Cone-Rod Dystrophy And Hearing Loss 1

A number sign (#) is used with this entry because of evidence that cone-rod dystrophy and hearing loss-1 (CRDHL1) is caused by homozygous or compound heterozygous mutation in the CEP78 gene (617110) on chromosome 9q21.

Description

CRDHL1 is characterized by cone-rod dystrophy and sensorineural hearing loss, with relatively late onset of both ocular and hearing impairment. The funduscopic findings are characteristic, showing ring-shaped atrophy along the major vascular arcades that manifests on fundus autofluorescence as a hypoautofluorescent band along the vascular arcades surrounded by hyperautofluorescent borders (Namburi et al., 2016).

Genetic Heterogeneity of Cone-Rod Dystrophy and Hearing Loss

CRDHL2 (618358) is caused by mutation in the CEP250 gene (609689) on chromosome 20q11.

Clinical Features

Nikopoulos et al. (2016) described a Greek man and a Swedish brother and sister who had cone-rod dystrophy associated with hearing loss. The 59-year-old Greek man had reduced vision in bright light since early adulthood, which progressed to severe central vision loss by age 40 years, with nystagmus, photophobia, and dyschromatopsia. Funduscopy at age 53 revealed macular coalescent hypochromatic lesions in the right eye and minor macular changes in the left eye. Visual field examination showed diffuse suppression bilaterally, with relative conservation of the peripapillary area and superior periphery. Full-field electroretinography (ERG) displayed flat cone responses, but some residual rod-mediated signals in the left eye. The proband also reported minor hearing problems; audiogram confirmed a mild deficit, but more severe than natural age-related hearing loss. The affected Swedish sibs both had visual problems from childhood, including loss of color sensitivity and central vision. Both also had a hearing deficit from a young age, and both used hearing aids; audiogram of the sister showed substantial sensorineural hearing loss, which was nonprogressive over 11 years of follow-up. Funduscopy showed macular degenerative changes in both sibs, with attenuated vessels and some spicular pigment in the midperiphery but fewer changes in the periphery. Progressive deterioration of the visual field was reported and documented as expanding from the center to the periphery; both sibs retained some residual peripheral vision, especially in low-light conditions. Full-field ERGs revealed almost no residual cone activity, but there were some rod-mediated responses even at ages 66 and 69 years.

Namburi et al. (2016) reported 6 individuals from 5 Jewish families of Iranian, Iraqi, or Afghan origin who exhibited both cone-rod dystrophy and sensorineural hearing loss (SNHL). All affected individuals presented with similar cone-dominated symptoms with a variable age of onset (10 to 35 years), including photophobia, low visual acuity, impaired color vision, and visual field defects, accompanied by SNHL which also had a variable age of onset (10 to 45 years). ERG testing showed progressive loss of cone photoreceptor function, followed by that of rods, and was in some patients accompanied by a reduced b/a wave ratio in the dark-adapted state (electronegative pattern). Electrooculography (EOG) was performed in 4 patients and showed a reduced Arden ratio, which the authors suggested was due to photoreceptor degeneration. Fundoscopic findings included prominent retinal atrophy along the major vascular arcades surrounding the macula, which expanded at older ages, as well as mild macular retinal pigment epithelium (RPE) changes and subtle peripheral salt-and-pepper changes; no bone spicule-like pigmentation was seen. Characteristic ring-shaped atrophy was evident on fundus autofluorescence (FAF) imaging, manifesting as a hypoautofluorescent band along the vascular arcades, surrounded by hyperautofluorescent borders. Testing performed in 3 patients confirmed severe deficiency of color vision. Audiometry tests revealed bilateral SNHL affecting the middle frequencies, high frequencies, or both. None of the affected individuals reported significant abnormalities of the vestibular system. Namburi et al. (2016) noted that the phenotype observed in these patients did not fall within the standard classification of Usher syndrome (see 276900), in which the retinal disease is typical retinitis pigmentosa with early rod dysfunction.

Fu et al. (2017) studied 4 affected sibs from 2 unrelated consanguineous Chinese families with juvenile or adult-onset cone-rod dystrophy and SNHL. In the first family, 2 sisters aged 33 years and 41 years reported several decades of progressive vision loss, with severely reduced visual acuity on examination. Photophobia, color vision loss, and recent progressive hearing loss were also noted. ERG testing showed similar results in both patients, with cone responses reduced more than rod responses. Funduscopy showed grayish retinal pigment mottling along the retinal vessels, with attenuated retinal arteries. FAF showed annular hypofluorescent patches around the posterior pole with an inner hyperfluorescent ring around the macular region, and ocular coherence tomography (OCT) showed reduced thickness of the macular region with loss of the ellipsoid zone. In the second family, a sister and brother were affected. The sister reported night blindness from early childhood, hypochromatopsia and mild hearing loss from age 8 years, and visual field decrease with central vision loss from age 10 years. At age 35, her visual acuities were 20/125 and 20/200, and hypochromatopsia was confirmed by color vision testing. Funduscopy showed attenuated vessels, waxy optic disc, and pigment deposits in the midperiphery, with macular involvement as well. Fundus fluorescein angiography (FFA) revealed aberrant vascular arcades and speckled areas of increased fluorescence in the midperiphery. Attenuation of the outer nucleus layer and RPE as well as loss of the ellipsoid zone were suggested by OCT, and both scotopic and photopic responses were abolished on ERG. Fu et al. (2017) designated the phenotype as an atypical form of Usher syndrome.

Mapping

In a consanguineous Jewish family with cone-rod dystrophy and sensorineural hearing loss, Namburi et al. (2016) performed homozygosity mapping and identified a 65.6-Mb region on chromosome 9, as well as a 34-Mb region on chromosome 19. Analysis of polymorphic markers in 2 affected sibs showed that they shared only a single homozygous region on chromosome 9, spanning 16 Mb and flanked by SNPs rs369854466 and rs728695.

Molecular Genetics

In a cohort of 34 probands with cone-rod dystrophy, 29 from Greece and 5 from Sweden, Nikopoulos et al. (2016) performed whole-exome sequencing and identified biallelic mutations in the CEPL78 gene (617110.0001-617110.0003) in a Greek man and a Swedish woman, who both also exhibited hearing loss. The mutations segregated with disease in each family and were not found in 350 controls or in public variant databases. The authors sequenced CEP78 in another cone-rod dystrophy cohort, involving 99 unrelated individuals of Swedish, Swiss, Dutch, and Pakistani origin, but did not find any additional causative variants.

In 2 affected brothers from a consanguineous Jewish family with cone-rod dystrophy and sensorineural hearing loss mapping to chromosome 9, Namburi et al. (2016) performed whole-exome sequencing and identified homozygosity for a splice site mutation in the CEP78 gene (617110.0004) that segregated with disease and was not found in an in-house database of 408 Israeli exomes or in public variant databases. The authors screened 4 more Jewish probands with a similar phenotype for the CEP78 splice site mutation and identified homozygosity for the mutation in 1 patient, and compound heterozygosity for the splice site mutation and a 1-bp deletion in CEP78 (617110.0005) in 1 patient. The remaining 2 patients were homozygous for the 1-bp deletion. Analysis of 249 Eastern Jewish probands with inherited retinal diseases did not reveal any additional CEP78 disease-causing mutations. The 5 mutation-carrying families were Jews of Iranian, Iraqi, or Afghan origin, and haplotype analysis revealed a shared and distinct haplotype for each mutation, confirming that these are founder mutations.

In 2 sisters from a consanguineous Han Chinese family with cone-rod dystrophy and sensorineural hearing loss, negative for mutation in known retinal disease genes, Fu et al. (2017) performed whole-exome sequencing and identified homozygosity for a splice site mutation in the CEP78 gene (617110.0006) that segregated with disease and was found to be extremely rare in the ExAC population database (1/30,990). In a similarly affected proband from a second consanguineous Chinese family, WES revealed homozygosity for a different splice mutation in CEP78 (617110.0007). The authors also screened 71 unsolved cases of Usher syndrome, but did not find any biallelic CEP78 mutations.