A new locus for congenital cataract, microcornea, microphthalmia, and atypical iris coloboma maps to chromosome 2.
OBJECTIVE
To report a novel phenotype of autosomal dominant atypical congenital cataract associated with variable expression of microcornea, microphthalmia, and iris coloboma linked to chromosome 2. Molecular analysis of this phenotype may improve our understanding of anterior segment development.


METHODS
Observational case study, genome linkage analysis, and gene mutation screening.


METHODS
Three families, 1 Egyptian and 2 Belgians, with a total of 31 affected were studied.


METHODS
Twenty-one affected subjects and 9 first-degree relatives underwent complete ophthalmic examination. In the Egyptian family, exclusion of PAX6, CRYAA, and MAF genes was demonstrated by haplotype analysis using microsatellite markers on chromosomes 11, 16, and 21. Genome-wide linkage analysis was then performed using 385 microsatellite markers on this family. In the 2 Belgian families, the PAX6 gene was screened for mutations by direct sequencing of all exons.


METHODS
Phenotype description, genome-wide linkage of the phenotype, linkage to the PAX6, CRYAA, and MAF genes, and mutation detection in the PAX6 gene.


RESULTS
Affected members of the 3 families had bilateral congenital cataracts inherited in an autosomal dominant pattern. A novel form of hexagonal nuclear cataract with cortical riders was expressed. Among affected subjects with available data, 95% had microcornea, 39% had microphthalmia, and 38% had iris coloboma. Seventy-five percent of the colobomata were atypical, showing a nasal superior location in 56%. A positive lod score of 4.86 was obtained at theta = 0 for D2S2309 on chromosome 2, a 4.9-Mb common haplotype flanked by D2S2309 and D2S2358 was obtained in the Egyptian family, and linkage to the PAX6, CRYAA, or MAF gene was excluded. In the 2 Belgian families, sequencing of the junctions and all coding exons of PAX6 did not reveal any molecular change.


CONCLUSIONS
We describe a novel phenotype that includes the combination of a novel form of congenital hexagonal cataract, with variably expressed microcornea, microphthalmia, and atypical iris coloboma, not caused by PAX6 and mapping to chromosome 2.


BACKGROUND
The authors have no proprietary or commercial interest in any materials discussed in this article.
Abouzeid
Hana
H
Jules-Gonin Eye Hospital, University of Lausanne, Switzerland.
Meire
Françoise M
FM
Osman
Ihab
I
ElShakankiri
Nihal
N
Bolay
Sylvain
S
Munier
Francis L
FL
Schorderet
Daniel F
DF
D000293:Adolescent; D000328:Adult; D002386:Cataract / Q000151:congenital*; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D003103:Coloboma / Q000235:genetics*; D003315:Cornea / Q000002:abnormalities*; D003459:Crystallins / Q000235:genetics; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D006239:Haplotypes; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007498:Iris / Q000002:abnormalities*; D008126:Lod Score; D051260:MafF Transcription Factor / Q000235:genetics; D008297:Male; D008850:Microphthalmos / Q000235:genetics*; D018895:Microsatellite Repeats; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics; D010375:Pedigree; D012097:Repressor Proteins / Q000235:genetics
C511246:CRYAA protein, human; D003459:Crystallins; D005136:Eye Proteins; D018398:Homeodomain Proteins; C484147:MAFF protein, human; D051260:MafF Transcription Factor; D009687:Nuclear Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins