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Genes 2017, 8(8), 208;

A Rare Form of Retinal Dystrophy Caused by Hypomorphic Nonsense Mutations in CEP290

Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Donders Institute for Brain, Cognition and Behaviour, 6525 EN Nijmegen, The Netherlands
Bartiméus Institute for the Visually Impaired, 3703 AJ Zeist, The Netherlands
The Rotterdam Eye Hospital, 3011 BH Rotterdam, The Netherlands
Sint Franciscus Gasthuis, Department of Internal Medicine, 3045 PM Rotterdam, The Netherlands
Department of Ophthalmology, Radboud University Medical Center, 6525 EX Nijmegen, The Netherlands
Author to whom correspondence should be addressed.
Received: 30 June 2017 / Revised: 11 August 2017 / Accepted: 13 August 2017 / Published: 22 August 2017
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Purpose: To identify the gene defect and to study the clinical characteristics and natural course of disease in a family originally diagnosed with oligocone trichromacy (OT), a rare congenital cone dysfunction syndrome. Methods: Extensive clinical and ophthalmologic assessment was 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 in the two siblings. Additionally, the identified CEP290 mutations were analyzed in persons with 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 color discrimination. Over time, the phenotype of OT evolved to a progressive degenerative disease without any CEP290-associated non-ocular features. In both siblings, two nonsense mutations (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 open 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 skipping was observed in a small fraction of CEP290 mRNA, resulting in a 36 aa in-frame deletion (p.(Glu1569_Trp1604del)). No additional cases carrying these variants were identified in the ACHM and CD cohorts. Conclusions: Compound heterozygous hypomorphic mutations in CEP290 may lead to a rare form of cone-dominated retinal dystrophy, a novel phenotype belonging to the CEP290-associated spectrum of ciliopathies. These findings provide insight into the effect of CEP290 mutations on the clinical phenotype. View Full-Text
Keywords: oligocone trichromacy; cone dysfunction syndrome; CEP290; ciliopathies; long-term follow up oligocone trichromacy; cone dysfunction syndrome; CEP290; ciliopathies; long-term follow up

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Roosing, S.; Cremers, F.P.M.; Riemslag, F.C.C.; Zonneveld-Vrieling, M.N.; Talsma, H.E.; Klessens-Godfroy, F.J.M.; den Hollander, A.I.; van den Born, L.I. A Rare Form of Retinal Dystrophy Caused by Hypomorphic Nonsense Mutations in CEP290. Genes 2017, 8, 208.

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