Genetic Abnormalities in Neurodevelopmental Disorders with Multidimensional Impairment

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.

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.

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.

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.