First genomic localization of oculo-oto-dental syndrome with linkage to chromosome 20q13.1.
OBJECTIVE
To characterize the phenotype of autosomal dominant oculo-oto-dental (OOD) syndrome, map the disease locus in a five-generation British family, and evaluate a candidate gene.


METHODS
Full clinical assessments in all affected patients included slit lamp and retina examination, refraction, A-scan ultrasound, audiograms, and dental assessments. Genomic DNA from all family members was genotyped, by polymerase chain reaction, for polymorphic genetic markers covering the entire genome. Two-point LOD scores were generated using a linkage analysis suite of computer programs. The gene for eyes absent 2 (EYA2) was screened for mutations by direct automated sequencing and Southern blot analysis.


RESULTS
All the affected individuals examined had iris and retina coloboma associated with high-frequency, progressive, sensorineural deafness and globodontia. This is the only genetic disease known to result in pathologically enlarged teeth. The locus for OOD (OOD1) was mapped to 20q13.1. A maximum two-point LOD score of 3.31 was obtained with marker locus D20S836 at a recombination fraction of theta; = 0.00. Two critical recombinations in the pedigree positioned this locus to a region flanked by marker loci D20S108 and D20S159, giving a critical disease interval of 12 centimorgans (cM). Mutation screening of one candidate gene, EYA2, revealed no disease-associated mutations or polymorphic variants.


CONCLUSIONS
This is the first genetic localization for the OOD phenotype (ODD1). The disease-causing gene is localized within a 12-cM critical region of chromosome 20q13.1. The identification of the disease gene is not only relevant to the study of vision and hearing defects, but also highlights an exceptional gene involved in the development of human dentition.
Vieira
Helena
H
Department of Cell and Molecular Biology, Faculty of Medicine, Imperial College, London, United Kingdom.
Gregory-Evans
Kevin
K
Lim
Natasha
N
Brookes
John L
JL
Brueton
Louise A
LA
Gregory-Evans
Cheryl Y
CY
D000328:Adult; D002675:Child, Preschool; D002874:Chromosome Mapping; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics*; D003103:Coloboma / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D007498:Iris / Q000002:abnormalities*; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008967:Molecular Biology; D010375:Pedigree; D012160:Retina / Q000002:abnormalities*; D013577:Syndrome; D014071:Tooth Abnormalities / Q000235:genetics*