April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Phenotypic variability of retinal dystrophies associated with mutations in CRX: with report of a novel macular dystrophy phenotype
Author Affiliations & Notes
  • Sarah Hull
    Moorfields Eye Hospital, 162 City Road, London, United Kingdom
    Inherited Eye Diseases, UCL Institute of Ophthalmology, London, United Kingdom
  • Gavin Arno
    Moorfields Eye Hospital, 162 City Road, London, United Kingdom
    Inherited Eye Diseases, UCL Institute of Ophthalmology, London, United Kingdom
  • Sarah Chamney
    Ophthalmology Department, Royal Victoria Hospital, Belfast, United Kingdom
  • Isabelle Russell-Eggitt
    Ophthalmology Department, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom
  • Anthony G Robson
    Moorfields Eye Hospital, 162 City Road, London, United Kingdom
    Inherited Eye Diseases, UCL Institute of Ophthalmology, London, United Kingdom
  • Graham E Holder
    Moorfields Eye Hospital, 162 City Road, London, United Kingdom
    Inherited Eye Diseases, UCL Institute of Ophthalmology, London, United Kingdom
  • Andrew Webster
    Moorfields Eye Hospital, 162 City Road, London, United Kingdom
    Inherited Eye Diseases, UCL Institute of Ophthalmology, London, United Kingdom
  • Anthony T Moore
    Moorfields Eye Hospital, 162 City Road, London, United Kingdom
    Inherited Eye Diseases, UCL Institute of Ophthalmology, London, United Kingdom
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 3279. doi:
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      Sarah Hull, Gavin Arno, Sarah Chamney, Isabelle Russell-Eggitt, Anthony G Robson, Graham E Holder, Andrew Webster, Anthony T Moore; Phenotypic variability of retinal dystrophies associated with mutations in CRX: with report of a novel macular dystrophy phenotype. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3279.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: To present the detailed clinical and molecular features of a series of patients with retinal dystrophies consequent upon mutations in the cone-rod homeobox (CRX) gene.

Methods: Eighteen patients from 11 families with retinal dystrophies and CRX mutations were identified; 7 from a large genetics database, 3 from results of exome analysis and 8 by direct sequencing of CRX in a selected panel of 65 cases. Detailed phenotyping included full clinical evaluation, electrophysiological testing, fundus photography, fundus autofluorescence imaging and optical coherence tomography. Bi-directional Sanger sequencing of all exons and intron-exon boundaries of CRX was performed on all 18 patients and available relatives.

Results: Eleven of 18 patients had generalized photoreceptor dysfunction and 7 had late onset macular dystrophy. Five families had more than 1 affected family member and within 3 families, significant phenotypic heterogeneity was found. Four patients presented in infancy with severe visual loss, featureless fundi, macular atrophy in 2 cases, and an undetectable ERG. Two patients presented aged 3 and 6 with reduced vision, evidence of severe retinal dysfunction rod more than cone on electroretinogram (ERG) and progressive deterioration to severe loss of vision by their mid-teens. Five patients presented 11-25 years old with reduced central vision and cone dysfunction greater than rod on ERG. Seven patients from 5 families presented with a bulls eye macular dystrophy at age 35-50 years. Electrophysiology showed an abnormal pattern ERG in all cases. The full field ERG showed reduced cone responses in 1 case and mild rod and cone dysfunction in 2 cases. Visual acuities at last review ranged from 0.2 to 1.3 logMAR. All 18 patients were heterozygous for a rare, likely disease-causing variant in CRX. Eight novel mutations were identified. A de novo mutation was confirmed in 3 families. There was no clear association between the severity, or age of onset and the type or position of CRX mutation.

Conclusions: Mutations in CRX demonstrate significant phenotypic heterogeneity both between and within pedigrees. A novel, late onset, predominantly macular dystrophy is described, extending the phenotypic spectrum associated with mutations in CRX.

Keywords: 696 retinal degenerations: hereditary • 537 gene screening  
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