Introduction
Inherited cone disorders are a heterogeneous group of diseases that primarily affect cone photoreceptors and have an estimated worldwide prevalence of 1:30,000–1:40,000.1–3 They can be divided into progressive forms of cone dystrophy (COD) and the more stationary disorders, also named cone-dysfunction syndromes. The stationary subtypes, such as achromatopsia (ACHM), are congenital, and children with ACHM present with congenital nystagmus, significantly reduced visual acuity, severe photophobia, poor or absent color vision, and normal fundi. Electroretinography (ERG) shows no or residual cone responses and normal rod responses. COD, on the other hand, starts in childhood or early adult life and causes progressive deterioration of visual acuity and color vision, as shown by reduced cone responses on ERG.4,5 The fundus examination in COD varies from normal to either a bull’s eye maculopathy or total atrophy of the macular region.1 A considerable amount of individuals with COD also develop rod dysfunction, leading to a cone-rod dystrophy (CRD) with panretinal degeneration. In CRD, the loss of rod function can also be concomitant with the loss of cone function. So, apart from the loss of central vision, individuals with CRD also experience night blindness and loss of peripheral vision, leading to legal blindness at an earlier age.1,6
Molecular genetic studies have identified five genes mutated in individuals with ACHM, eight genes implicated in COD, and 17 genes implicated in CRD (RetNet, see Web Resources).1,7–9 Cone disorders can follow all modes of Mendelian inheritance and manifest as nonsyndromic and syndromic forms.1,2 Cone-disease-associated genes encode proteins that fulfill crucial roles in the cone phototransduction cascade, transport processes toward or through the connecting cilium, cell membrane morphogenesis and maintenance, synaptic transduction, and the retinoid cycle.1,7–9
Whole-exome sequencing (WES) has proven to be very effective in the discovery of genetic defects in inherited retinal diseases.10–14 Here, we report the identification by WES of mutations in POC1B (MIM 614784), encoding a protein previously associated with basal body stability,15 underlying autosomal-recessive COD or CRD. In addition, we provide an integrated functional approach to substantiate the causality of the identified mutations.