A number sign (#) is used with this entry because of evidence that cone dystrophy-4 (COD4) and achromatopsia-5 (ACHM5) can be caused by homozygous or compound heterozygous mutation in the PDE6C gene (600827) on chromosome 10q34.

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

Cone photoreceptor disorders form a clinical spectrum of diseases that include progressive cone dystrophy (COD) and complete and incomplete achromatopsia (ACHM). Impairment or death of cone photoreceptor cells is the clinical hallmark of these disorders. COD is a progressive cone disorder in which patients may initially have normal cone function but develop progressive visual acuity loss, increasing photophobia, color vision disturbances, and diminished cone responses on ERG, usually in the first or second decade of life. The visual acuity of these patients generally worsens to legal blindness before the fourth decade of life. ACHM is a stationary congenital autosomal recessive cone disorder characterized by low visual acuity, photophobia, nystagmus, and severe color vision defects. Patients with the complete ACHM subtype have no cone function on electroretinography, whereas those with incomplete ACHM show residual cone function (summary by Thiadens et al., 2009).

Thiadens et al. (2009) reported affected members of 4 families with early-onset cone dystrophy due to PDE6C mutations. In 1 family, 2 brothers had severe color vision defects with a reduced cone response on ERG when first examined at ages 6 and 7 years, respectively; they also had photophobia and nystagmus, with progressive decline in their visual acuity during their teens, and ERG examination at ages 51 and 47 years, respectively, revealed no cone responses whereas rod responses were normal. A sister and brother with incomplete achromatopsia, born of consanguineous parents, had nystagmus but no photophobia upon initial examination at ages 7 and 10, respectively, and initial visual acuities of 0.16 (20/100) in their best eyes declined to 0.10 (20/200) over the next decade. The brother showed significantly reduced but measurable cone responses on ERG examinations at ages 10 and 20 years, with normal rod parameters. Two sisters were clinically diagnosed with complete achromatopsia and were first examined at ages 11 and 12 years, respectively. They had severe photophobia, nystagmus, and visual acuities of 0.16 (20/100) in their best eyes, which declined to 1.10 (20/200) over the next 2 decades. ERG examinations showed no cone responses even in childhood, but normal rod responses were observed at ages 36 and 37 years, respectively. In the fourth family, Thiadens et al. (2009) reported a 4-year-old boy with complete achromatopsia. At 4 years of age, the patient had a visual acuity of 0.10 (20/200) with severe photophobia and nystagmus; ERG revealed nonrecordable cone function, with completely normal rod function. Cross-sectional retinal imaging using optical coherence tomography (OCT) in patients with PDE6C mutations revealed a more pronounced absence of cone photoreceptors in patients with achromatopsia compared to patients with early-onset cone dystrophy. ERG analysis in the sib pair with early-onset cone dystrophy, who represented the 2 oldest mutation-positive patients at ages 47 and 51 years, respectively, showed absent cone responses but no abnormal rod responses, and normal rod responses were also observed in the 3 patients with complete achromatopsia. Thiadens et al. (2009) concluded that rod involvement does not appear to be a major consequence of PDE6C mutations, although they noted that some dysfunction of rods may still occur later in life.

Chang et al. (2009) studied patients with PDE6C mutations who presented with a clinical picture 'typical for' complete achromatopsia, as exemplified by 2 sisters who had photophobia and reduced visual acuity from earliest infancy and reported congenital nystagmus that persisted into adulthood. Upon examination at ages 24 and 26 years, respectively, both were myopic and had complete lack of color discrimination and a central scotoma. ERG recordings showed extinguished responses under photopic and 30-Hz flicker stimulation, whereas scotopic ERG responses were essentially normal. Funduscopy revealed atrophy of the retinal pigment epithelium in the macula; Chang et al. (2009) noted that this is an atypical feature in patients with achromatopsia, but has been seen in patients with progressive cone dystrophy.

Cone dystrophy-4 and achromatopsia-5 are autosomal recessive disorders (Thiadens et al., 2009).

In 116 patients with autosomal recessive early-onset cone photoreceptor disorders, including 85 with autosomal recessive cone dystrophy (arCD), 20 with early-onset arCD, and 11 with achromatopsia, in all of whom involvement of known genes for ACHM and arCD had been excluded, Thiadens et al. (2009) performed high-resolution SNP analysis and identified large homozygous regions spanning the PDE6C gene (600827) on chromosome 10 in 1 sib pair with early-onset arCD and 1 sib pair with incomplete ACHM. Sequence analysis of the PDE6C gene detected homozygous missense mutations in both sib pairs (600827.0001 and 600827.0002, respectively). Additional sequence analysis of PDE6C in 104 patients with arCD and 10 with ACHM identified compound heterozygous PDE6C mutations in 3 patients with complete ACHM from 2 families (600827.0003-600827.0006, respectively).

In 4 families with achromatopsia in at least 2 affected sibs, who were negative for mutation in known achromatopsia genes, Chang et al. (2009) performed segregation analysis using satellite markers flanking the PDE6C gene and found a pattern compatible with linkage in 2 families; screening the PDE6C gene in those 2 families revealed compound heterozygosity for 4 different mutations in affected individuals (600827.0007-600827.0010, respectively). Screening of 24 additional simplex achromatopsia patients identified 2 patients who were compound heterozygous and homozygous, respectively, for mutations in PDE6C (600827.0011-600827.0013).

In a cohort of 176 patients diagnosed with achromatopsia, who were negative for mutation in the CNGA3 (600053), CNGB3 (605080), and GNAT2 (139340) genes, Weisschuh et al. (2018) screened for mutations in the PDE6C gene and identified 18 potentially pathogenic homozygous and compound heterozygous variants in 15 probands, including 1 patient compound heterozygous for the previously reported R29W mutation (600827.0001) and another missense mutation (I279T; 600827.0014).

Chang et al. (2009) demonstrated that the spontaneous mouse mutant cpfl1, in which there is lack of cone function and rapid degeneration of cone photoreceptors, represents a homologous mouse model for PDE6C (600827)-associated achromatopsia.