Homozygous deletions of a copy number change detected by array CGH: a new cause for mental retardation?

We describe two unrelated patients with mental retardation and normal karyotypes found to have relatively large homozygous deletions (>150 kb) of different regions detected by array comparative genomic hybridization (aCGH). Patient 1 showed a 157-214 kb deletion at 8q24.2, containing BAC clone RP11-17M8. This patient was born to phenotypically normal parents and has microcephaly, distinctive craniofacial features, brachymetacarpia, brachymetatarsia and severe mental retardation. This BAC clone is listed as a copy number variant on the Database of Genomic Variants (http://projects.tcag.ca/variation/). Heterozygosity for the deletion was found in the mother (father is deceased) and uniparental disomy of chromosome 8 was excluded. Patient 2 showed a 812-902 kb deletion at 12q21.1, containing BAC clone RP11-89P15. This region was not listed in any public database as a known variant. This patient has mild craniofacial dysmorphic features, bifid uvula, peripheral pulmonic stenosis and developmental delay. Heterozygosity for this deletion was confirmed in the phenotypically normal parents and two normal siblings, but surprisingly, homozygosity for the deletion in an apparently normal younger sibling brings into question whether this large homozygous copy number change (CNC) is causal. Homozygous deletions of CNCs have not previously been reported in association with a phenotype or mental retardation. These cases represent homozygosity for presumably benign CNCs, and while causality for the phenotypes cannot be confirmed, similar deletions are bound to be identified more frequently as aCGH is used with increasing regularity. Such homozygous deletions should be viewed as potentially clinically relevant.