ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 11q13.3-q13.4
  • GRCh37/hg19 chr11: 70,313,961-70,935,842
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr11: 70,467,854-71,252,724
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000011.9) (NC_000011.10)
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
20473310 Berkel et al 2010 (Nature Communications): performed genome-wide microarray analysis (Affymetrix 6.0 SNP platform) for CNVs in a German cohort of 184 unrelated individuals with intellectual disability along with a parallel study of 396 Canadian ASD cases using the Affymetrix 6.0 and/or Illumina1M-single SNP platform. All ASD cases were diagnosed using the Autism Diagnostic Interview?revised and Autism Diagnostic Observation Schedule measures (supp data). Authors identified 2 de novo SHANK2 deletions, one of which spanned 120 kb in size involving loss of exon 7 and the other 69 kb in size involving loss of exons 6 and 7. The patient involving loss of exons 6 and 7 was reported to have ASD while the deletion involving loss of only exon 7 had mild to moderate intellectual disability (Table 1). Both deletions disrupt the highly conserved PDZ domain of SHANK2, causing a frameshift and presumably functional loss of one allele. SHANK2 CNVs (losses and gains) were absent in the Database of Genomic Variants and in 5,023 controls of European ancestry. The authors also sequenced the exons of the neuronal isoform of SHANK2 (SHANK2_1, see Fig 1a in paper) in the same cohort of 184 intellectually disabled and 396 ASD individuals. This was done in parallel with 659 controls of European ancestry for the same exons. Putative mutations were identified among 8 different individuals comprising one de novo nonsense mutation (R462X - - reported as having autism) and six inherited missense variants (R26W, P208S, S231Y, R1048W, T1127M and A1350T, see Supp Fig S3). With the exception of one variant (P208S) that was detected twice (in a case with intellectual disability and an ASD case), all other variants were found only once. None of these variants were identified in the 2 individuals carrying the de novo deletion, and none were detected in controls or in dbSNP (build 130). Parents transmitting the variants were undiagnosed for ASD but in some instances showed depression and/or anxiety (mothers of A1350T and the P208S variant). Siblings carrying the same missense variant as the ASD patient showed a similar phenotype or milder symptoms like speech delay, attention difficulties, articulation difficulties, or anxiety.
22346768 Leblond et al 2012 (PLoS Genetics) genotyped 260 patients with ASD (290 controls) using Illumina 1M Duo SNP arrays. A de novo 421.2 kb deletion (affecting exons 5-16) within SHANK2 in a male patient with autism, moderate ID, language delay, and minor signs of dysmorphism were observed. Of note, the same patient with the de novo 421 kb deletion carried a second hit involving a maternally inherited 496 kb duplication encompassing CHRNA7 in the BP5 region of chromosome 15q13. The 2012 Leblond et al study references a 2010 study by Pinto et al (PMID: 20531469), where another de novo 68 kb deletion partially disrupting SHANK2 was reported in individual with autism, mild ID and language delay. This de novo 68 kb deletion also contained a second hit involving a paternally-inherited BP1-BP2 deletion of 468 kb, removing NIPA1, NIPA2, CYFIP1, and TUBGCP5. The authors also sequenced the exons of the longest SHANK2E isoform in the same case control cohort in which CNVs were identified. Additionally, the isoform that corresponds to the major SHANK2 isoform in the brain was sequenced in a sample of 225 patients and 201 controls. A total of 24 nonsynonymous heterozygous variants were detected and were found to be inherited from one of the parents. Overall there was no enrichment of rare variants of SHANK2 (MAF<1%) in patients with ASD compared with controls. However, an enrichment of variants affecting conserved amino acids, such as R818H and S557N, in patients compared with controls was detected (p = 0.013). The majority of the variants affecting conserved residues were shown to alter the ability of SHANK2 to increase the number of synapses in vitro (based on functional studies performed on rat primary neuronal cells). The authors comment that the assays performed in the study show that variants affecting conserved amino acids can potentially impact the function of the protein, but they do not confirm that they have deleterious effects on neuronal function in vivo among individuals that carry them.
25560758 Peykov et al 2015 (Molecular Psychiatry) sequenced the SHANK2 gene in 481 schizophrenia (SCZ) patients and in 659 controls, including 177 individual parental DNA. The frequency of rare (MAF < 1%) missense variants in SCZ individuals (33/481) was higher vs. control (26/659) (P=0.039). The authors note that the difference in frequency of rare predicted deleterious variants between patients and controls did not reach statistical significance but a trend was noted. Ten of the fifteen missense variants in SCZ individuals occurred in the patient group and were absent from controls (remaining 5 were listed as non-disease causing polymorphisms ? Supp Table 3). Five of the ten missense variants were inherited (T438M, P1144L, V1608I, L1646M, A1731S) from an apparently unaffected parent. The schizophrenic subtype of the 10 individuals with SHANK2 variants showed phenotypic heterogeneity ranging from paranoia, disorganized or schizoaffective behavior. The most frequent SHANK2 variant in this study was the A1731S; identified in four unrelated SCZ patients. This variant was predicted to be benign by several prediction programs, but it was chosen for further functional analysis because of its repeated occurrence in SCZ patients and absence in controls. In addition, S610Y, R958S and P1119T were also selected for further analysis because they had the highest expected probability for a functional effect by three different in silico prediction tools. Primary hippocampal neurons from rat and fibroblast cell lines were used to co-transfect the four variants and the wild-type construct with a GFP-expression vector. A reduced number of SHANK2-positive synapses and reduced ability to increase dendritic spine volume was observed in the hippocampal neurons. These experiments showed that some degree of functional impairment for each one of the four missense variants is present, but the exact molecular mechanisms and networks affected by SHANK2 mutations in SCZ remain unclear.

Haploinsufficiency phenotype comments:

Overall de novo deletion CNVs reported in Berkel et al 2010 and the nonsense mutation (R462X) are the penetrant mutations in SHANK2 in which the probands have either autism and/or intellectual disability. The additional deletions referenced in Leblond et al 2012 also have a second deletion/duplication elsewhere in the genome which may confound interpretation of the phenotype based solely on pathogenic variants in SHANK2. This co-occurrence may also point to a possible genetic epistasis in the SHANK2 pathway and other nonallelic variants in the genome. Further, the observation that some individuals carrying rare inherited SHANK2 sequence variants do not express an ASD phenotype is consistent with a multigenic threshold model for autism as previously proposed (Berkel et al 2010). In addition, SNVs reported to affect conserved amino acids of SHANK2 are proposed to act as susceptibility variants rather than causal, suggesting ancillary genetic/epigenetic or environmental factors might be necessary to develop ASD (Leblond et al 2012). Taken together, the occurrence of deleterious mutations in SHANK2 infrequently act as independent risk factors for autism, rather multigenic hits are necessary to develop a phenotype which can in turn vary in expressivity among families.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

To date, no gross duplications/insertions cataloged in HGMD or reported in literature