Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome

Journal of Medical Genetics (Impact Factor: 6.34). 11/2006; 43(10):822-8. DOI: 10.1136/jmg.2005.038604
Source: PubMed


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.
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.
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.
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.

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    • "Point mutations or small intragenic mutations contribute to a small percentage of SHANK causing ASD cases studied (Moessner et al., 2007; Berkel et al., 2010; Bonaglia et al., 2011; Berkel et al., 2012; Boccuto et al., 2013). Chromosome translocation with a breakpoint within the SHANK3 gene has also been reported (Bonaglia et al., 2005). The fact that microdeletions usually disrupt entire SHANK genes generally supports haploinsufficiency as the molecular mechanism underlying the pathogenesis in these patients. "
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    Developmental Neurobiology 02/2014; 74(2). DOI:10.1002/dneu.22084 · 3.37 Impact Factor
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    • "Observed deletion encompasses only the last exon of the SHANK3 gene, the gene that is proposed to be a candidate gene for the clinical phenotype of 22q13.3 deletion syndrome (Bonaglia et al., 2006; Phelan and McDermid, 2012; Wilson et al., Fig. 1. a: Physical map of the deletion in our proband detected by array CGH analysis presented in UCSC Genome Browser. The breakpoints of the deletion were determined to be arr22q13.33(51163647–51193651)x1 "
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    Gene 04/2013; 524(2). DOI:10.1016/j.gene.2013.03.141 · 2.14 Impact Factor
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    • "Diverse molecular mechanisms that generate and stabilize broken chromosomes were proposed. Terminal deletions can be stabilized by telomere healing, the addition of a telomere (TTAGGG) n repeat sequences by the enzyme telomerase (Bonaglia et al. 2006, 2011; Flint et al. 1994; Lamb et al. 1993; Varley et al. 2000; Verdun and Karlseder 2007; Wilkie et al. 1990), by a telomerase-independent mechanism mediated by nonallelic homologous recombination (NAHR) in which telomere repeats are acquired from homologous chromosome or a sister chromatid (Stankiewicz and Lupski 2002), or by a nonhomologous endjoining (NHEJ) recombination mechanism with another chromosome resulting in the formation of a derivative chromosome (Flint et al. 1996; Ballif et al. 2004; D'Angelo et al. 2009). In addition, numerous studies indicate that some subtelomeric rearrangements may be mediated by interspersed repetitive elements such as Alu, LINE, long-terminal repeats and simple tandem repeats. "
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