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. 2025 Oct 2;75(4):135.
doi: 10.1007/s12031-025-02424-6.

Genetic Abnormalities in Neurodevelopmental Disorders with Multidimensional Impairment

Cyril Hanin  1   2   3 , Paloma Torres  1   2 , Isabelle Millet  1   2 , Joana Matos  1 , Cora Cravero  1   2   3 , Marianna Giannitelli  1   2 , Anne-Sophie Pellen  1   2   3 , Hugues Pellerin  1 , Charline Grossard  1 , Ingrid Zammouri  1   3 , Astrid De Foucaud  1   3 , Claudine Laurent-Levinson  1   2   3 , David Cohen  4   5   6   7
Affiliations

Genetic Abnormalities in Neurodevelopmental Disorders with Multidimensional Impairment

Cyril Hanin et al. J Mol Neurosci. .

Abstract

Objectives: Many children with neurodevelopmental disorders (NDD) show complex, multidimensional impairments meeting criteria for multiple NDD, yet remain "diagnostically homeless" as DSM-5 lacks a Multidimensional Impairment (MDI) category. We investigated the prevalence of genetic abnormalities in such complex NDD cases.

Methods: Between 2017 and 2019, we diagnosed MDI in 666 patients. Among them, 122 (18%) underwent genetic assessment (DNA microarrays, karyotype, gene panels, FISH, FMR1 testing, exome/genome sequencing). We used univariate analyses and clustering to explore associations between clinical dimensions and genetic findings.

Results: Genetic abnormalities were identified in 78 patients. Of these: (1) 41 had known abnormalities usually linked to complex NDD (e.g., del22q11.2); (2) 16 had mutations associated with severe ASD/ID (e.g., GRIA3 on Xq25); (3) 11 showed novel abnormalities not previously linked to NDD (e.g., duplication Xq21.1 including POU3F4); (4) 10 had variants of uncertain significance. Depending on classification, prevalence ranged from 47% (57/122, definite or predisposition) to 64% (78/122, including uncertain/possible pathogenic variants). Neither clinical dimensions nor severity clusters were associated with the presence of genetic abnormalities.

Conclusion: Despite a referral bias toward severe cases, the high rate of genetic findings in this cohort underscores the need for more systematic genetic testing in complex NDD with multidimensional impairment.

Keywords: Copy number variations; Genome sequencing; Neurodevelopmental disorders; Phenotype; Psychometrics.

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Conflict of interest statement

Declarations. Competing Interests: The authors declare no competing interests.

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