The constitutional deletion of 22q13 is an example of a new microdeletion syndrome, known as the 22q13.3 deletion syndrome, telomeric 22q13 monosomy syndrome, or Phelan-McDermid syndrome (OMIM #606232). It was identified by the detection of a cytogenetic rearrangement in advance of its clinical definition. The clinical definition came following the introduction of new methods aimed at checking telomere integrity which confirmed the previously observed phenotype consisting of global developmental delay, generalized hypotonia, absent or delayed speech, and normal to advanced growth. Since then, continued improvements in molecular cytogenetic techniques have increased the diagnostic yield of 22q13 deletions further leading to improved definition of the clinical phenotype, although the incidence of the syndrome has still to be estimated. The deletion occurs with equal frequency in males and females and it has been reported in mosaic and non-mosaic forms; it may occur de novo or be inherited and be associated with ring chromosome 22 and in rare cases with proximal inverted duplications. Rare terminal duplications of 22q13 have also been found. Haploinsufficiency of the SHANK3/ProSAP2 gene, less than 200 kb proximal to the chromosome 22q telomere, is very likely the cause of the major neurological features associated with 22q13 deletion, since the gene is always found disrupted or deleted in patients with the syndrome and a recurrent breakpoint within SHANK3, mediated by a repeated non-B DNA-forming sequence, has been identified in several patients. Owing to its emerging role in neuropsychiatric disorders and the overlap of phenotypes between autism and 22q13.3 deletion syndrome, SHANK3 became eligible for mutation screening in patients with autistic spectrum disorders (ASD) and several studies have discovered de novo mutations in such patients. In this chapter, we review the current knowledge regarding pathological copy number variants of 22q13.3 in developmental delay and ASD.
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