Abstract
Purpose :
CEP250 encodes the C-Nap1 protein which is expressed in the photoreceptor cilia and involved in cilia formation. Variants in CEP250 have been described in a few families with retinal dystrophy and hearing impairment, but a genotype-phenotype correlation is still unclear. In this study, we searched for additional cases with CEP250 variants and investigated their vision, hearing and other clinical features.
Methods :
Whole exome sequencing (WES) was performed to identify causative variants in a cohort of genetically unexplained retinal diseased individuals, and revealed CEP250 variants in five affected individuals from four different families. Clinical follow-up was available for all five subjects, and additional ophthalmic examinations were performed.
Results :
In all index patients, homozygous loss-of-function variants in CEP250 were identified. Unaffected family members were analyzed for the presence of these variants which confirmed co-segregation of the variant with the phenotypes in the families. No rare variants in C2ORF71 were seen, which excluded a digenic inheritance pattern that was previously suggested in literature in a family with early-onset RP (Khateb et al., J Med Genet, 51:460-469, 2014). All five subjects (aged 13-53 years) presented with low visual acuity since birth, and only mild deterioration over time. Subtle macular changes were observed on funduscopy in all five, with abnormalities on OCT. Peripheral defects varied from none in the oldest subject, to subtle RPE alterations, to regional degenerative changes. Multifocal ERG was abnormal in all five subjects, whereas full-field ERG was normal in two, and abnormal in three subjects. Hearing impairment occurred in all five. Other signs possibly related to CEP250 variants were diabetes in one, and intellectual disability, lung abnormalities, and pancreas insufficiency in another subject. These extraocular findings may be in line with the described ciliary function of CEP250.
Conclusions :
With the description of four additional unrelated families, this study provides clear evidence for the pathogenicity of loss-of-function variants in CEP250. The phenotype may vary form a local cone dysfunction to a more generalized retinal disorder, in combination with hearing impairment. This enables recognition and rapid genetic diagnosis of affected individuals by targeted gene sequencing.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.