Homozygosity mapping in patients with cone-rod dystrophy: novel mutations and clinical characterizations.
OBJECTIVE
To determine the genetic defect and to describe the clinical characteristics in a cohort of mainly nonconsanguineous cone-rod dystrophy (CRD) patients.


METHODS
One hundred thirty-nine patients with diagnosed CRD were recruited. Ninety of them were screened for known mutations in ABCA4, and those carrying one or two mutations were excluded from further research. Genome-wide homozygosity mapping was performed in the remaining 108. Known genes associated with autosomal recessive retinal dystrophies located within a homozygous region were screened for mutations. Patients in whom a mutation was detected underwent further ophthalmic examination.


RESULTS
Homozygous sequence variants were identified in eight CRD families, six of which were nonconsanguineous. The variants were detected in the following six genes: ABCA4, CABP4, CERKL, EYS, KCNV2, and PROM1. Patients carrying mutations in ABCA4, CERKL, and PROM1 had typical CRD symptoms, but a variety of retinal appearances on funduscopy, optical coherence tomography, and autofluorescence imaging.


CONCLUSIONS
Homozygosity mapping led to the identification of new mutations in consanguineous and nonconsanguineous patients with retinal dystrophy. Detailed clinical characterization revealed a variety of retinal appearances, ranging from nearly normal to extensive retinal remodeling, retinal thinning, and debris accumulation. Although CRD was initially diagnosed in all patients, the molecular findings led to a reappraisal of the diagnosis in patients carrying mutations in EYS, CABP4, and KCNV2.
Littink
Karin W
KW
The Rotterdam Eye Hospital, Rotterdam, The Netherlands.
Koenekoop
Robert K
RK
van den Born
L Ingeborgh
LI
Collin
Rob W J
RW
Moruz
Luminita
L
Veltman
Joris A
JA
Roosing
Susanne
S
Zonneveld
Marijke N
MN
Omar
Amer
A
Darvish
Mahshad
M
Lopez
Irma
I
Kroes
Hester Y
HY
van Genderen
Maria M
MM
Hoyng
Carel B
CB
Rohrschneider
Klaus
K
van Schooneveld
Mary J
MJ
Cremers
Frans P M
FP
den Hollander
Anneke I
AI
D000071916:AC133 Antigen; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000293:Adolescent; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics; D002648:Child; D002874:Chromosome Mapping; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005451:Fluorescein Angiography; D006023:Glycoproteins / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009887:Ophthalmoscopy; D010455:Peptides / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics*; D041623:Tomography, Optical Coherence
C056475:ABCA4 protein, human; D000071916:AC133 Antigen; D018528:ATP-Binding Cassette Transporters; D015703:Antigens, CD; C514441:CABP4 protein, human; D002135:Calcium-Binding Proteins; C533105:EYS protein, human; D005136:Eye Proteins; D006023:Glycoproteins; C489610:KCNV2 protein, human; C000606023:PROM1 protein, human; D010455:Peptides; D024642:Potassium Channels, Voltage-Gated; D017853:Phosphotransferases (Alcohol Group Acceptor); C066324:ceramide kinase