Genotype-phenotype correlation of 30 patients with Smith-Magenis syndrome (SMS) using comparative genome hybridisation array: cleft palate in SMS is associated with larger deletions

Background: Smith-Magenis syndrome ( SMS) is rare ( prevalence 1 in 25 000) and is associated with psychomotor delay, a particular behavioural pattern and congenital anomalies. SMS is often due to a chromosomal deletion of <4 Mb at the 17p11.2 locus, leading to haploinsufficiency of numerous genes. Mutations of one of these gemes, RAI1, seems to be responsible for the main features found with heterozygous 17p11.2 deletions. Methods: We studied DNA from 30 patients with SMS using a 300 bp amplimers comparative genome hybridisation array encompassing 75 loci from a 22 Mb section from the short arm of chromosome 17. Results: Three patients had large deletions ( 10%). Genotype phenotype correlation showed that two of them had cleft palate, which was not found in any of the other patients with SMS ( p<0.007, Fisher's exact test). The smallest extra-deleted region associated with cleft palate in SMS is 1.4 Mb, contains,16 genes and is located at 17p11.2-17p12. Gene expression array data showed that the ubiquitin B precursor ( UBB) is significantly expressed in the first branchial arch in the fourth and fifth weeks of human development. Conclusion: These data support UBB as a good candidate gene for isolated cleft palate.