Protein-truncating variants and deletions of SHANK2 are associated with autism spectrum disorder and other neurodevelopmental concerns
Abstract Background SHANK2 disorder is a rare neurodevelopmental disorder caused by a deletion or pathogenic sequence variant of the SHANK2 gene and is associated with autism spectrum disorder (ASD), intellectual disability (ID), and developmental delay. To date, research in SHANK2 has focused on la...
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BMC
2025-04-01
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| Series: | Journal of Neurodevelopmental Disorders |
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| Online Access: | https://doi.org/10.1186/s11689-025-09600-0 |
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| author | Hailey Silver Rori Greenberg Paige M. Siper Jessica Zweifach Renee Soufer Mustafa Sahin Elizabeth Berry-Kravis Latha Valluripalli Soorya Audrey Thurm Jonathan A. Bernstein Alexander Kolevzon Dorothy E. Grice Joseph D. Buxbaum Tess Levy |
| author_facet | Hailey Silver Rori Greenberg Paige M. Siper Jessica Zweifach Renee Soufer Mustafa Sahin Elizabeth Berry-Kravis Latha Valluripalli Soorya Audrey Thurm Jonathan A. Bernstein Alexander Kolevzon Dorothy E. Grice Joseph D. Buxbaum Tess Levy |
| author_sort | Hailey Silver |
| collection | DOAJ |
| description | Abstract Background SHANK2 disorder is a rare neurodevelopmental disorder caused by a deletion or pathogenic sequence variant of the SHANK2 gene and is associated with autism spectrum disorder (ASD), intellectual disability (ID), and developmental delay. To date, research in SHANK2 has focused on laboratory-based in vivo and in vitro studies with few prospective clinical studies in humans. Methods A remote assessment battery was comprised of caregiver interviews with a psychiatrist, psychologists, and a genetic counselor, caregiver-reports, and review of records. Results from this cohort were reported using descriptive statistics. An age-matched sample of participants with SHANK3 haploinsufficiency (Phelan-McDermid syndrome, PMS) was used to compare adaptive behavior between the two groups. Results All ten participants demonstrated delays in adaptive behavior, with most motor skills preserved and a weakness in communication. According to parent report, 90% of participants carried a formal diagnosis of ASD, 50% of participants carried a diagnosis of attention-deficit/hyperactivity disorder (ADHD), and mild-to-moderate developmental delays were noted. Sensory hyperreactivity and seeking behaviors were more pronounced than sensory hyporeactivity. Medical features included hypotonia, recurrent ear infections, and gastrointestinal abnormalities. No similar facial dysmorphic features were observed. Compared to PMS participants, individuals with SHANK2 disorder had significantly higher adaptive functioning. Conclusions Consistent with previous studies of SHANK2 disorder, these results indicate mild to moderate developmental impairment. Overall, SHANK2 disorder is associated with developmental and adaptive functioning delays, high rates of autism, including sensory symptoms and repetitive behaviors, and ADHD. This study was limited by its remote nature, diverse age range, and the homogeneous racial and ethnic sample. Future studies should examine larger, diverse cohorts, add cognitive testing, capture longitudinal data, and include in-person assessments. |
| format | Article |
| id | doaj-art-e1896779290a464e92a10a7763f793a6 |
| institution | OA Journals |
| issn | 1866-1955 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neurodevelopmental Disorders |
| spelling | doaj-art-e1896779290a464e92a10a7763f793a62025-08-20T02:11:09ZengBMCJournal of Neurodevelopmental Disorders1866-19552025-04-0117111210.1186/s11689-025-09600-0Protein-truncating variants and deletions of SHANK2 are associated with autism spectrum disorder and other neurodevelopmental concernsHailey Silver0Rori Greenberg1Paige M. Siper2Jessica Zweifach3Renee Soufer4Mustafa Sahin5Elizabeth Berry-Kravis6Latha Valluripalli Soorya7Audrey Thurm8Jonathan A. Bernstein9Alexander Kolevzon10Dorothy E. Grice11Joseph D. Buxbaum12Tess Levy13Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount SinaiSeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount SinaiSeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount SinaiSeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount SinaiSeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount SinaiDepartment of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical SchoolDevelopmental Synaptopathies Consortium, Rare Disease Clinical Research NetworkDevelopmental Synaptopathies Consortium, Rare Disease Clinical Research NetworkDevelopmental Synaptopathies Consortium, Rare Disease Clinical Research NetworkDevelopmental Synaptopathies Consortium, Rare Disease Clinical Research NetworkSeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount SinaiSeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount SinaiSeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount SinaiSeaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount SinaiAbstract Background SHANK2 disorder is a rare neurodevelopmental disorder caused by a deletion or pathogenic sequence variant of the SHANK2 gene and is associated with autism spectrum disorder (ASD), intellectual disability (ID), and developmental delay. To date, research in SHANK2 has focused on laboratory-based in vivo and in vitro studies with few prospective clinical studies in humans. Methods A remote assessment battery was comprised of caregiver interviews with a psychiatrist, psychologists, and a genetic counselor, caregiver-reports, and review of records. Results from this cohort were reported using descriptive statistics. An age-matched sample of participants with SHANK3 haploinsufficiency (Phelan-McDermid syndrome, PMS) was used to compare adaptive behavior between the two groups. Results All ten participants demonstrated delays in adaptive behavior, with most motor skills preserved and a weakness in communication. According to parent report, 90% of participants carried a formal diagnosis of ASD, 50% of participants carried a diagnosis of attention-deficit/hyperactivity disorder (ADHD), and mild-to-moderate developmental delays were noted. Sensory hyperreactivity and seeking behaviors were more pronounced than sensory hyporeactivity. Medical features included hypotonia, recurrent ear infections, and gastrointestinal abnormalities. No similar facial dysmorphic features were observed. Compared to PMS participants, individuals with SHANK2 disorder had significantly higher adaptive functioning. Conclusions Consistent with previous studies of SHANK2 disorder, these results indicate mild to moderate developmental impairment. Overall, SHANK2 disorder is associated with developmental and adaptive functioning delays, high rates of autism, including sensory symptoms and repetitive behaviors, and ADHD. This study was limited by its remote nature, diverse age range, and the homogeneous racial and ethnic sample. Future studies should examine larger, diverse cohorts, add cognitive testing, capture longitudinal data, and include in-person assessments.https://doi.org/10.1186/s11689-025-09600-0SHANK2Autism spectrum disorderDevelopmental delayIntellectual and developmental disabilityPhenotype |
| spellingShingle | Hailey Silver Rori Greenberg Paige M. Siper Jessica Zweifach Renee Soufer Mustafa Sahin Elizabeth Berry-Kravis Latha Valluripalli Soorya Audrey Thurm Jonathan A. Bernstein Alexander Kolevzon Dorothy E. Grice Joseph D. Buxbaum Tess Levy Protein-truncating variants and deletions of SHANK2 are associated with autism spectrum disorder and other neurodevelopmental concerns Journal of Neurodevelopmental Disorders SHANK2 Autism spectrum disorder Developmental delay Intellectual and developmental disability Phenotype |
| title | Protein-truncating variants and deletions of SHANK2 are associated with autism spectrum disorder and other neurodevelopmental concerns |
| title_full | Protein-truncating variants and deletions of SHANK2 are associated with autism spectrum disorder and other neurodevelopmental concerns |
| title_fullStr | Protein-truncating variants and deletions of SHANK2 are associated with autism spectrum disorder and other neurodevelopmental concerns |
| title_full_unstemmed | Protein-truncating variants and deletions of SHANK2 are associated with autism spectrum disorder and other neurodevelopmental concerns |
| title_short | Protein-truncating variants and deletions of SHANK2 are associated with autism spectrum disorder and other neurodevelopmental concerns |
| title_sort | protein truncating variants and deletions of shank2 are associated with autism spectrum disorder and other neurodevelopmental concerns |
| topic | SHANK2 Autism spectrum disorder Developmental delay Intellectual and developmental disability Phenotype |
| url | https://doi.org/10.1186/s11689-025-09600-0 |
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