Cone-Rod Dystrophy and Retinitis Pigmentosa via the CFAP418/C8orf37 Gene

Cone rod dystrophies (CORDs/CRDs) are 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. Cone rod dystrophies (1/40,000) are 10 times less common than RP (Hamel. 2007). Retinitis pigmentosa (RP) represents a group of hereditary retinal dystrophies with a worldwide prevalence of ~1 in 4000 (Booij et al. 2005). RP is clinically characterized by retinal pigment deposits visible on fundus examination, nyctalopia ("night blindness"), followed by progressive degeneration of the photoreceptors, which eventually leads to blindness (van Soest et al. 1999).

Genes that are associated with both autosomal recessive (ar) CRD and RP encode proteins that are involved in phototransduction, retinoid metabolism, transport through connecting cilium, cell-to-cell signaling or synaptic interaction (Estrada-Cuzcano et al. 2012). Mutations in CFAP418/C8orf37 can lead to an early or adolescent-onset arCRD or arRP phenotype with early macular atrophy. Postaxial polydactyly has been reported in one family, which suggests a syndromic phenotype (van Huet et al. 2013). CFAP418 encoded polypeptide function is unknown because it lacks known functional protein domains. CFAP418 is expressed ubiquitously. High mRNA expression levels were found in brain, heart, and retina. Immunohistochemical studies revealed that CFAP418 localization at the base of the photoreceptor connecting cilia (Estrada-Cuzcano et al. 2012). Immunolocalization study, and the presence of postaxial polydactyly in one of the families who had CFAP418 mutations suggested a plausible ciliary function of the CFAP418 encoded polypeptide (Estrada-Cuzcano et al. 2012; van Huet et al. 2013). These studies also suggest that CFAP418 may be implicated in Bardet-Biedl syndrome or in other ciliopathies. Only a few causative mutations have been reported in CFAP418. These are missense, nonsense and splicing (Human Gene Mutation Database). CFAP418 mutation analysis in 4 unrelated consanguineous families with retinal dystrophies identified homozygous CFAP418 mutations in all affected individuals (Estrada-Cuzcano et al. 2012).

Predicting clinical sensitivity for the CFAP418 gene is challenging due to genetic heterogeneity of both cone rod dystrophy and retinitis pigmentosa and also due to the limited number of documented cases. However, analytical sensitivity is expected to be high because all mutations reported are detectable by this method (Human Gene Mutation Database).

This test is performed using Next-Generation sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the CFAP418 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.