Cone-Rod Dystrophy via the ADAM9 Gene

Cone-rod dystrophy (CORD/CRD) is a rare hereditary retinal disorder with a worldwide prevalence of ~1 in 40,000. CRD is characterized by dysfunction or degeneration of cone photoreceptors with relative preservation of rod function in the initial stages. The most common symptoms are photophobia and epiphora in bright light, decreased visual acuity, and dyschromatopsia. Fundus changes may vary from mild pigment granularity to a distinct atrophic lesion in the central macula. As the disease progresses, degeneration of rod photoreceptors also occurs and leads to progressive night blindness and peripheral visual field loss (Hamel 2007).

Non syndromic CRD is genetically heterogeneous and exhibits autosomal dominant (ad), autosomal recessive (ar) and, rarely, X-linked (xl) inheritance (Hamel 2007). So far, about 25 genes have been implicated in different forms of CRD (RetNet). Autozygosity mapping in four consanguineous families with recessively inherited early-onset CRD identified ADAM9 is associated with arCRD. ADAM9 encoded membrane-anchored metalloprotease is one of the first ADAM (A Disintegrin And Metalloproteinase) family proteins to be identified and characterized (Guaiquil et al. 2009; Peduto et al. 2005). ADAM proteins are involved in wide range of physiological processes therefore been associated with various diseases, including cancers. ADAM9 is shown to be up-regulated in mouse models for prostate, breast, and intestinal carcinoma, which suggests its role in tumorigenesis (Micocci et al. 2013; Peduto et al. 2005). Mouse mutant studies have shown that the absence of ADAM9 compromises the contact between photoreceptor outer segments (POSs) and the RPE apical surface and leads to retinal degeneration (Parry et al. 2009). This abnormal gap at the POS-RPE junction suggests the ADAM proteins have a role in adhesion and fusion processes by binding to integrins (Zigrino et al. 2010; Guaiquil et al. 2009). Mouse model studies suggest that ADAM9 has a critical role in the development of pathological neovascularization in the retina and choroid (Guaiquil et al. 2010). There are about five known pathogenic variations in ADAM9, which are associated with autosomal recessive cone-rod dystrophy (Human Gene Mutation Database).

Direct sequencing of ADAM9 in pedigrees of three CORD9-linked families identified mutations in affected individuals, which were absent in over 100 ethnically matched controls (Parry et al. 2009).

This test provides full coverage of all coding exons of the ADAM9 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).