Coffin-Siris syndrome: genes and variants

Genes linked to Coffin-Siris syndrome

• ARID1B: AT-rich interactive domain-containing protein 1B

  It helps SWI/SNF chromatin-remodeling complexes regulate access to developmental gene programs, especially in the nervous system. Haploinsufficiency is a major cause of Coffin-Siris syndrome and related neurodevelopmental disorders.

  9 disease-causing and 112 uncertain variants in ARID1B are linked to Coffin-Siris syndrome.

• SMARCE1: SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1

  It helps SWI/SNF chromatin-remodeling complexes interact with nucleosomes and transcriptional regulators. Germline loss-of-function variants predispose to clear-cell meningiomas, often presenting at young ages or at multiple sites.

  3 disease-causing and 15 uncertain variants in SMARCE1 are linked to Coffin-Siris syndrome.

• SMARCB1: SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1

  Within SWI/SNF complexes, it constrains oncogenic transcription and supports normal chromatin regulation. Biallelic tumor-cell inactivation is characteristic of malignant rhabdoid tumors, while germline variants predispose to rhabdoid tumors or schwannomatosis.

  2 disease-causing and 0 uncertain variants in SMARCB1 are linked to Coffin-Siris syndrome.

• ARID2: AT-rich interactive domain-containing protein 2

  It contributes DNA targeting and regulatory specificity to PBAF chromatin-remodeling complexes. Somatic loss-of-function alterations occur in melanoma, liver cancer, and other tumors, while germline variants can cause a Coffin-Siris-spectrum neurodevelopmental disorder.

  1 disease-causing and 43 uncertain variants in ARID2 are linked to Coffin-Siris syndrome.

• ARID1A: AT-rich interactive domain-containing protein 1A

  It helps BAF chromatin-remodeling complexes open or reposition nucleosomes at regulatory regions and thereby control lineage-specific transcription. Somatic loss is frequent in several cancers, while germline haploinsufficiency can cause Coffin-Siris syndrome.

  1 disease-causing and 9 uncertain variants in ARID1A are linked to Coffin-Siris syndrome.

• SMARCA4: SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4

  Its ATPase activity drives nucleosome remodeling in BAF-family complexes and thereby controls access to regulatory DNA. Germline pathogenic variants cause Coffin-Siris syndrome or rhabdoid-tumor predisposition, while somatic loss defines several aggressive cancers.

  0 disease-causing and 2 uncertain variants in SMARCA4 are linked to Coffin-Siris syndrome.

Weakly linked (only a few uncertain records): SMARCA2.

Known disease-causing variants in Coffin-Siris syndrome

Which prediction tools work for Coffin-Siris syndrome

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

• AlphaMissense: 99 out of 100
• MutPred2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 82 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 81 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 72 out of 100

Same protein, different disease

• Familial meningioma is also caused by SMARCE1 variants; they fall mostly in different places as the Coffin-Siris syndrome variants (4 disease-causing).

Diseases related to Coffin-Siris syndrome

• Rhabdoid tumor predisposition syndrome 2, also linked to SMARCA4 and SMARCB1
• Lung adenocarcinoma, also linked to ARID1A and SMARCA4
• Hepatocellular carcinoma, also linked to ARID1A and ARID2
• Colorectal cancer, also linked to ARID1A
• Non-small cell lung carcinoma, also linked to SMARCA4
• Familial meningioma, also linked to SMARCE1
• NK-cell enteropathy, also linked to SMARCB1
• SMARCA4-related BAFopathy, also linked to SMARCA4
• Medulloblastoma, also linked to SMARCA4
• Melanoma, also linked to ARID2
• Marfanoid habitus and intellectual disability, also linked to ARID1B
• ARID1A-related BAFopathy, also linked to ARID1A

Frequently asked questions

Which genes are linked to Coffin-Siris syndrome?

In CATVariant, Coffin-Siris syndrome is linked to 6 analyzed proteins: ARID1B (AT-rich interactive domain-containing protein 1B), SMARCE1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1), SMARCB1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1), ARID2 (AT-rich interactive domain-containing protein 2), ARID1A (AT-rich interactive domain-containing protein 1A) and SMARCA4 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4).

How many genetic variants are linked to Coffin-Siris syndrome?

305 variants: 16 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 182 are of uncertain significance or have conflicting reports.

Which uncertain variants in Coffin-Siris syndrome 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 Coffin-Siris syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.99, based on 9 disease-causing and 185 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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