Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci

Chilian, B; Abdollahpour, H; Bierhals, T; Haltrich, I; Fekete, G; Nagel, I; Rosenberger, G; Kutsche, K

doi:10.1111/cge.12105

Cited by 85Genetics and Neurodevelopmental DisordersGenomic variations and chromosomal abnormalitiesAutism Spectrum Disorder Research

Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci

Chilian, B, Abdollahpour, H, Bierhals, T, Haltrich, I, Fekete, G, Nagel, I, Rosenberger, G, Kutsche, K·2013·Clinical Genetics

DOI 10.1111/cge.12105

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Abstract

Synaptopathies constitute a group of neurological diseases including autism spectrum disorders (ASD) and intellectual disability (ID). They have been associated with mutations in genes encoding proteins important for the formation and stabilization of synapses, such as SHANK1-3. Loss-of-function mutations in the SHANK genes have been identified in individuals with ASD and ID suggesting that other factors modify the neurological phenotype. We report a boy with severe ID, behavioral anomalies, and language impairment who carries a balanced de novo triple translocation 46,XY,t(11;17;19)(q13.3;q25.1;q13.42). The 11q13.3 breakpoint was found to disrupt the SHANK2 gene. The patient also carries copy number variations at 15q13.3 and 10q22.11 encompassing ARHGAP11B and two synaptic genes. The CHRNA7 gene encoding α7-nicotinic acetylcholine receptor subunit and the GPRIN2 gene encoding G-protein-regulated inducer of neurite growth 2 were duplicated. Co-occurrence of a de novo SHANK2 mutation and a CHRNA7 duplication in two reported patients with ASD and ID as well as in the patient with t(11;17;19), severe ID and behavior problems suggests convergence of these genes on a common synaptic pathway. Our results strengthen the oligogenic inheritance model and highlight the presence of a large effect mutation and modifier genes collectively determining phenotypic expression of the synaptopathy.

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For SHANK2, additional genetic/epigenetic factors might be necessary to develop ASD.
“for SHANK2, additional genetic/epigenetic factors might be necessary to develop ASD [18], [19], [46].”
From Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments (2014) · cites this paper as [46]

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Additional file 4 of Expression profiles of the autism-related SHANK proteins in the human brain
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Additional file 12 of Expression profiles of the autism-related SHANK proteins in the human brain
Woelfle, S., Pedro, M. T., Wagner, J., Schön, M., & Boeckers, T. M. (2024) · Figshare · doi:10.6084/m9.figshare.26638893
Additional file 9 of Expression profiles of the autism-related SHANK proteins in the human brain
Woelfle, S., Pedro, M. T., Wagner, J., Schön, M., & Boeckers, T. M. (2024) · Figshare · doi:10.6084/m9.figshare.26638884
Additional file 5 of Expression profiles of the autism-related SHANK proteins in the human brain
Woelfle, S., Pedro, M. T., Wagner, J., Schön, M., & Boeckers, T. M. (2024) · Figshare · doi:10.6084/m9.figshare.26638872
Additional file 7 of Expression profiles of the autism-related SHANK proteins in the human brain
Woelfle, S., Pedro, M. T., Wagner, J., Schön, M., & Boeckers, T. M. (2024) · Figshare · doi:10.6084/m9.figshare.26638878
Additional file 10 of Expression profiles of the autism-related SHANK proteins in the human brain
Woelfle, S., Pedro, M. T., Wagner, J., Schön, M., & Boeckers, T. M. (2024) · Figshare · doi:10.6084/m9.figshare.26638887
Additional file 6 of Expression profiles of the autism-related SHANK proteins in the human brain
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Additional file 8 of Expression profiles of the autism-related SHANK proteins in the human brain
Woelfle, S., Pedro, M. T., Wagner, J., Schön, M., & Boeckers, T. M. (2024) · Figshare · doi:10.6084/m9.figshare.26638881
Additional file 3 of Expression profiles of the autism-related SHANK proteins in the human brain
Woelfle, S., Pedro, M. T., Wagner, J., Schön, M., & Boeckers, T. M. (2024) · Figshare · doi:10.6084/m9.figshare.26638863
Additional file 13 of Expression profiles of the autism-related SHANK proteins in the human brain
Woelfle, S., Pedro, M. T., Wagner, J., Schön, M., & Boeckers, T. M. (2024) · Figshare · doi:10.6084/m9.figshare.26638896
Additional file 2 of Expression profiles of the autism-related SHANK proteins in the human brain
Woelfle, S., Pedro, M. T., Wagner, J., Schön, M., & Boeckers, T. M. (2024) · Figshare · doi:10.6084/m9.figshare.24550321
Additional file 1 of Expression profiles of the autism-related SHANK proteins in the human brain
Woelfle, S., Pedro, M. T., Wagner, J., Schön, M., & Boeckers, T. M. (2023) · Figshare · doi:10.6084/m9.figshare.24550055
Additional file 1 of Enhanced fear limits behavioral flexibility in Shank2-deficient mice
Yun, M., Kim, E., & Jung, M. W. (2022) · Figshare · doi:10.6084/m9.figshare.21268985
Additional file 11 of Expression profiles of the autism-related SHANK proteins in the human brain
Woelfle, S., Pedro, M. T., Wagner, J., Schön, M., & Boeckers, T. M. (2024) · Figshare · doi:10.6084/m9.figshare.26638890
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Authors: Chilian, B., Abdollahpour, H., Bierhals, T., Haltrich, I., Fekete, G., Nagel, I., Rosenberger, G., & Kutsche, K.
Affiliations: University Medical Center Hamburg-Eppendorf (DE)
Semmelweis University (HU)
Christian-Albrechts-Universität zu Kiel (DE)
Corresponding author: Kutsche, K
ORCID: Bierhals, T
Haltrich, I
Nagel, I
Rosenberger, G
Kutsche, K
Venue: Clinical Genetics
Publisher: Wiley
Published: 2013-02-21
Volume: 84
Issue: 6
Pages: 560-565
ISSN: 0009-9163 (ISSN-L)
1399-0004
DOI: 10.1111/cge.12105
OpenAlex: W1939889341
Cited by: 85
References: 32
Citations by year: 2026: 1 · 2025: 2 · 2024: 16 · 2023: 4 · 2022: 8 · 2021: 7 · 2020: 6 · 2018: 6 · 2017: 4 · 2016: 4 · 2015: 11 · 2014: 12 · 2013: 4
FWCI: 6.85
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Clinical Genetics (publishedVersion)
PubMed (publishedVersion)
Semmelweis University Repository (Semmelweis University) (submittedVersion)
Funders: Deutsche Forschungsgemeinschaft
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords: Shank2, CHRNA7, intellectual disability, language impairment, synaptopathy, genetic epistasis, oligogenic inheritance, de novo translocation, copy number variation, 15q13.3, alpha7 nicotinic acetylcholine receptor, autism spectrum disorder, genetic modifiers, synaptic genes
MeSH terms: Epistasis, Genetic, Humans, Infant, Male, Intellectual Disability, Nerve Tissue Proteins, Phenotype, Translocation, Genetic, In Situ Hybridization, Fluorescence, Facies, Comparative Genomic Hybridization, Genetic Association Studies, DNA Copy Number Variations, alpha7 Nicotinic Acetylcholine Receptor

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Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci

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