A number sign (#) is used with this entry because of evidence that cone-rod dystrophy and hearing loss-2 (CRDHL2) is caused by homozygous or compound heterozygous mutation in the CEP250 gene (609689) on chromosome 20q11.

Cone-rod dystrophy and hearing loss-2 (CRDHL2) is characterized by retinal dystrophy, with photophobia and progressive reduction in visual acuity, associated with sensorineural hearing loss (Kubota et al., 2018).

For a discussion of genetic heterogeneity of cone-rod dystrophy and hearing loss, see CRDHL1 (617236).

Khateb et al. (2014) studied a large consanguineous family of Iranian Jewish origin (MOL0028) in which 6 sibs had early-onset severe sensorineural hearing loss, 3 of whom also had relatively mild retinal degeneration and 3 of whom had early-onset severe retinitis pigmentosa (RP). Their father had relatively mild RP with age-related hearing loss, and their mother was unaffected. Funduscopy of affected individuals with milder retinal degeneration showed peripheral retinal atrophy with white scars in the far periphery with a few areas of bone spicule-like pigmentation. There were measurable scotopic and photopic responses on electroretinography (ERG), and optical coherence tomography (OCT) showed preservation of retinal layers in the posterior pole. Goldman visual field testing revealed a constricted visual field with preserved central vision. The 3 sibs with severe RP had visual acuity of light perception only and nondetectable ERG responses, with diffuse retinal atrophy on funduscopy and OCT.

Kubota et al. (2018) reported 2 Japanese sisters with mild cone-rod dystrophy (CRD) and mild high-frequency sensorineural hearing loss. The 24-year-old sister experienced photophobia and a gradual reduction of vision; examination showed best-corrected visual acuities (BCVAs) of about 20/200 and 20/140 in the right and left eyes, with no fundus abnormalities. She had full visual fields by Goldman perimetry, with a relative reduction of central sensitivity by Humphrey Visual Field Analyzer. Her 22-year-old sister also had reduced visual acuity, with BCVAs of about 20/30 and 20/25, and no fundus abnormalities. Spectral domain (SD)-OCT in the affected sisters revealed blurred ellipsoid zones and discontinuous interdigitation zones. Full-field and multifocal ERGs showed slight reduction of b-wave amplitudes bilaterally in the older sister; the younger sister had slightly reduced responses in both eyes to light-adapted 3.0 flicker. High-resolution fundus imaging showed patient cone densities at 2 to 8 degrees horizontally from the foveal center that were lower by more than 1 standard deviation than those of 34 controls.

Fuster-Garcia et al. (2018) described a Spanish woman (RP1973) who had onset of moderate to severe progressive hearing loss at age 13 years, and presented at age 44 years with progressive diminution of vision bilaterally with photophobia. BCVA was about 20/30 and 20/40 in the right and left eyes, and fundus examination showed migration of pigment in a bone-spicule pattern within a midperipheral annular zone bilaterally, with narrowing of the peripheral retinal blood vessels. Humphrey perimetry revealed peripheral field constriction with relative defects in the paracentral region in both eyes. OCT showed normal macular thickness, with loss of retinal pigment epithelium and discontinuity of the outer segment layer around the foveal center bilaterally. Full-field ERG showed only mild alterations in the scotopic flash responses, whereas macular ERG showed an absence of response in both eyes.

The transmission pattern of CRDHL2 in the family reported by Khateb et al. (2014) was consistent with autosomal recessive inheritance.

By whole-exome sequencing in a large consanguineous family of Iranian Jewish origin (MOL0028) in which 6 sibs had hearing loss and retinal dystrophy, Khateb et al. (2014) identified mutations in 2 genes: all 6 affected sibs were homozygous for a nonsense mutation in the CEP250 gene (R1155X; 609689.0001), and the 3 sibs who had early-onset severe RP were also homozygous for a nonsense mutation (Q1097X) in a known RP gene, C2ORF71 (PCARE, 613425; see RP54, 613428); the 3 sibs with a milder retinal phenotype were heterozygous for the C2ORF71 mutation. Their father, who had relatively mild RP and age-related hearing problems, was homozygous for the C2ORF71 mutation but heterozygous for the CEP250 mutation, whereas their unaffected mother and an unaffected sister were both heterozygous for both mutations. The authors concluded that the severe retinal involvement in the double homozygotes indicated an additive effect caused by nonsense mutations in 2 genes encoding ciliary proteins.

In a cohort of 33 families from Argentina, Saudi Arabia, and Spain diagnosed with 'inherited retinal dystrophy,' de Castro-Miro et al. (2016) performed whole-exome sequencing and identified an affected sister and brother (family A3) who were homozygous for a missense mutation (A609V) in the CEP250 gene that segregated with disease. The patients were tabulated as having autosomal recessive RP; no further clinical information was reported. The authors noted that a known autosomal recessive RP-associated mutation, C948Y in the CRB1 gene (604210.0013), segregated in heterozygosity in this family, and might contribute to the severity of the phenotype.

By whole-exome sequencing in a 24-year-old Japanese woman with mild cone-rod dystrophy and sensorineural hearing loss, Kubota et al. (2018) identified compound heterozygous nonsense mutations in the CEP250 gene, R121X (609689.0002) and R188X (609689.0003). Sanger sequencing showed that her affected 22-year-old sister was also compound heterozygous for the mutations, whereas their unaffected parents were each heterozygous for 1 of the variants and their unaffected sister did not carry either of them. The authors stated that no pathogenic variants in the C2ORF71 gene were found in the proband.

In a cohort of 58 Spanish patients diagnosed with Usher syndrome (see 276900), Fuster-Garcia et al. (2018) performed targeted exome sequencing for variation in 10 known Usher-associated genes and 4 candidate genes, and identified a woman (RP1973) with hearing loss and mild retinal degeneration involving the macula who was compound heterozygous for nonsense mutations in the CEP250 gene: K1113X (609689.0004) and R1336X (609689.0005). Her unaffected parents were each heterozygous for 1 of the mutations, and her unaffected sister did not carry either of them. The authors noted that the proband was also heterozygous for a missense mutation in the USH2A gene (608400; R1521C, rs773526991).