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Cited by 634Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchGenomic variations and chromosomal abnormalities

The DOI matches its Crossref record; 58 of the 58 references it cites were found in a registry or an index; none of the 37 sources its claims cite is checked for support yet.

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments

Open access
Leblond, Claire S., Nava, Caroline, Polge, Anne, Gauthier, Julie, Huguet, Guillaume, Lumbroso, Serge, Giuliano, Fabienne, Stordeur, Coline, Depienne, Christel, Mouzat, Kevin, Pinto, Dalila, Howe, Jennifer, Lemière, Nathalie, Durand, Christelle M., Guibert, Jessica, Ey, Elodie, Toro, Roberto, Peyre, Hugo, Mathieu, Alexandre, Amsellem, Frédérique, Rastam, Maria, Gillberg, I. Carina, Rappold, Gudrun A., Holt, Richard, Monaco, Anthony P., Maestrini, Elena, Galan, Pilar, Heron, Delphine, Jacquette, Aurélia, Afenjar, Alexandra, Rastetter, Agnès, Brice, Alexis, Devillard, Françoise, Assouline, Brigitte, Laffargue, Fanny, Lespinasse, James, Chiesa, Jean, Rivier, François, Bonneau, Dominique, Regnault, Beatrice, Zelenika, Diana, Delepine, Marc, Lathrop, Mark, Sanlaville, Damien, Schluth-Bolard, Caroline, Edery, Patrick, Perrin, Laurence, Tabet, Anne Claude, Schmeisser, Michael J., Boeckers, Tobias M., Coleman, Mary, Sato, Daisuke, Szatmari, Peter, Scherer, Stephen W., Rouleau, Guy A., Betancur, Catalina, Leboyer, Marion, Gillberg, Christopher, Delorme, Richard, Bourgeron, Thomas·2014·PLoS Genetics
DOI 10.1371/journal.pgen.1004580PMC PMC4154644
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Abstract

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.

Overview

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Written from the paper’s full text.

TL;DR

This meta-analysis plus new screening found SHANK copy-number and truncating coding-sequence variants in ~1% of patients with ASD, with a gene-specific gradient of cognitive severity: SHANK1 in normal-IQ autism, SHANK2 in mild ID, and SHANK3 in moderate-to-profound ID. SHANK3 mutations were the most frequent and clinically relevant, accounting for more than 1 in 50 cases with ASD plus intellectual disability.

Key findings

  • SHANK1 mutations were rare: CNVs in 0.04% of ASD cases (2/5,657) versus 0/19,163 controls (meta-analysis fixed-effect P=0.19, OR=2.73, 95% CI 0.60–12.48), and no truncating coding-sequence variants were found (0/760 ASD, 0/492 controls). Damaging missense variants were more frequent in ASD (3.16% vs 1.02%, P=0.012, OR=3.17), but this did not survive Bonferroni correction; carriers had normal IQ (mean IQ=107) and ASD.
  • SHANK2 mutations were associated with mild ID: CNVs in 0.05% of ASD cases (3/5,657) versus 0/19,163 controls (P=0.076, OR=3.76), truncating coding-sequence variants in 0.12% (1/851 ASD vs 0/1,090 controls), and damaging missense variants in 4.58% vs 2.66% (P=0.025, OR=1.76). Carriers had mild to moderate ID (mean IQ=62±17).
  • SHANK3 mutations were most frequent and severe: CNVs in 0.18% of ASD cases (10/5,657) versus 0.01% of controls (2/19,163; P=0.019, OR=4.05), and truncating coding-sequence variants in 0.51% (11/2,147 ASD vs 0/1,031 controls; P=0.29, OR=2.85). In ASD with ID (IQ<70), de novo or truncating SHANK3 mutations reached 2.12% (CNVs 6/917=0.65%; coding-sequence 9/611=1.47%), versus 0% in ASD without ID and 0.01% in controls; carriers had moderate to severe/profound ID (mean IQ=31±8).
  • Across genes, truncating/CNV mutations were present in ~1% of ASD cases: SHANK1 0.04%, SHANK2 0.17%, SHANK3 0.69%, with a gradient from normal IQ (SHANK1) to mild ID (SHANK2) to moderate-to-profound ID (SHANK3).

Methods

  • Meta-analysis of SHANK copy-number variants (5,657 ASD cases and 19,163 controls from 11 studies, including this one) and coding-sequence variants (760–2,147 ASD cases and 492–1,090 controls depending on gene, from 10 studies, including this one). New screening included 46 ASD cases/454 controls for CNVs, 251 ASD cases/492 controls for SHANK1 exons, and 429 ASD cases/80 controls added to SHANK3 coding-sequence screening; de novo or truncating mutation carriers underwent extended clinical investigation.
  • ASD diagnosis used ADI-R, and in some cases ADOS or DISCO-10; IQ was measured with age-appropriate Wechsler scales, Raven’s Standard Progressive Matrices, or PPVT, plus systematic physical examination for dysmorphic and neurological features.
  • Statistical analysis used two-sided Fisher’s exact tests, Bonferroni correction for 12 tests (corrected α=0.0042), inverse-variance fixed- and random-effects meta-analysis, heterogeneity statistics (Q, I², Tau²), and power calculations; SHANK2 and SHANK3 reference sequences were corrected before screening.

Limitations

  • The paper states that inherited SHANK1 and SHANK2 variant associations did not survive Bonferroni correction, and the study was underpowered for low-effect-size inherited variants: power to detect an OR of 1.5 for SHANK1, SHANK2, and SHANK3 missense inherited damaging variants was 8%, 34%, and 17%, respectively; larger IQ-stratified cohorts are needed.
  • The paper notes that only non-synonymous mutations in known exons were screened; splicing isoforms, synonymous mutations, and regulatory variants were rarely reported, and whole-exome sequencing studies were excluded because of very low SHANK3 coverage. Some father DNA was unavailable for two SHANK3 truncating cases, two SHANK2 deletion patients were not included in prevalence calculations because the exact number screened was unavailable, and two unvalidated SHANK3 control deletions should be interpreted with caution.
  • Evident from the text: the meta-analysis relied on combining heterogeneous published cohorts, and although the authors contacted corresponding authors to avoid overlapping samples, control data for SHANK1 coding variants were incomplete in one prior study and were excluded from that analysis.

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Registry

Crossref · 10.1371/journal.pgen.1004580

Cites

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Statistics

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Figures

Figure 1 SHANK variants in patients with ASD and controls. Coding-sequence variants identified only in patients with ASD (upper panel), shared by patients and controls (lower panel and underlined), and present only in controls (lower panel). Truncating variants are indicated in red. The variants predicted as deleterious or benign are indicated in orange and green, respectively. Coding-sequence variants with a proven in vitro functional impact are indicated with black stars. Conserved domains are represented in color: SPN (yellow), Ankyrin (red), SH3 (orange), PDZ (blue) and SAM (green).
Figure 1 SHANK variants in patients with ASD and controls. Coding-sequence variants identified only in patients with ASD (upper panel), shared by patients and controls (lower panel and underlined), and present only in controls (lower panel). Truncating variants are indicated in red. The variants predicted as deleterious or benign are indicated in orange and green, respectively. Coding-sequence variants with a proven in vitro functional impact are indicated with black stars. Conserved domains are represented in color: SPN (yellow), Ankyrin (red), SH3 (orange), PDZ (blue) and SAM (green).CC BY · PubMed Central
Figure 2 Prevalence and meta-analysis of copy number variant studies in ASD. A. The prevalence and the confidence interval from a set of single copy number variant studies and the pooled prevalence and the confidence interval of the meta-analysis. The prevalence is indicated by circles in red, pink, purple and black for “ASD all” (all ASD patients), “ASD IQ<70” (patients with ID; IQ<70), “ASD IQ>70” (patients with IQ in the normal range), and “CTRL” (controls), respectively. The plotted circles are proportional to the corresponding sample size. B. Meta-analysis of the copy number variants altering SHANK genes. For each study, the Odds ratio and confidence interval are given. Each meta-analysis is calculated using inverse variance method for fixed (IV-FEM) and random effects (IV-REM). The statistics measuring heterogeneity (Q, I2 and Tau2) are indicated. The number under the scatter plot correspond to independent studies: 1 = “[The Paris cohort: this study+Durand et al. 2007 [6]; Sato et al. 2012 [19]; Leblond et al. 2012 [18]]”, 2 = “[Moessner et al. (2007) [13]; Marshall et al. (2008) [52]; Pinto et al. (2010) [8]; Berkel et al. (2010) [14]; Sato et al. (2012) [19]]”, 3 = “Bremer et al. (2010) [53]”, 4 = “Glessner et al. (2009) [34]”, 5 = “Sanders et al. (2011) [9]”, and 6 = “Sebat et al. (2007) [51]”. IV, Inverse Variance; FEM, Fixed Effect Method; REM, Random Effect Method; OR, Odds Ratio; CI, Confidence Interval; IQ, Intellectual Quotient; CNV, Copy Number Variant.
Figure 2 Prevalence and meta-analysis of copy number variant studies in ASD. A. The prevalence and the confidence interval from a set of single copy number variant studies and the pooled prevalence and the confidence interval of the meta-analysis. The prevalence is indicated by circles in red, pink, purple and black for “ASD all” (all ASD patients), “ASD IQ<70” (patients with ID; IQ<70), “ASD IQ>70” (patients with IQ in the normal range), and “CTRL” (controls), respectively. The plotted circles are proportional to the corresponding sample size. B. Meta-analysis of the copy number variants altering SHANK genes. For each study, the Odds ratio and confidence interval are given. Each meta-analysis is calculated using inverse variance method for fixed (IV-FEM) and random effects (IV-REM). The statistics measuring heterogeneity (Q, I2 and Tau2) are indicated. The number under the scatter plot correspond to independent studies: 1 = “[The Paris cohort: this study+Durand et al. 2007 [6]; Sato et al. 2012 [19]; Leblond et al. 2012 [18]]”, 2 = “[Moessner et al. (2007) [13]; Marshall et al. (2008) [52]; Pinto et al. (2010) [8]; Berkel et al. (2010) [14]; Sato et al. (2012) [19]]”, 3 = “Bremer et al. (2010) [53]”, 4 = “Glessner et al. (2009) [34]”, 5 = “Sanders et al. (2011) [9]”, and 6 = “Sebat et al. (2007) [51]”. IV, Inverse Variance; FEM, Fixed Effect Method; REM, Random Effect Method; OR, Odds Ratio; CI, Confidence Interval; IQ, Intellectual Quotient; CNV, Copy Number Variant.CC BY · PubMed Central
Figure 3 Prevalence and meta-analysis of coding-sequence variant studies in ASD. A. The prevalence and the confidence interval from a set of single coding-sequence variant studies, and the pooled prevalence and the confidence interval of the meta-analysis. The prevalence is indicated by circles in red, pink, purple and black for “ASD all” (all ASD patients), “ASD IQ<70” (patients with ID; IQ<70), “ASD IQ>70” (patients with normal IQ), and “CTRL” (controls), respectively. Three categories are used to study the prevalence of coding-sequence variants in ASD and controls: all or “A” (all mutation), Damaging or “D” (damaging missense mutation; score obtained from polyphen-2), and Truncating or “T” (mutation altering SHANK protein). The plotted circles are proportional to the corresponding sample size. B. Meta-analysis of coding-sequence variant studies altering SHANK genes. For each study, the Odds ratio and confidence interval is given. Each meta-analysis is calculated using inverse variance method for fixed (IV-FEM) and random effects (IV-REM). The statistics measuring heterogeneity (Q, I2 and Tau2) are indicated. The number under the scatter plot correspond to independent studies: 1 = “This study”, 2 = “ Sato et al. (2012) [19]”, 3 = “Berkel et al. (2010) [14]”, 4 = “Leblond et al. (2012) [18]”, 5 = “Boccuto et al. (2012) [17]”, and 6 = “[This Study and Durand et al. 2007 [6]]”, 7 = “[Gauthier et al. (2009–2010) [16], [47]]”, 8 = “Moessner et al. (2007) [13]”, 9 = “Schaff et al. (2011) [35]”. IV, Inverse Variance; FEM, Fixed Effect Method; REM, Random Effect Method; OR, Odds Ratio; CI, Confidence Interval; IQ, Intellectual Quotient; CNV, Copy Number Variant.
Figure 3 Prevalence and meta-analysis of coding-sequence variant studies in ASD. A. The prevalence and the confidence interval from a set of single coding-sequence variant studies, and the pooled prevalence and the confidence interval of the meta-analysis. The prevalence is indicated by circles in red, pink, purple and black for “ASD all” (all ASD patients), “ASD IQ<70” (patients with ID; IQ<70), “ASD IQ>70” (patients with normal IQ), and “CTRL” (controls), respectively. Three categories are used to study the prevalence of coding-sequence variants in ASD and controls: all or “A” (all mutation), Damaging or “D” (damaging missense mutation; score obtained from polyphen-2), and Truncating or “T” (mutation altering SHANK protein). The plotted circles are proportional to the corresponding sample size. B. Meta-analysis of coding-sequence variant studies altering SHANK genes. For each study, the Odds ratio and confidence interval is given. Each meta-analysis is calculated using inverse variance method for fixed (IV-FEM) and random effects (IV-REM). The statistics measuring heterogeneity (Q, I2 and Tau2) are indicated. The number under the scatter plot correspond to independent studies: 1 = “This study”, 2 = “ Sato et al. (2012) [19]”, 3 = “Berkel et al. (2010) [14]”, 4 = “Leblond et al. (2012) [18]”, 5 = “Boccuto et al. (2012) [17]”, and 6 = “[This Study and Durand et al. 2007 [6]]”, 7 = “[Gauthier et al. (2009–2010) [16], [47]]”, 8 = “Moessner et al. (2007) [13]”, 9 = “Schaff et al. (2011) [35]”. IV, Inverse Variance; FEM, Fixed Effect Method; REM, Random Effect Method; OR, Odds Ratio; CI, Confidence Interval; IQ, Intellectual Quotient; CNV, Copy Number Variant.CC BY · PubMed Central
Figure 4 Scatter plots of the intellectual quotient and the Autism Diagnostic Interview-Revised (ADI-R) scores of the patients with ASD screened for SHANK1-3 mutations. Mutations in SHANK1-3 are associated with a gradient of severity in cognitive impairment. SHANK1 mutations were reported in patients without ID (green dots). SHANK2 mutations were reported in patients with mild ID (orange dots). SHANK3 mutations were found in patients with moderate to severe deficit (red dots). Black dots correspond to the patients enrolled in the PARIS cohort screened for deleterious SHANK1-3 mutations (n = 498). In addition to the PARIS cohort [6], [8], [18], three patients with a SHANK1 deletion [19] and two patients with a SHANK2 deletion [14] were included in the scatter plot. A high score of the ADI-R is associated with a more severe profile. The threshold of the “Social”, “Verbal”, “Non-Verbal” and “Repetitive Behavior” Scores are 10, 8, 7 and 3, respectively.
Figure 4 Scatter plots of the intellectual quotient and the Autism Diagnostic Interview-Revised (ADI-R) scores of the patients with ASD screened for SHANK1-3 mutations. Mutations in SHANK1-3 are associated with a gradient of severity in cognitive impairment. SHANK1 mutations were reported in patients without ID (green dots). SHANK2 mutations were reported in patients with mild ID (orange dots). SHANK3 mutations were found in patients with moderate to severe deficit (red dots). Black dots correspond to the patients enrolled in the PARIS cohort screened for deleterious SHANK1-3 mutations (n = 498). In addition to the PARIS cohort [6], [8], [18], three patients with a SHANK1 deletion [19] and two patients with a SHANK2 deletion [14] were included in the scatter plot. A high score of the ADI-R is associated with a more severe profile. The threshold of the “Social”, “Verbal”, “Non-Verbal” and “Repetitive Behavior” Scores are 10, 8, 7 and 3, respectively.CC BY · PubMed Central

Verification

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53 Own result · 26 Not checked yet · 15 Own interpretation · 11 Own method · 4 No basis given

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  • Probably not a substantial claim. 26
  • It may state two separate claims as one. 26
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53 of 53

  • The paper relies on this without support.

    The published studies included in the meta-analysis used comparable methods for detecting SHANK variants and comparable ASD/control ascertainment.

    “This meta-analysis included the published data from 14 studies in addition to a new screening of SHANK copy-number variants and coding sequence variants.”

  • The paper relies on this without support.

    Rare coding-sequence variants predicted as damaging by polyphen-2 are functionally deleterious.

    “rare inherited coding-sequence variants predicted as damaging were, however, more frequent in patients with ASD than in controls”

  • The paper relies on this without support.

    The clinical phenotype associated with SHANK mutations is primarily attributable to the SHANK gene affected rather than to other genetic or environmental factors.

    “Mutations in SHANK1-3 are associated with a gradient of severity in cognitive impairment.”

  • The paper relies on this without support.

    Patients carrying de novo or truncating SHANK mutations who underwent clinical investigation are representative of all individuals with such mutations.

    “When possible, the patients carrying truncating mutations altering SHANK genes underwent further clinical investigations (Table 2 & S7).”

  • The paper relies on this without support.

    The cohorts included in the meta-analysis are representative of the whole ASD population.

    “In the whole spectrum of ASD, we estimated that 0.04%, 0.17% and 0.69% of cases with ASD had heterozygous truncating mutations in SHANK1, SHANK2 or SHANK3, respectively (Table 1).”

  • The paper relies on this without support.

    The control groups included in the meta-analysis are representative of the general population without ASD.

    “0.01% in controls”

  • The paper relies on this without support.

    The SHANK mutations classified as truncating or damaging are pathogenic.

    “we estimated that 0.04%, 0.17% and 0.69% of cases with ASD had heterozygous truncating mutations in SHANK1, SHANK2 or SHANK3, respectively (Table 1).”
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Metadata

Authors
Leblond, C. S., Nava, C., Polge, A., Gauthier, J., Huguet, G., Lumbroso, S., Giuliano, F., Stordeur, C., Depienne, C., Mouzat, K., Pinto, D., Howe, J., Lemière, N., Durand, C. M., Guibert, J., Ey, E., Toro, R., Peyre, H., Mathieu, A., Amsellem, F., Rastam, M., Gillberg, I. C., Rappold, G. A., Holt, R., Monaco, A. P., Maestrini, E., Galan, P., Heron, D., Jacquette, A., Afenjar, A., Rastetter, A., Brice, A., Devillard, F., Assouline, B., Laffargue, F., Lespinasse, J., Chiesa, J., Rivier, F., Bonneau, D., Regnault, B., Zelenika, D., Delepine, M., Lathrop, M., Sanlaville, D., Schluth-Bolard, C., Edery, P., Perrin, L., Tabet, A. C., Schmeisser, M. J., Boeckers, T. M., Coleman, M., Sato, D., Szatmari, P., Scherer, S. W., Rouleau, G. A., Betancur, C., Leboyer, M., Gillberg, C., Delorme, R., & Bourgeron, T.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Centre Hospitalier Universitaire de Nîmes (FR)
  • Centre Hospitalier Universitaire Sainte-Justine (CA)
  • Centre Hospitalier Universitaire de Nice (FR)
  • Icahn School of Medicine at Mount Sinai (US)
  • University of Toronto (CA)
  • Institut Pasteur (FR)
  • University of Gothenburg (SE)
  • Heidelberg University (DE)
  • Centre for Human Genetics (GB)
  • University of Bologna (IT)
  • Conservatoire National des Arts et Métiers (FR)
  • Assistance Publique – Hôpitaux de Paris (FR)
  • Hôpital Armand-Trousseau (FR)
  • Hôpital Couple Enfant (FR)
  • Centre Hospitalier Universitaire de Clermont-Ferrand (FR)
  • Inserm (FR)
  • Lyon 1 Université (FR)
  • Universität Ulm (DE)
  • Montreal Neurological Institute and Hospital (CA)
  • University College London (GB)
Corresponding author
Bourgeron, Thomas
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2014-09-04
Volume
10
Issue
9
Pages
e1004580
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1004580
PMC
PMC4154644
OpenAlex
W2141041915
Semantic Scholar
765f93019a616c818b4b4525f202bb4aeb20152c
Cited by
630
References
58
Citations by year
2026: 30 · 2025: 38 · 2024: 72 · 2023: 61 · 2022: 65 · 2021: 62 · 2020: 51 · 2019: 50 · 2018: 58 · 2017: 57 · 2016: 43 · 2015: 39 · 2014: 4
FWCI
6.30
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
  • HAL (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship@McGill (McGill) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Lund University Publications (Lund University) (submittedVersion, other-oa)
Funders
  • Fondation FondaMental
  • Fondation Cognacq-Jay
  • Fondation Orange
  • Deutsche Forschungsgemeinschaft
  • Agence Nationale de la Recherche (ANR-08-MNPS-0037)
  • Institut National de la Santé et de la Recherche Médicale
  • Centre National de la Recherche Scientifique
  • Université Paris Diderot
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
autism spectrum disorder, SHANK3, Shank2, Shank1, copy number variation, truncating mutations, intellectual disability, cognitive impairment severity, de novo mutations, postsynaptic density, glutamatergic synapses, dendritic spines, mutation detection
MeSH terms
Child, Child Development Disorders, Pervasive, Cognition, Cognition Disorders, Female, Humans, Male, Intellectual Disability, Mutation, Nerve Tissue Proteins, Neurons, Synapses, Case-Control Studies, DNA Copy Number Variations

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