A rare form of retinal dystrophy caused by hypomorphic nonsense mutations in CEP290

Abstract

Purpose: To identify the gene defect and to study the clinical characteristics and natura course of disease in a family originally diagnosed with oligocone trichromacy (OT), a rare congenita cone dysfunction syndrome. Methods: Extensive clinical and ophthalmologic assessment wa performed on two siblings with OT and long-term follow up data were analyzed. Subsequently whole exome sequencing (WES) and Sanger sequence analysis of CEP290 was performed i the two siblings. Additionally, the identified CEP290 mutations were analyzed in persons wit achromatopsia (ACHM) (n = 23) and autosomal recessive or isolated cone dystrophy (CD; n = 145) Results: In the first decade of life, the siblings were diagnosed with OT based on low visual acuity photophobia, nystagmus, and absent cone response on electroretinography, but with normal colo discrimination. Over time, the phenotype of OT evolved to a progressive degenerative diseas without any CEP290-associated non-ocular features. In both siblings, two nonsense mutation (c.451C>T; p.(Arg151*) and c.4723A>T; p.(Lys1575*)) in CEP290 were found. Previously, p.(Arg151* was demonstrated to induce nonsense-mediated alternative splicing events leading to intact ope reading frames of the resulting mRNA products (p.(Leu148_Glu165del) and p.(Leu148_Lys172del)) mRNA analysis for p.(Lys1575*) confirmed a suspected hypomorphic character, as exon 36 skippin was observed in a small fraction of CEP290 mRNA, resulting in a 36 aa in-frame deletio (p.(Glu1569_Trp1604del)). No additional cases carrying these variants were identified in the ACH and CD cohorts. Conclusions: Compound heterozygous hypomorphic mutations in CEP290 ma lead to a rare form of cone-dominated retinal dystrophy, a novel phenotype belonging to th CEP290-associated spectrum of ciliopathies. These findings provide insight into the effect of CEP29 mutations on the clinical phenotype.