Wiedemann-Steiner syndrome: genes and variants

Genes linked to Wiedemann-Steiner syndrome

• KMT2A: Histone-lysine N-methyltransferase 2A

  It maintains transcription of developmental and hematopoietic genes through chromatin-regulatory complexes and H3K4 methylation. Rearrangements create potent fusion oncoproteins that drive acute leukemias, while germline loss-of-function variants cause Wiedemann-Steiner syndrome.

  25 disease-causing and 105 uncertain variants in KMT2A are linked to Wiedemann-Steiner 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.

  1 disease-causing and 0 uncertain variants in CHD7 are linked to Wiedemann-Steiner syndrome.

Where Wiedemann-Steiner syndrome variants cluster

• KMT2A CXXC-type (positions 1147–1195): 10 of 25 disease-causing changes, 32.4× more than its size predicts.
• KMT2A PHD-type 1 (positions 1431–1482): 4 of 25 disease-causing changes, 12.2× more than its size predicts.

Known disease-causing variants in Wiedemann-Steiner syndrome

Which prediction tools work for Wiedemann-Steiner syndrome

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

• AlphaMissense: 97 out of 100
• PolyPhen-2: 96 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)
• EVE: 94 out of 100
• MetaLR: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 76 out of 100

Same protein, different disease

• CHARGE syndrome is also caused by CHD7 variants; they fall mostly in different places as the Wiedemann-Steiner syndrome variants (42 disease-causing).
• CHD7-related CHARGE syndrome is also caused by CHD7 variants; they fall mostly in different places as the Wiedemann-Steiner syndrome variants (8 disease-causing).
• Hypogonadotropic hypogonadism 5 with or without anosmia is also caused by CHD7 variants; they fall mostly in different places as the Wiedemann-Steiner syndrome variants (7 disease-causing).

Diseases related to Wiedemann-Steiner syndrome

• CHARGE 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 Wiedemann-Steiner syndrome?

In CATVariant, Wiedemann-Steiner syndrome is linked to 2 analyzed proteins: KMT2A (Histone-lysine N-methyltransferase 2A) and CHD7 (ATP-dependent chromatin remodeler CHD7).

How many genetic variants are linked to Wiedemann-Steiner syndrome?

190 variants: 26 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 105 are of uncertain significance or have conflicting reports.

Which uncertain variants in Wiedemann-Steiner 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 Wiedemann-Steiner syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.97, based on 21 disease-causing and 105 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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