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

Abstract

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.

Discovery of variants unmasked by hemizygous deletions

“…This constellation of homozygous losses in a patient with healthy parents carrying heterozygous losses is similar to that of two patients reported in the literature. 37 By interaction with HSF1 (heat shock factor 1, the major transcriptional activator of heat shock genes), HSBP1 has been shown to negatively regulate the heat shock response in C. elegans, in Xenopus tadpoles and in cultures of mammalian cells. 38,39 Knockdown of Hsbp1, which is a part of the AKT1-DNA transcription network, in C57Bl/6 mice diminished neuroblast migration.…”

Co-occurrence of recurrent duplications of the DiGeorge syndrome region on both chromosome 22 homologues due to inherited and de novo events

“…For example, multiple patients with homozygosity of the Charcot-Marie-Tooth type 1A (CMT1A) duplication have been reported with the mutation transmitted from both parents who carry the duplication 8 9 21. A homozygous deletion of >150 kb on chromosome 8q24.2 transmitted from phenotypically normal parents with heterozygous deletion has been reported in one patient with mental retardation, although it is unclear whether this homozygous deletion is causative 22. Of the three families studied here, families 2 and 3 have the 22q duplications transmitted from both parents.…”

Benign copy number changes in clinical cytogenetic diagnostics by array CGH

“…A diagnosis of a normal variant (bCNV) should not generally be considered an abnormality, nor should it be (by itself) a major factor in interpretation of a laboratory result. Of note, one should consider the possibility that bCNVs can be observed in homozygous form, and these may in fact not be clinically insignificant (Curry et al, 2008).…”