Table 7. Neural circuit-level endophenotypes in genetic NDDs.

Genetic mutation	Neuroimaging finding	Circuit dysfunction	Behavioral/phenotypic outcome
16p11.2 Del/Dup	Altered cortical thickness, white matter microstructure (diffusion tensor imaging changes)	Excitation/inhibition imbalance, altered functional connectivity	ASD, ID, macro/microcephaly
SCN2A loss-of-function	Reduced functional connectivity (default mode network)	Decreased sodium current → reduced neuronal excitability	ASD, ID without epilepsy
SCN2A gain-of-function	Regional hyperexcitability (fMRI/EEG)	Impaired inactivation → persistent sodium current → hypersynchrony	Early-infantile epileptic encephalopathy
CACNA1I gain-of-function	Thalamic hyperconnectivity, altered sleep spindles	Increased T-type calcium current → lower burst threshold in thalamic reticular nucleus	Absence seizures, ASD, sleep disturbances
22q11.2 Del	Cortical thinning (prefrontal, temporal), reduced gyrification	Dopamine dysregulation, altered prefrontal-thalamic connectivity	Schizophrenia, ID, psychosis (25–30% lifetime risk)
NRXN1 deletion (3' exons)	Reduced gray matter volume, altered white matter integrity	Synaptic adhesion defect → impaired synaptic transmission	ASD, ID, schizophrenia (variable penetrance)
MAPK8IP3 (missense)	Cerebellar and thalamic structural alterations	JNK signaling disruption → impaired neuronal migration and synaptic plasticity	Global developmental delay, ID, ASD, movement abnormalities
ADGRB3 (BAI3) biallelic duplication	Cerebellar atrophy, reduced cerebello-frontal connectivity	Synapse formation defect → disrupted cerebellar-frontal circuit development	ID, ataxia, behavioral disorder, cognitive impairment
ARF3, WDR45B, PPP1R21-related brainstem pathology	Brainstem structural abnormalities (Z-shaped morphology, hypoplasia), ventriculomegaly	Brainstem arousal system dysfunction → altered cortical maturation via experience-dependent plasticity	Global developmental delay, seizures, autonomic dysfunction, sleep disturbances

This table links specific genetic mutations associated with NDDs to intermediate phenotypes at the neural circuit level, as assessed by neuroimaging (structural/fMRI, diffusion tensor imaging, EEG) and electrophysiology. For each genetic lesion, the table provides: the observed neuroimaging or electrophysiological endophenotype, the proposed circuit-level dysfunction (e.g., excitation/inhibition imbalance, altered connectivity, channel biophysics), and the resulting behavioral or clinical outcome. These endophenotypes serve as bridges between genotype and clinical manifestation, and they are increasingly used for patient stratification and as surrogate endpoints in clinical trials. ASD, autism spectrum disorder; EEG, electroencephalography; fMRI, functional magnetic resonance imaging; ID, intellectual disability; NDD, neurodevelopmental disorder.