CHARGE syndrome: genes and variants

Genes linked to CHARGE syndrome

• CHD7: ATP-dependent chromatin remodeler CHD7

  It regulates chromatin accessibility and developmental gene programs across multiple embryonic tissues. Haploinsufficiency is the major cause of CHARGE syndrome, which can affect the eyes, heart, choanae, growth, genital development, ears, and nervous system.

  42 disease-causing and 1,114 uncertain variants in CHD7 are linked to CHARGE syndrome.

Where CHARGE syndrome variants cluster

• CHD7 Helicase C-terminal (positions 1294–1464): 7 of 42 disease-causing changes, 2.9× more than its size predicts.
• CHD7 Helicase ATP-binding (positions 980–1154): 7 of 42 disease-causing changes, 2.9× more than its size predicts.

Known disease-causing variants in CHARGE syndrome

Uncertain variants in CHARGE syndrome that look disease-causing

Which prediction tools work for CHARGE syndrome

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

• EVE: 96 out of 100
• AlphaMissense: 96 out of 100
• REVEL: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 93 out of 100
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 71 out of 100
• phyloP: 67 out of 100

Same protein, different disease

• CHD7-related CHARGE syndrome is also caused by CHD7 variants; they fall partly in the same places as the CHARGE syndrome variants (8 disease-causing).
• Hypogonadotropic hypogonadism 5 with or without anosmia is also caused by CHD7 variants; they fall partly in the same places as the CHARGE syndrome variants (7 disease-causing).

Diseases related to CHARGE syndrome

• Wiedemann-Steiner syndrome, also linked to CHD7
• CHD7-related CHARGE syndrome, also linked to CHD7
• Joubert syndrome, also linked to CHD7
• Hypogonadotropic hypogonadism 5 with or without anosmia, also linked to CHD7
• Hypogonadotropic hypogonadism, also linked to CHD7

Frequently asked questions

Which genes are linked to CHARGE syndrome?

In CATVariant, CHARGE syndrome is linked to 1 analyzed protein: CHD7 (ATP-dependent chromatin remodeler CHD7).

How many genetic variants are linked to CHARGE syndrome?

1,495 variants: 42 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,114 are of uncertain significance or have conflicting reports.

Which uncertain variants in CHARGE syndrome look disease-causing?

2 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example CHD7 R1345C and CHD7 N1030T. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for CHARGE syndrome?

Among tools not trained on clinical labels, EVE separates this disease's known disease-causing variants from harmless ones best (AUROC 0.96, based on 25 disease-causing and 16 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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