Autism: genes and variants

Genes linked to Autism

• NLGN3: Neuroligin-3

  It organizes postsynaptic adhesion and helps align synaptic signaling machinery with presynaptic release sites. Rare pathogenic variants can cause neurodevelopmental disorders with autism-related features and intellectual disability, although phenotype and penetrance vary.

  5 disease-causing and 7 uncertain variants in NLGN3 are linked to Autism.

• MECP2: Methyl-CpG-binding protein 2

  It interprets DNA methylation and organizes transcriptional and chromatin states that are especially important in mature neurons. Loss-of-function variants cause Rett syndrome, whereas increased dosage causes MECP2 duplication syndrome.

  1 disease-causing and 5 uncertain variants in MECP2 are linked to Autism.

• 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 0 uncertain variants in CHD8 are linked to Autism.

• DRD2: D(2) dopamine receptor

  Its activation by dopamine modulates cyclic-AMP signaling and neuronal excitability in circuits governing movement, motivation, reward, and endocrine control. It is a major pharmacologic target of antipsychotic drugs and dopamine agonists, and rare variants can produce movement or neuropsychiatric phenotypes.

  0 disease-causing and 0 uncertain variants in DRD2 are linked to Autism.

• HTR2A: 5-hydroxytryptamine receptor 2A

  Its activation by serotonin engages Gq signaling in cortical, vascular, and other tissues and influences perception, mood, cognition, and smooth-muscle responses. It is a major target of many antipsychotic drugs and psychedelic compounds, while common genetic effects on behavior are generally modest.

  0 disease-causing and 0 uncertain variants in HTR2A are linked to Autism.

• HTR2C: 5-hydroxytryptamine receptor 2C

  Its serotonin-dependent signaling in hypothalamic and limbic circuits suppresses appetite and modulates mood, reward, and neuroendocrine function. Altered signaling can affect body weight and psychiatric drug responses, and the receptor is a pharmacologic target of several neuropsychiatric agents.

  0 disease-causing and 0 uncertain variants in HTR2C are linked to Autism.

• SHANK1: SH3 and multiple ankyrin repeat domains protein 1

  It organizes postsynaptic protein networks at excitatory synapses and links glutamate receptors to signaling and cytoskeletal machinery. Rare disruptive variants have been associated with neurodevelopmental and psychiatric phenotypes, although penetrance and causal evidence vary.

  0 disease-causing and 0 uncertain variants in SHANK1 are linked to Autism.

• 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.

  1 disease-causing and 18 uncertain variants in SHANK2 are linked to Autism.

• CDKL5: Cyclin-dependent kinase-like 5

  It phosphorylates neuronal substrates involved in synapse development, cytoskeletal organization, and signaling during early brain maturation. Loss-of-function variants cause CDKL5 deficiency disorder with very early epilepsy and severe developmental impairment.

  1 disease-causing and 0 uncertain variants in CDKL5 are linked to Autism.

• CNTNAP2: Contactin-associated protein-like 2

  It organizes specialized neuronal membrane domains and contributes to axonal development, synaptic connectivity, and clustering of potassium channels at juxtaparanodes. Biallelic loss-of-function variants can cause severe neurodevelopmental disease with epilepsy and language impairment, while heterozygous associations are more complex.

  0 disease-causing and 36 uncertain variants in CNTNAP2 are linked to Autism.

• NLGN4X: Neuroligin-4, X-linked

  It contributes to synaptic adhesion and maturation, particularly in excitatory and inhibitory neural circuits. Rare X-linked loss-of-function variants have been associated with autism and intellectual disability, but variant interpretation requires care because penetrance is variable.

  0 disease-causing and 16 uncertain variants in NLGN4X are linked to Autism.

Weakly linked (only a few uncertain records): ADNP, GRIN1, LAMB3 and NRXN2.

Known disease-causing variants in Autism

Same protein, different disease

• Angelman syndrome-like is also caused by CDKL5 variants; they fall mostly in different places as the Autism variants (41 disease-causing).
• CDKL5 disorder is also caused by CDKL5 variants; they fall mostly in different places as the Autism variants (32 disease-causing).
• Rett syndrome is also caused by MECP2 variants; they fall mostly in different places as the Autism variants (88 disease-causing).
• Severe neonatal-onset encephalopathy with microcephaly is also caused by MECP2 variants; they fall mostly in different places as the Autism variants (29 disease-causing).
• X-linked intellectual disability-psychosis-macroorchidism syndrome is also caused by MECP2 variants; they fall mostly in different places as the Autism variants (4 disease-causing).

Diseases related to Autism

• Schizophrenia, also linked to DRD2, HTR2A and HTR2C
• Parkinson disease, also linked to DRD2, HTR2A and HTR2C
• Rett syndrome, also linked to CDKL5 and MECP2
• Complex neurodevelopmental disorder, also linked to CHD8 and SHANK2
• Angelman syndrome, also linked to CDKL5 and MECP2
• Angelman syndrome-like, also linked to CDKL5
• CDKL5 disorder, also linked to CDKL5
• Severe neonatal-onset encephalopathy with microcephaly, also linked to MECP2
• Intellectual developmental disorder with autism and macrocephaly, also linked to CHD8
• Self-limited epilepsy with centrotemporal spikes, also linked to CNTNAP2
• Paediatric disorders, also linked to CHD8
• Focal epilepsy, also linked to MECP2

Frequently asked questions

Which genes are linked to Autism?

In CATVariant, Autism is linked to 11 analyzed proteins: NLGN3 (Neuroligin-3), MECP2 (Methyl-CpG-binding protein 2), CHD8 (ATP-dependent chromatin remodeler CHD8), DRD2 (D(2) dopamine receptor), HTR2A (5-hydroxytryptamine receptor 2A), HTR2C (5-hydroxytryptamine receptor 2C) and 5 more.

How many genetic variants are linked to Autism?

99 variants: 8 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 85 are of uncertain significance or have conflicting reports.

Which uncertain variants in Autism look disease-causing?

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

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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