High resolution SNP based microarray mapping of mosaic supernumerary marker chromosomes 13 and 17: Delineating novel loci for apraxia

Abstract

High resolution comparative genomic hybridization is emerging as a powerful tool for delineating chromosomal rearrangements such as duplications, deletions, and unbalanced translocations, but it has not yet been broadly applied for structural aberrations such as supernumerary marker chromosomes (SMCs). In this report, we present the clinical and molecular analysis of a patient with de novo mosaic SMC (17) and SMC (13). High resolution single nucleotide polymorphism (SNP) based microarray mapping successfully identified the parent of origin for the SMCs and allowed delineation of the breakpoints which include a 5.1 Mb duplication from 17p11.2 to 17q11.2 as well as duplication of chromosome 13 that includes 2.2 Mb from 13q11 to 13q12.11. Interestingly, the patient has markedly severe oral and verbal apraxia, a characteristic feature of patients with 17p11.2 duplication syndrome (Potocki-Lupski syndrome, PTLS). Fine mapping indicates that the patient's duplication overlaps with a subset of PTLS patients, but not with PTLS patients harboring the common microduplication. FISH analysis confirms that the patient lacks duplication of RAI1, a dosage sensitive gene within the common microduplication interval. Taken together, these results demonstrate the utility of SNP microarray based methodology for mapping disease-causing genes, including those within SMCs, and provide the opportunity to identify novel candidate genes for verbal apraxia.