High–Density SNP Genome Scan Identifies a New Locus for Autosomal Dominant Oculo–Otodental Dysplasia

Abstract

Purpose: : To identify the chromosomal localisation of the disease–causing gene in a 3–generation family with oculo–otodental dysplasia.

Methods: : Full clinical assessment of twenty–two family members of Brazilian descent included retinal fundoscopy, audiograms and dental examination. High quality DNA from blood samples or buccal swabs was ascertained from 11 affected members, 9 unaffected members and 2 spouses. A genome–wide scan was performed using the Affymetrix GeneChip Human Mapping 10K Array Xba 142 2.0 version with 10,204 SNPs, in comparison to a traditional 10 cM microsatellite marker genome scan (Marshfield). Genotypes were exported to the graphical user interface, ALOHOMORA, for gender checking, PedCheck and conversion of data for parametric linkage analysis under a fully penetrant dominant model using Merlin. Two further families of British and Belgian descent were subsequently genotyped in this study. Direct PCR cycle sequencing (Big Dye Terminator Kit) was used to screen candidate genes inside the linked region for mutations.

Results: : All patients had the unique phenotype of grossly enlarged molar teeth (globodontia) segregating with high frequency sensorineural hearing loss. Parametric Merlin calculations revealed a single LOD score peak of 3.9 showing that oculo–otodental dysplasia in the Brazilian family was linked to chromosome 11q13.1–13.3. Three obligatory recombination events defined a 7.6 Mb interval between SNP A–1512811 and SNP A–1519064. Genotyping in a British family also revealed linkage to chromosome 11 between markers loci D11S2006 and D11S2002, and in a small Belgian family a linked haplotype across the critical region was observed. Sequencing of 3 candidates genes expressed in the teeth, ear and eye has not revealed any pathologic mutations.

Conclusions: : We report the mapping of a new locus for oculo–otodental dysplasia on chromosome 11q13. The critical region contains 127 known genes and screening of these genes is ongoing. A systematic approach to family ascertainment combined with SNP genome scans is a rapid and highly effective scheme for mapping autosomal dominant diseases.

Keywords: linkage analysis • development • gene screening