Achromatopsia 7

A number sign (#) is used with this entry because of evidence that achromatopsia-7 (ACHM7) is caused by homozygous or compound heterozygous mutation in the ATF6 gene (605537) on chromosome 1q23.

Description

Achromatopsia (ACHM) is an autosomal recessive disorder resulting from lack of cone photoreceptor function. Affected individuals present from birth or early infancy with photophobia, nystagmus, severely reduced visual acuity, and color blindness (summary by Kohl et al., 2015).

For a general description and a discussion of genetic heterogeneity of achromatopsia, see ACHM2 (216900).

Clinical Features

Ansar et al. (2015) studied 2 sibs, their female cousin (the proband), and their nephew from a multiply consanguineous Pakistani family. All 4 affected individuals had had severe photophobia, nystagmus, and absence of color discrimination from early childhood. They had normal night vision, but in daylight they experienced extreme discomfort and exhibited extensive blinking. Visual acuity ranged from 20/100 to 20/250, and the Ishihara 24-color plate test revealed severe defects in all 4 affected individuals. Fundus examination of the proband at the age of 16 years was normal except for loss of foveal reflex. Full-field electroretinography (ffERG) in the proband was typical for achromatopsia: normal amplitude and latency of scotopic or rod response in dark-adapted phase at 30 Hz or lower, but subnormal rod response at 120 Hz; absent photopic flicker response with loss of regular sinusoidal waveforms; and normal latency but severely diminished amplitude of photopic or single-cone flash response. In addition, oscillatory potentials were demonstrated during scotopic responses at 30 Hz, which the authors suggested represented amacrine cell function during the rod response.

Kohl et al. (2015) studied 18 patients from 10 unrelated families with achromatopsia (ACHM), 16 of whom had a clinical diagnosis of complete ACHM and 2 of incomplete ACHM. Nystagmus and photophobia were present in all patients from birth or early infancy, and all had very poor or absent color vision and markedly reduced visual acuity. Only 1 patient showed evidence of disease progression. Best corrected visual acuity was severely reduced, ranging from 20/63 to 20/200, and refractive error ranged from -9.5 to +6.0 diopters (spherical), with variable degrees of astigmatism. Patients who underwent visual field testing showed central scotomas. Funduscopy showed macular changes ranging from relatively normal areas to well-demarcated atrophic areas that did not appear to be related to age. Spectral-domain optical coherence tomography (SD-OCT) scans showed foveal hypoplasia with a missing foveal pit in all patients, as well as variable disruption of the inner segment ellipsoid layer (photoreceptor layer) at the fovea. Dark adaptation was evaluated in an affected Irish brother and sister, ages 19 and 16 years, who showed rod-mediated function lacking the rod-cone break and cone branch, with normal dark-adaptation thresholds. Their scotopic ffERG responses were within normal limits, consistent with normal rod function, whereas photopic ffERG responses were severely reduced or undetectable, consistent with absent or markedly reduced cone system function. Adaptive optics scanning light ophthalmoscopy (AOSLO) in the affected Irish sibs revealed an average cone density that was considerably lower than controls, and indicated that only cones in the macular and part of the paramacular area were affected.

Mapping

Ansar et al. (2015) performed genomewide homozygosity mapping in 11 members of a consanguineous Pakistani family with ACHM and identified a 15.12-Mb region of homozygosity on chromosome 1q23.1-q24.3. A maximum 2-point lod score of 3.1 (theta = 0) was obtained at rs6700867 (chr1:162.21 Mb; GRCh37), and a statistically significant maximum multipoint lod score of 3.6 was obtained for markers between rs1538971 (chr1:161.68 Mb) and rs17350579 (chr1:172.07 Mb).

In a nonconsanguineous family of Irish descent in which 3 sibs had ACHM, Kohl et al. (2015) performed haplotype analysis and homozygosity mapping and identified the largest region of homozygosity on chromosome 1p13.2-q23.3. The homozygous interval consisted of 624 consecutive SNPs spanning a 2.4-Mb region flanked by rs4656862 and rs164418 (chr1:159,953,102-162,354,150, GRCh37).

Molecular Genetics

In the proband from a consanguineous Pakistani family with ACHM mapping to chromosome 1q23.1-q24.3, Ansar et al. (2015) performed exome sequencing and identified a homozygous 1-bp duplication in the ATF6 gene (605537.0001). The mutation, which segregated with disease in the family, was not found in 470 ethnically matched control chromosomes, in exome sequence data from 130 unrelated Pakistani controls without eye disease, or in the dbSNP or ExAC databases.

In 1 of 3 affected sibs from a nonconsanguineous family of Irish descent with ACHM mapping to chromosome 1, Kohl et al. (2015) performed whole-exome sequencing and identified homozygosity for a missense mutation in the ATF6 gene (R324C; 605537.0002). The mutation segregated with disease in the family. Further whole-exome sequencing and candidate gene screening in 301 ACHM patients revealed 15 more individuals from 9 unrelated families with homozygous or compound heterozygous mutations in the ATF6 gene (see, e.g., 605537.0003-605537.0006). All 18 mutation-positive patients exhibited marked foveal hypoplasia, including persistent inner retinal layers at the fovea and a poorly formed or absent foveal pit. Noting that the absence of foveal development is rare, Kohl et al. (2015) suggested that severe foveal hypoplasia with a poorly formed or absent foveal pit could be a hallmark of ATF6-related disease.