Genetic Abnormalities in Neurodevelopmental Disorders with Multidimensional Impairment.

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.