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(Investigative Ophthalmology and Visual Science. 2002;43:2540-2545.)
© 2002 by The Association for Research in Vision and Ophthalmology, Inc.

First Genomic Localization of Oculo-Oto-Dental Syndrome with Linkage To Chromosome 20q13.1

Helena Vieira1, Kevin Gregory-Evans2, Natasha Lim2, John L. Brookes2, Louise A. Brueton3 and Cheryl Y. Gregory-Evans1

1 From the Departments of Cell and Molecular Biology and 2 Ophthalmology, Faculty of Medicine, Imperial College, London, United Kingdom; and the 3 Department of Medical Genetics, Birmingham Women’s Hospital, Birmingham, United Kingdom.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. 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.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
In developed countries 15% to 45% of childhood visual impairment is thought to be due to genetic disease.1 2 In Europe, the overall prevalence of early (congenital) eye malformation is approximately 3.7/10,000 newborns. The commonest developmental defects are microphthalmia (1–2/10,000),3 4 congenital cataract (0.6/10,000), and ocular coloboma (0.5/10,000).4

Ocular coloboma is a developmental anomaly that results from abnormal closure of the embryonic fissure in the developing optic vesicle. Various sized clefts occur that can be unilateral or bilateral. These can affect the cornea, iris, lens, choroid-retina, or optic nerve. There is often significant risk of rhegmatogenous retinal detachment. Lens colobomas are also associated with giant retinal tears. Although some cases of typical coloboma are noninherited (e.g., those caused by teratogens, such as thalidomide, retinoic acid, and alcohol), coloboma often runs in families with autosomal dominant,5 recessive,6 7 or X-linked8 inheritance. Ocular coloboma is usually an isolated abnormality, but it is also found in a large number of systemic syndromes9 10 and is a common finding in children with chromosomal abnormalities.11 12

Limited molecular genetic studies have been reported. Autosomal recessive nonsyndromic microphthalmia with iris coloboma is caused by loss of function of CHX10.13 Coloboma and congenital cataract have also been associated with a MAF gene mutation.14 Ocular coloboma, in association with renal disease, is seen with an autosomal dominant mutation of PAX215 and a compound heterozygous mutation of retinol binding protein (RBP).7 Human genomic loci associated with coloboma have been localized to chromosomes 15q12-q15,5 9q34.3 (Joubert syndrome),9 22q,11 and 16q.12 Coloboma is also seen in the mouse associated with mutation of Vax1,16 Snap25,17 and Tcm.18

The current study focused on coloboma in a family with oto-dental syndrome.10 Oto-dental syndrome itself is a rare, autosomal dominant condition.19 20 21 Reports have documented simplex cases22 23 and affected families of Italian,24 25 Polish,26 Germanic,21 and Brazilian27 descent. The dental anomaly affects primary (deciduous) and secondary (permanent) dentition. The hearing deficit is progressive through to the fourth decade of life, correlating with difficulties in speech development.

We have identified and enrolled a British family described with coloboma and oto-dental syndrome10 (oculo-oto-dental syndrome, OOD) and extended the original clinical study. We report new clinical features and demonstrate the first locus for this disease (OOD1) on chromosome 20q13.1.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The study protocol adhered to the tenets of the Declaration of Helsinki for all individuals. Previous work had identified three generations with five affected individuals.10 We have extended this British pedigree to five generations with nine affected persons (Fig. 1) . Full clinical assessments of the family members, including slit lamp and retina examination, refraction, A-scan ultrasound, audiograms, and dental assessment, were undertaken in seven affected and six unaffected individuals and two spouses. Historical clinical data were available for two deceased affected individuals.



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  		Figure 1. Pedigree of family affected by OOD, with haplotype data. Circles: females; squares: males; filled symbols: affected individuals; open symbols: unaffected individuals; crossed symbols: deceased individuals; shaded bar: affected haplotype. Marker locus D20S159 showed two recombinations in V-2 and V-6, placing the disease proximal to this marker. D20S108 showed recombination in V-6, placing the OOD1 distal to this marker. *IV-3 was not available for study.

 
DNA Extraction
Peripheral blood or saline mouthwash samples were collected, with informed consent, from family members. High-molecular-weight genomic DNA extraction from the blood samples was performed with a kit (Nucleon II; Scotlab Bioscience, Glasgow, Scotland, UK) and from the mouthwash samples by standard procedures.

Microsatellite and Linkage Analysis
Linkage analysis was used to determine whether candidate loci, known to contain genes expressed in the developing eye, ear, and craniofacial mesenchyme, were involved in the disease phenotype in this family. Tightly linked markers were genotyped for each candidate locus. After excluding all candidates, a total genome search was undertaken at 10- to 20-cM intervals. DNA samples were genotyped with microsatellite markers by polymerase chain reaction (PCR), incorporating [33P]-{alpha}-dATP. PCR products were separated by 6% denaturing polyacrylamide gel electrophoresis and visualized after 16 to 24 hours of autoradiography. Genotypic data were used to calculate LOD scores using a pedigree information package (Cyrillic; Cherwell Scientific, Oxford, UK) and the MLINK program of the LINKAGE package (provided in the public domain by the Human Genome Mapping Program Resource Center, Cambridge, UK, and available at www.hgmp.mrc.ac.uk/genomeweb/linkage.html). Allele frequencies were calculated from the spouses in this family and an ethnically matched control population (a total of 10 individuals28 ). The phenotype was analyzed as an autosomal dominant trait, with complete penetrance and a frequency of 0.0001 for the affected allele.

Mutation Screening
Intronic forward and reverse primers were designed for the 15 exons of EYA2 and 5' untranslated region (UTR) region (Table 1) . The PCR reactions (50 µL) were performed on 100-ng DNA samples from family members under standard conditions (200 µM dNTPs, 10 mM Tris-HCl, 50 mM KCl, 1.5 mM MgCl2, and 20 pmol of each primer) using 1 U Taq DNA polymerase (Bio-Line, London, UK) and primer-specific annealing temperatures. Products of PCR amplification were purified through spin columns (S-400; Amersham Pharmacia Biotech, Little Chalfont, UK), sequenced by using a commercially available kit (Big Dye Terminator Reaction; PE-Applied Biosystems, Warrington, UK), and analyzed on an automated sequencer (model 377; PE-Applied Biosystems). All PCR products were sequenced in the forward and reverse directions.


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  		Table 1. Sequence of the Forward and Reverse Primers Used for the Amplification of EYA2 Exons in the DNA Samples of the Family Members Affected by OOD

 
Southern blot standard protocol was performed with genomic DNA samples from affected and unaffected family members digested with BamHI, EcoRI, PstI, or TaqI (Life Technologies, Paisley, UK) under the manufacturer’s recommended conditions. The fragments resulting from digestion with each enzyme were determined using the sequences available and tested on normal control DNA for comparison. The EYA2 probe was amplified by PCR from human placenta cDNA, using forward and reverse primers on exons 4 and 11, respectively, separated on a 1% agarose gel, and gel extracted with a commercially available kit (QIAquick Kit; Qiagen, Crawley, UK). The probe was labeled by incorporating [32P]-{alpha}-dCTP with a commercially available kit (RadPrime; Life Technologies), and hybridization to a membrane (Hybond N+; Amersham Pharmacia Biotech) was performed at 65°C in Church buffer (0.125 M sodium phosphate buffer [pH 7.2], 7% SDS, and 1 mM EDTA).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clinical Assessment
Clinical data from eight affected individuals are presented in Table 2 . Complete penetrance was seen in all affected patients examined who exhibited ocular, dental, and auditory clinical signs. Although virtually all affected eyes demonstrated abnormality, it was markedly variable. Abnormality ranged from transillumination defects in the inferior iris, due to iris pigment epithelium defects to severe chorioretinal coloboma (Fig. 2) . Other ocular signs in selected, affected patients were microcornea, microphthalmos, lens opacity, and lens coloboma. Of particular note, marked asymmetry in eye signs was seen in some individuals (III-2, IV-7, and V-2; Fig. 1 ). All affected individuals demonstrated a sensorineural high-frequency hearing deficit that started in infancy and progressed to a plateau by approximately 35 years of age. Cook et al.25 have suggested that the cochlea is the primary site for this sensorineural deficit. Speech defects due to this early hearing loss were minor. All wore hearing aids with great benefit.


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  		Table 2. Clinical Details of Eight Affected Patients

 


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  		Figure 2. Color photographs of individuals with OOD syndrome demonstrating the range of phenotype. (A) Microcornea (horizontal diameter, 9 mm) and iris coloboma (IV-2, Fig. 1 ). (B) Iris coloboma and cataract (III-2). (C) Choroidal and optic nerve head coloboma (IV-2). (D) Dental enamel hypoplasia (pitted, yellow teeth) and grossly enlarged molars (globodontia, IV-5).

 
Dental anomalies were striking, and all adult patients had undergone extensive orthodontic corrective surgery (Fig. 2) . Eruption of primary, deciduous dentition was delayed in all affected individuals, and all children had enlarged posterior teeth. There was relative sparing of the incisors. In adults, eruption of the permanent teeth was also delayed, and premolars were often missing or small. Canine and molar teeth were enlarged (globodontia). Again, there was relative sparing of the incisors, but it is important to state that these teeth were not normal. Similar to all other teeth, the incisors that had not been removed demonstrated the yellowing and pitting indicative of enamel defects (Fig. 2) . In all affected individuals who had undergone radiography, enlarged pulp chambers (taurodontism), pulp stones, and abnormal roots were seen.

Molecular Genetic Assessment
Candidate loci encompassing the developmental genes PAX6, PAX2, TGFB2, DLX2, BMP4, RIEG1, ODD, MSX1, HOXC, PDGFRA, DLX3, HOXA1, FOXC1, RIEG2, MAF, BARX1, and BARX2 were assessed. Significant molecular genetic linkage was excluded, with microsatellite loci encompassing these candidates (data not shown). A genome-wide search identified significant linkage to chromosome 20q. Additional marker loci in this region were genotyped, haplotypes were constructed (Fig. 1) , and two-point LOD scores calculated (summarized in Table 3 ). A maximum LOD score of 3.31 was obtained at D20S836 at a recombination fraction of {theta} = 0.00, at which the alleles in all meioses were fully informative. Positive LOD scores, ranging from 2.09 to 2.82 at {theta} = 0.00, were also obtained with other markers within the region. Recombination events involving marker locus D20S108 in individual V-6 and D20S159 in individuals V-2 and V-6, defined the centromeric and telomeric boundaries, respectively, of the 12-cM disease locus between these markers (Figs. 1 3) .


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  		Table 3. Two-Point LOD Scores of Family with OOD Syndrome for Chromosome-20q13.1 Microsatellite Markers

 


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  		Figure 3. Chromosome 20 locus of OOD1. Ten markers are listed between 57.38 and 69.50 cM. The seven affected individuals inherited the same allele for eight of these markers. Two of the affected recombined at D20S108 and D20S159, defining these as the flanking markers of the 12-cM region for the OOD1 locus. The highest LOD score was obtained with marker D20S836 at 64.88 cM, where EYA2 is mapped. (The markers and genetic distances were taken from a genetic map provided by Marshfield Laboratories, Marshfield, WI, and available at www.marshfieldclinic.org/research/genetics).

 
Bioinformatic assessment was performed to identify candidate genes in this region by using the Genome Web Browser (provided in the public domain by The Sanger Centre, Hinxton Hall, UK, and available at http://www.ensembl.org/). This revealed 36 known genes and approximately 10 others predicted in a 7-Mb region between marker loci D20S108 and D20S176. An excellent candidate was EYA2, because it is expressed in the eye and craniofacial mesenchyme. The 15 coding exons, splice sites, and 5'UTR were analyzed for DNA base changes by direct sequencing and Southern blot. The cDNA probe used for the Southern blot was amplified with forward and reverse primers on exons 4 and 11, respectively, to permit identification of rearrangements or intronic alterations within the gene (Table 1) . Neither method revealed a disease-associated mutation or polymorphic variants.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the current study, we identified the first locus for autosomal dominant OOD and extended the clinical study of a previously described pedigree.10 Although oto-dental syndrome is a rare condition, several cases and families have now been described.10 19 20 21 22 23 24 25 26 27 The family described in this report is the only one currently known that has disease with associated ocular features. We significantly extended the pedigree and in particular focused our clinical assessment on ocular features of all eyes examined. New ocular features—microcornea, microphthalmos, lenticular opacity, and lens coloboma—are now included in this phenotype, in addition to the iris and chorioretinal colobomas previously recorded. Furthermore, it is noted that individuals previously described as having normal eyes (IV-7, right eye of III-2; Fig. 1 ) in fact had marked iris pigment epithelial atrophy on slit lamp examination, which represents the mildest ocular abnormality in the phenotype. Similarly, patient II-5 (deceased) was described historically as having normal eyes, but may also have had mild iris pigment epithelial atrophy. Markedly variable ocular phenotype, throughout the pedigree, is perhaps not surprising in an autosomal dominant condition. However, it is unclear how to explain the marked phenotype asymmetry between eyes in individual patients as a simple inherited genetic defect. Possibly, other genetic or environmental effects may influence disease severity in different eyes.

The disease locus (OOD1) maps to chromosome 20q13.1. This 12-cM region, flanked by marker loci D20S108 and D20S159, now linked to OOD (Fig. 3) , contains a large number of genes. One particular candidate, EYA2, codes for a transcription factor, a class of genes that have been associated with ocular developmental defects. Examples include PAX2 (ocular coloboma plus renal disease15 ) and CHX10 (iris coloboma with microphthalmia13 ). In addition, EYA2 is known to be expressed in the eye, ear, and craniofacial mesenchyme very early during development (ninth week after conception) in humans.29 Other members of the EYA gene family have been associated with branchio-oto-renal syndrome (EYA1)29 and nonsyndromic dominant deafness (EYA4).30 We screened all 15 EYA2 coding exons, respective splice sites, and the 5'UTR, but found no disease-associated mutation. Although our results exclude a simple exonic or splice site EYA2 mutation, a promoter mutation in EYA2 is still possible.

To narrow the list of other candidate genes mapping to human chromosome 20q13.1, we looked for mouse mutants with phenotypes similar to OOD syndrome. No comparable mouse model has been reported as mapping to the syntenic region of mouse chromosome 2. The fact that ocular coloboma has only been reported in this oto-dental-affected family may complicate the search for the responsible genetic defect. It is possible that the ocular component in this family is caused by a unique mutation in the oto-dental gene not found in other affected families. Alternatively, the eye defect in this family may be due to a contiguous gene defect, possibly affecting EYA2 expression. A third explanation could be that the OOD gene is an entirely different gene from that causing oto-dental dysplasia, but that the gene’s products interact or function within the same biochemical pathway.

Although OOD syndrome is rare, the disease gene may be relevant, not only to this phenotype, but to other diseases affecting the eye, ear, or teeth. Identifying the gene is therefore of importance in our understanding of the development of a wide range of tissues, not just the eye. Certainly, as the only disease entity known to result in abnormally enlarged teeth, the OOD gene will hold an important place in improving our understanding of the genetic control of tooth development.


   Acknowledgements
 
The authors thank Gerald B. Winter and Jane R. Goodman, Eastman Dental Hospital, London, United Kingdom, and the patients within the family that participated in this study.


   Footnotes
 
Supported by the Fund for Science and Technology of Portugal.

Submitted for publication January 24, 2002; revised March 27, 2002; accepted April 9, 2002.

Commercial relationships policy: N.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Cheryl Y. Gregory-Evans, Section of Cell and Molecular Biology, Faculty of Medicine, Imperial College, Exhibition Road, London SW7 2AZ, UK; c.gregory-evans{at}ic.ac.uk.


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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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