Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms

Wilson, Heather L.; Wong, Andrew; Shaw, Steven R.; Tse, W. S.; Stapleton, Gail A.; Phelan, Mary C.; Hu, Shanshan; Marshall, Jan D.; McDermid, Heather E.

doi:10.1136/jmg.40.8.575

Cited by 340 publications

(363 citation statements)

References 49 publications

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“…The PSD has been identified in several glutamate synapses. SHANK3 haploinsufficiency seems to be responsible for the major neurological symptoms in 22q13 deletion syndrome (MIM #606232), 25,26 a condition characterized by speech delay, neonatal hypotonia, and behavioral problems along with other features.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

et al. 2012

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Autism spectrum disorders (ASDs) include three main conditions: autistic disorder (AD), pervasive developmental disorder, not otherwise specified (PDD-NOS), and Asperger syndrome. It has been shown that many genes associated with ASDs are involved in the neuroligin-neurexin interaction at the glutamate synapse: NLGN3, NLGN4, NRXN1, CNTNAP2, and SHANK3. We screened this last gene in two cohorts of ASD patients (133 patients from US and 88 from Italy). We found 5/221 (2.3%) cases with pathogenic alterations: a 106 kb deletion encompassing the SHANK3 gene, two frameshift mutations leading to premature stop codons, a missense mutation (p.Pro141Ala), and a splicing mutation (c.1820-4 G4A). Additionally, in 17 patients (7.7%) we detected a c.1304 þ 48C4T transition affecting a methylated cytosine in a CpG island. This variant is reported as SNP rs76224556 and was found in both US and Italian controls, but it results significantly more frequent in our cases than in the control cohorts. The variant is also significantly more common among PDD-NOS cases than in AD cases. We also screened this gene in an independent replication cohort of 104 US patients with ASDs, in which we found a missense mutation (p.Ala1468Ser) in 1 patient (0.9%), and in 8 patients (7.7%) we detected the c.1304 þ 48C4T transition. While SHANK3 variants are present in any ASD subtype, the SNP rs76224556 appears to be significantly associated with PDD-NOS cases. This represents the first evidence of a genotype-phenotype correlation in ASDs and highlights the importance of a detailed clinical-neuropsychiatric evaluation for the effective genetic screening of ASD patients.

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Section: Introductionmentioning

confidence: 99%

Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

et al. 2012

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“…20 SHANK3 dosage was also tested by MAPH (Multiplex Amplifiable Probe Hybridisation). MAPH probes were chosen throughout SHANK3, according to the gene structure previously determined, 6 using the exon numbering from Durand et al 12 Probes covering 13/24 SHANK3 exons and two 22q11 control probes are given in Table 2. MAPH was performed on 0.5 -1 mg genomic DNA using conditions previously described.…”

Section: Cytogenetic Studiesmentioning

confidence: 99%

“…6 FISH using both cosmids and BACs that span the region of interest was used to characterize the proximal and distal breakpoints of the deletions in patients A, B and BX (Figure 3).…”

Section: Molecular Analysis: Definition Of the Deletionmentioning

confidence: 99%

“…1,3,6 Although one study 3 showed the severity of global developmental delay increased with the size of the deletion in 16 patients (plus 17 patients with r(22)), only 4/12 measures of developmental assessment showed some correlation with deletion size in a study of 56 patients. 6 If SHANK3 is responsible for most of the neurological abnormalities in these patients, this would imply that deletion of the region proximal to SHANK3 might have a mild phenotype that is largely masked by the terminal deletion of SHANK3.…”

Section: Introductionmentioning

confidence: 99%

“…In two studies representing 72 patients, the size of the deletion was determined at the molecular level to range from 130 kb to deletions larger than 9 Mb in size. 3,6 The smallest deletions were found to contain the gene SHANK3, which encodes a synapse structural protein and is located approximately 130 kb from the telomere. Among the 72 patients specifically tested for SHANK3, 61 were hemizyogous at this locus.…”

Section: Introductionmentioning

confidence: 99%

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Interstitial 22q13 deletions: genes other than SHANK3 have major effects on cognitive and language development

et al. 2008

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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.

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Recurrent Rearrangements in Synaptic and Neurodevelopmental Genes and Shared Biologic Pathways in Schizophrenia, Autism, and Mental Retardation

Guilmatre

Dubourg

Mosca

et al. 2009

Arch Gen Psychiatry

395

284

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Weakly to moderately recurrent CNVs (transmitted or occurring de novo) seem to be causative or contributory factors for these diseases. Most of these CNVs (which contain genes involved in neurotransmission or in synapse formation and maintenance) are present in the 3 pathologic conditions (schizophrenia, autism, and mental retardation), supporting the existence of shared biologic pathways in these neurodevelopmental disorders.

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Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms

Cited by 340 publications

References 49 publications

Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

Interstitial 22q13 deletions: genes other than SHANK3 have major effects on cognitive and language development

Recurrent Rearrangements in Synaptic and Neurodevelopmental Genes and Shared Biologic Pathways in Schizophrenia, Autism, and Mental Retardation

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