gene: ADAMTS9 were changed from Nephronophthisis-Related Ciliopathy to Nephropathy-related ciliopathy, MONDO:0022409, ADAMTS9-related
Gene: adamts9 has been classified as Amber List (Moderate Evidence).
Gene: adamts9 has been classified as Green List (High Evidence).
Gene: adamts9 has been classified as Green List (High Evidence).
gene: ADAMTS9 was added gene: ADAMTS9 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: ADAMTS9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADAMTS9 were set to 30609407 Phenotypes for gene: ADAMTS9 were set to Nephronophthisis-Related Ciliopathy Review for gene: ADAMTS9 was set to GREEN
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.