1. ¹Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada
2. ²National Genetics Reference Laboratory (NGRL) and Wessex Regional Genetics Laboratory (WRGL), Salisbury District Hospital, Salisbury, UK
3. ³Sheffield Childrens Hospital, Sheffield, UK
4. ⁴Dipartimento di Pediatria, Universit di Padova, Via Giustiniani 3, Padova, Italy
5. ⁵Istituto CSS-Mendel, University La Sapienza, Rome, Italy
6. ⁶Department of Child Health, Tokyo Kasei University, 1-18-1 Kaga, Itabashi, Tokyo, Japan
7. ⁷National Genetics Reference Laboratory, Salisbury District Hospital, Salisbury, UK

Correspondence: Dr HE McDermid, Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada. Tel: +1 780 492 5377; Fax: +1 780 492 9234; E-mail: hmcdermi@ualberta.ca

⁸Present address: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada

Received 17 August 2007; Revised 18 April 2008; Accepted 22 April 2008; Published online 4 June 2008.

Abstract

The severe mental retardation and speech deficits associated with 22q13 terminal deletions have been attributed in large part to haploinsufficiency of SHANK3, which maps to all 22q13 terminal deletions, although more proximal genes are assumed to have minor effects. We report two children with interstitial deletions of 22q13 and two copies of SHANK3, but clinical features similar to the terminal 22q13 deletion syndrome, including mental retardation and severe speech delay. Both these interstitial deletions are completely contained within the largest terminal deletion, but do not overlap with the nine smallest terminal deletions. These interstitial deletions indicate that haploinsufficiency for 22q13 genes other than SHANK3 can have major effects on cognitive and language development. However, the relatively mild speech problems and normal cognitive abilities of a parent who transmitted her identical interstitial deletion to her more severely affected son suggests that the phenotype associated with this region may be more variable than terminal deletions and therefore contribute to the relative lack of correlation between clinical severity and size of terminal deletions. The phenotypic similarity between the interstitial deletions and non-overlapping small terminal 22q13 deletions emphasizes the general nonspecificity of the clinical picture of the 22q13 deletion syndrome and the importance of molecular analysis for diagnosis.