Submission Details

The ADAM9 gene was first reported in relation to an inherited retinal dystrophy, cone-rod dystrophy with an autosomal recessive mode of inheritance, in 2009 (Parry et al., PMID: 19409519). Affected individuals with causal variants in ADAM9 have since been identified in a second publication (PMID: 25091951), with cases generally showing onset in the first decade of life. Presenting phenotypes include a combination of reduced visual acuity, retinal pigment epithelial abnormalities, and decreased amplitude of both the rod- and cone-based electroretinogram responses. Additional features can include macular atrophy, attenuation of retinal blood vessels, optic disc pallor, peripheral retinal degeneration, subcapsular cataracts, and/or myopia. These cases with causal variants in ADAM9 are specifically diagnosed with cone-rod dystrophy 9. To account for a spectrum of retinal phenotypes that may be caused by variants in this gene, and in accordance with the ClinGen Lumping and Splitting guidelines, the disease entity used for this curation is ADAM9-related retinopathy (MONDO:0800398).

Six suspected deleterious variants in ADAM9 were scored as part of this curation (three nonsense and three affecting splicing), which have been collectively reported in six probands in three publications (PMID: 19409519, PMID: 25091951, PMID: 23661369). All probands were members of consanguineous families and were homozygous for the variant of interest. The mechanism of pathogenicity appears to be loss of function in ADAM9, characterized in at least some cases by variants predicted to trigger the absence of the gene product. One large family with co-segregation of the genotype and phenotype among affected members was scored as part of this curation, (PMID: 11581183), while other segregation evidence was not included in this curation as the maximum scoring for this evidence type had already been reached.

This gene-disease association is also supported by expression evidence that retinal pigment epithelium is one of the tissue types with highest levels of ADAM9 mRNA (PMID: 30239781). Biochemical data similarly support a structural function in the retina by showing that the ADAM9 protein mediates cell adhesion through interaction with integrins (PMID: 11162558) and regulates ocular vascularization by enhancing proteolytic shedding of the ectodomains of membrane proteins involved in angiogenesis (PMID: 19273593). A canine model of biallelic ADAM9 loss-of-function recapitulates the visual defects, retinal atrophy, and progressive nature of the human disease state (PMID: 20691256). A murine model of biallelic Adam9 loss-of-function further recapitulates the reduced amplitudes of both cone- and rod-based electroretinogram responses (PMID: 19409519) and indicates an underlying adhesion defect at the interface between the retina pigment epithelium and the photoreceptor outer segment.

In summary, ADAM9 is definitively associated with ADAM9-related retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a definitive classification. This classification has been approved by the ClinGen Retina GCEP on September 1st, 2022 (SOP Version 9).