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Introduction: The 22q13.3 deletion syndrome (MIM 606232) is characterised by neonatal hypotonia, normal to accelerated growth, absent to severely delayed speech, global developmental delay, and minor dysmorphic facial features. We report the molecular characterisation of the deletion breakpoint in two unrelated chromosome 22q13.3 deletion cases. Methods: The deletions were characterised by FISH, checked for other abnormalities by array-CGH, and confirmed by Real-Time PCR, and finally the breakpoints were cloned, sequenced, and compared. Results: Both cases show the cardinal features of the 22q13.3 deletion syndrome associated with a deletion involving the last 100 kb of chromosome 22q13.3. The cases show a breakpoint within the same 15 bp repeat unit, overlapping the results obtained by Wong and colleagues in 1997 and suggesting that a recurrent deletion breakpoint exists within the SHANK3 gene. The direct repeat involved in these 22q13 deletion cases is presumably able to form slipped (hairpin) structures, but it also has a strong potential for forming tetraplex structures. Discussion: Three cases with a common breakpoint within SHANK3 share a number of common phenotypic features, such as mental retardation and developmental delay with severely delayed or absent expressive speech. The two cases presented here, having a deletion partially overlapping the commercial subtelomeric probe, highlight the difficulties in interpreting FISH results and suggest that many similar cases may be overlooked.

Gene dose alterations can cause mental retardation (MR), congenital malformations and miscarriages. Standard chromosome analysis by G-banding has a limited resolution, but molecular cytogenetic techniques, such as multi-subtelomeric FISH, microdeletion FISH, multicolour FISH and comparative genomic hybridisation (CGH), have played an important role for the diagnosis of MR during the past decade.1 A complete set of subtelomeric FISH probes was presented in 1996 and updated in 2000.2 Consequently, screening for subtelomeric abnormalities has become a diagnostic test that is offered by diagnostic laboratories, and a number of studies reporting new subtelomeric rearrangements have been published.3–16 However, these probes only reveal chromosome rearrangements located in the subtelomeric region. To cover the whole genome, genome wide screening for chromosomal imbalances using microsatellite markers has been reported,17,18 as well as metaphase CGH.19–22 Yet none of these techniques is able to offer a high resolution screening of the whole genome for chromosome imbalances. The development of accurate and sensitive genome wide screening methods would facilitate the clinical diagnosis of patients with very small or subtle rearrangements. Screening for chromosomal imbalances by array CGH, whether using cDNA23 or BAC clones,24 has mainly been performed on cancer samples,25–30 which usually contain large gene dose alterations. Although array CGH has provided a higher resolution compared to conventional CGH, it has not yet become a widely applied method for the analysis of gene dose alterations in individuals with idiopathic mental retardation. It has been a challenge to achieve the adequate performance needed for the reliable detection of single copy losses or gains of very small regions. Chromosome specific micro-arrays have however been used in a few cases to determine the critical regions in microdeletion disorders.31,32 In this report we used a cDNA micro-array and …