Complex neurodevelopmental disorder: genes and variants

Genes linked to Complex neurodevelopmental disorder

• SCN2A: Sodium channel protein type 2 subunit alpha

  The protein forms Nav1.2, a voltage-gated sodium channel that carries sodium current during neuronal action potentials. By shaping neuronal excitability and signal propagation, it supports brain circuits involved in development, learning, and seizure susceptibility.

  22 disease-causing and 10 uncertain variants in SCN2A are linked to Complex neurodevelopmental disorder.

• SCN8A: Sodium channel protein type 8 subunit alpha

  The protein forms Nav1.6, a voltage-gated sodium channel that sets the threshold and propagation of neuronal action potentials. It is widely important for neuronal excitability, and SCN8A variants are associated with developmental and epileptic encephalopathies.

  8 disease-causing and 1 uncertain variants in SCN8A are linked to Complex neurodevelopmental disorder.

• GRIN2B: Glutamate receptor ionotropic, NMDA 2B

  It confers distinct developmental and signaling properties on NMDA receptors and is highly expressed during early brain development. De novo pathogenic variants can cause intellectual disability, developmental delay, epilepsy, abnormal movements, and autism-related phenotypes.

  5 disease-causing and 1 uncertain variants in GRIN2B are linked to Complex neurodevelopmental disorder.

• KCNA2: Potassium voltage-gated channel subfamily A member 2

  Its current helps repolarize neuronal membranes and regulate action-potential firing and neurotransmitter release. Both loss- and gain-of-function variants can cause developmental and epileptic encephalopathy, often with ataxia, movement abnormalities, or intellectual disability.

  2 disease-causing and 0 uncertain variants in KCNA2 are linked to Complex neurodevelopmental disorder.

• CHD2: ATP-dependent chromatin remodeler CHD2

  It remodels chromatin to regulate transcription and is particularly important for neuronal development and activity-dependent gene expression. Haploinsufficiency commonly causes developmental and epileptic encephalopathy, often with photosensitive seizures and intellectual disability.

  1 disease-causing and 1 uncertain variants in CHD2 are linked to Complex neurodevelopmental disorder.

• DYRK1A: Dual specificity tyrosine-phosphorylation-regulated kinase 1A

  It phosphorylates numerous transcriptional, synaptic, and cell-cycle targets during brain development and is highly dosage sensitive. Haploinsufficiency causes DYRK1A syndrome, typically with microcephaly, developmental delay, intellectual disability, and frequent seizures or autism-related features.

  0 disease-causing and 0 uncertain variants in DYRK1A are linked to Complex neurodevelopmental disorder.

• SYNGAP1: Ras/Rap GTPase-activating protein SynGAP

  It restrains RAS-family signaling at excitatory synapses and is critical for activity-dependent synaptic maturation and plasticity. Haploinsufficiency causes SYNGAP1-related neurodevelopmental disorder, typically with intellectual disability, generalized epilepsy, behavioral abnormalities, and severe speech impairment.

  0 disease-causing and 0 uncertain variants in SYNGAP1 are linked to Complex neurodevelopmental disorder.

• ANK2: Ankyrin-2

  It organizes membrane proteins and ion-handling complexes by linking them to the cytoskeleton, with especially important roles in cardiomyocytes and neurons. Pathogenic variants can disrupt cardiac electrical organization and cause ankyrin-B syndrome, including sinus-node dysfunction, arrhythmias, and variable QT abnormalities.

  0 disease-causing and 5 uncertain variants in ANK2 are linked to Complex neurodevelopmental disorder.

• SHANK2: SH3 and multiple ankyrin repeat domains protein 2

  It scaffolds receptors, signaling proteins, and actin-regulatory complexes within excitatory postsynaptic densities. Haploinsufficiency and disruptive variants can contribute to neurodevelopmental disorders, including intellectual disability and autism spectrum phenotypes.

  0 disease-causing and 1 uncertain variants in SHANK2 are linked to Complex neurodevelopmental disorder.

• CHD8: ATP-dependent chromatin remodeler CHD8

  It remodels chromatin at neurodevelopmental and cell-cycle regulatory genes and influences expression of many autism-associated pathways. Haploinsufficiency causes a neurodevelopmental syndrome frequently marked by autism-related features, developmental delay, and macrocephaly.

  0 disease-causing and 5 uncertain variants in CHD8 are linked to Complex neurodevelopmental disorder.

• CHAMP1: Chromosome alignment-maintaining phosphoprotein 1

  A chromosome-segregation protein that helps align chromosomes at metaphase and maintain their attachment to spindle microtubules. Its work at the kinetochore helps cells distribute genetic material accurately during mitosis.

  0 disease-causing and 3 uncertain variants in CHAMP1 are linked to Complex neurodevelopmental disorder.

Weakly linked (only a few uncertain records): GRIN2A, CUL3, KMT2E, NRXN1, SCN1A and SHANK1.

Where Complex neurodevelopmental disorder variants cluster

• SCN8A S4 of repeat II (positions 840–857): 3 of 8 disease-causing changes, 41.2× more than its size predicts.
• SCN2A S3 of repeat IV (positions 1593–1610): 3 of 22 disease-causing changes, 15.2× more than its size predicts.
• SCN2A II (positions 741–1013): 5 of 22 disease-causing changes, 1.7× more than its size predicts.
• GRIN2B Extracellular (positions 27–555): 3 of 5 disease-causing changes, 1.7× more than its size predicts.

Known disease-causing variants in Complex neurodevelopmental disorder

Which prediction tools work for Complex neurodevelopmental disorder

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• AlphaMissense: 96 out of 100
• CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• ESM1b (LLR): 94 out of 100
• MetaLR: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 90 out of 100
• SIFT: 89 out of 100
• PolyPhen-2: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 77 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Seizures, benign familial infantile, 3 is also caused by SCN2A variants; they fall mostly in different places as the Complex neurodevelopmental disorder variants (167 disease-causing).
• Episodic ataxia type 2 is also caused by SCN2A variants; they fall mostly in different places as the Complex neurodevelopmental disorder variants (15 disease-causing).
• West syndrome is also caused by SCN2A variants; they fall mostly in different places as the Complex neurodevelopmental disorder variants (11 disease-causing).
• Benign familial infantile epilepsy is also caused by SCN2A variants; they fall mostly in different places as the Complex neurodevelopmental disorder variants (6 disease-causing).
• Infantile spasms is also caused by SCN2A variants; they fall mostly in different places as the Complex neurodevelopmental disorder variants (3 disease-causing).
• Early-infantile DEE is also caused by SCN8A variants; they fall mostly in different places as the Complex neurodevelopmental disorder variants (90 disease-causing).
• Cognitive impairment with or without cerebellar ataxia is also caused by SCN8A variants; they fall mostly in different places as the Complex neurodevelopmental disorder variants (22 disease-causing).
• Seizures, benign familial infantile, 3 is also caused by SCN8A variants; they fall mostly in different places as the Complex neurodevelopmental disorder variants (12 disease-causing).
• Autosomal recessive inheritance is also caused by SCN8A variants; they fall mostly in different places as the Complex neurodevelopmental disorder variants (3 disease-causing).
• Myoclonus, familial, 2 is also caused by SCN8A variants; they fall mostly in different places as the Complex neurodevelopmental disorder variants (3 disease-causing).

Diseases related to Complex neurodevelopmental disorder

• Cardiac arrhythmia, also linked to ANK2, SCN2A and SCN8A
• Epilepsy, also linked to GRIN2B, SCN2A and SCN8A
• Infantile spasms, also linked to GRIN2B, SCN2A and SCN8A
• Genetic developmental and epileptic encephalopathy, also linked to KCNA2, SCN2A and SCN8A
• Seizures, benign familial infantile, 3, also linked to SCN2A and SCN8A
• Amyotrophic lateral sclerosis, also linked to SCN2A and SCN8A
• Autism, also linked to CHD8 and SHANK2
• Self-limited epilepsy with centrotemporal spikes, also linked to CHD2 and SCN2A
• Lennox-Gastaut syndrome, also linked to SCN2A and SCN8A
• Undetermined early-onset epileptic encephalopathy, also linked to KCNA2 and SCN8A
• Early-infantile DEE, also linked to SCN8A
• Long QT syndrome, also linked to ANK2

Frequently asked questions

Which genes are linked to Complex neurodevelopmental disorder?

In CATVariant, Complex neurodevelopmental disorder is linked to 11 analyzed proteins: SCN2A (Sodium channel protein type 2 subunit alpha), SCN8A (Sodium channel protein type 8 subunit alpha), GRIN2B (Glutamate receptor ionotropic, NMDA 2B), KCNA2 (Potassium voltage-gated channel subfamily A member 2), CHD2 (ATP-dependent chromatin remodeler CHD2), DYRK1A (Dual specificity tyrosine-phosphorylation-regulated kinase 1A) and 5 more.

How many genetic variants are linked to Complex neurodevelopmental disorder?

105 variants: 38 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 34 are of uncertain significance or have conflicting reports.

Which uncertain variants in Complex neurodevelopmental disorder look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Complex neurodevelopmental disorder?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.96, based on 37 disease-causing and 277 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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