Phenotypic variability in patients with retinal dystrophies due to mutations in CRB1.
OBJECTIVE
To identify CRB1 mutations in a large cohort of patients with recessive retinal dystrophies and to document the retinal phenotype and visual prognosis.


METHODS
A hospital-based cross-sectional study of children and adults with recessive retinal dystrophies.


METHODS
Three hundred and six patients with Leber congenital amaurosis (LCA), early-onset childhood retinal dystrophy or juvenile onset retinitis pigmentosa were recruited to the study and gave blood samples for molecular genetic analysis.


METHODS
A detailed clinical examination was performed, including: logMAR visual acuity, refraction, Goldmann visual fields, slit-lamp biomicroscopy, fundus photography, autofluorescence imaging and optical coherence tomography. The results of electrophysiology testing were available in all patients. DNA was obtained for molecular genetic analysis. Initial screening for mutations was performed using the LCA chip. Patients who had one or more CRB1 mutations identified on the chip, and other patients whose phenotype suggested a CRB1 genotype, underwent direct sequencing. In addition, consanguineous families segregating recessive RP underwent a whole genome scan using Affymetrix gene chips, and affected family members showing linkage to the RP12 locus underwent sequencing of the CRB1 gene.


METHODS
Identification of patients with mutations in CRB1 and detailed documentation of the clinical phenotype.


RESULTS
Mutations in CRB1, including 17 novel mutations, were identified in 41 patients from 32 families. The authors identified both disease mutations in 34 patients from 26 families, and these patients underwent detailed phenotyping. Common phenotypic features included hypermetropic refractive error, nummular pigmentation at the level of the RPE and increased retinal thickness on optical coherence tomography. Most patients had a clinical and electrophysiological phenotype consistent with a diagnosis of LCA or rod-cone dystrophy, but three patients had electroretinogram evidence of cone-rod degeneration. A minority of patients developed peripheral retinal telangiectasia, which in some cases led to seclusio pupillae and angle-closure glaucoma.


CONCLUSIONS
Mutations in CRB1 are associated with a range of recessively inherited retinal dystrophies, including LCA, childhood- and juvenile-onset rod-cone and cone-rod dystrophies. Although the phenotype is usually severe, in milder cases there is a window of opportunity for therapeutic intervention in early childhood.
Moorfields Eye Hospital, London, UK. r.henderson@ucl.ac.uk
Robert H
RH
Henderson
Donna S
DS
Mackay
Zheng
Z
Li
Phillip
P
Moradi
Panagiotis
P
Sergouniotis
Isabelle
I
Russell-Eggitt
Dorothy A
DA
Thompson
Anthony G
AG
Robson
Graham E
GE
Holder
Andrew R
AR
Webster
Anthony T
AT
Moore
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D011379:Prognosis; D058499:Retinal Dystrophies / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000235:genetics; D014792:Visual Acuity / Q000235:genetics*; D055815:Young Adult
C448939:CRB1 protein, human; D005136:Eye Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins