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<p>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:<OrderedList> <ListItem> <ItemNumber>(1)</ItemNumber> <ItemContent> <p>41 had known abnormalities usually linked to complex NDD (e.g., del22q11.2);</p> </ItemContent> </ListItem> <ListItem> <ItemNumber>(2)</ItemNumber> <ItemContent> <p>16 had mutations associated with severe ASD/ID (e.g., <i>GRIA3</i> on Xq25);</p> </ItemContent> </ListItem> <ListItem> <ItemNumber>(3)</ItemNumber> <ItemContent> <p>11 showed novel abnormalities not previously linked to NDD (e.g., duplication Xq21.1 including <i>POU3F4</i>);</p> </ItemContent> </ListItem> <ListItem> <ItemNumber>(4)</ItemNumber> <ItemContent> <p>10 had variants of uncertain significance.</p> </ItemContent> </ListItem> </OrderedList> 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.</p>

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Genetic Abnormalities in Neurodevelopmental Disorders with Multidimensional Impairment

  • 期刊论文

  • 发表日期：

    2025年10月2日

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  • Cyril Hanin,
  • Paloma Torres,
  • Isabelle Millet,
  • Joana Matos,
  • Cora Cravero,
  • Marianna Giannitelli,
  • Anne-Sophie Pellen,
  • Hugues Pellerin,
  • Charline Grossard,
  • Ingrid Zammouri,
  • Astrid De Foucaud,
  • Claudine Laurent-Levinson,
  • David Cohen

摘要

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.