Congenital heart defects and skeletal malformations syndrome: genes and variants

Genes linked to Congenital heart defects and skeletal malformations syndrome

• ABL1: Tyrosine-protein kinase ABL1

  It coordinates cytoskeletal remodeling, adhesion, DNA-damage responses, and growth signaling through tightly regulated tyrosine phosphorylation. Fusion with BCR removes normal control and creates the constitutively active kinase that drives chronic myeloid leukemia and subsets of acute lymphoblastic leukemia.

  14 disease-causing and 16 uncertain variants in ABL1 are linked to Congenital heart defects and skeletal malformations syndrome.

Known disease-causing variants in Congenital heart defects and skeletal malformations syndrome

Which prediction tools work for Congenital heart defects and skeletal malformations syndrome

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

• AlphaMissense: 96 out of 100
• CATVariant: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 81 out of 100
• MutPred2: 46 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Leukemia, Philadelphia chromosome-positive, resistant to imatinib is also caused by ABL1 variants; they fall partly in the same places as the Congenital heart defects and skeletal malformations syndrome variants (5 disease-causing).
• Chronic myeloid leukemia is also caused by ABL1 variants; they fall mostly in different places as the Congenital heart defects and skeletal malformations syndrome variants (3 disease-causing).

Diseases related to Congenital heart defects and skeletal malformations syndrome

• Gastrointestinal stromal tumor, also linked to ABL1
• Colorectal cancer, also linked to ABL1
• Microcephaly, also linked to ABL1
• Leukemia, Philadelphia chromosome-positive, resistant to imatinib, also linked to ABL1
• Lip and oral cavity carcinoma, also linked to ABL1
• Chronic myeloid leukemia, also linked to ABL1

Frequently asked questions

Which genes are linked to Congenital heart defects and skeletal malformations syndrome?

In CATVariant, Congenital heart defects and skeletal malformations syndrome is linked to 1 analyzed protein: ABL1 (Tyrosine-protein kinase ABL1).

How many genetic variants are linked to Congenital heart defects and skeletal malformations syndrome?

35 variants: 14 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 16 are of uncertain significance or have conflicting reports.

Which uncertain variants in Congenital heart defects and skeletal malformations 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 Congenital heart defects and skeletal malformations syndrome?

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 9 disease-causing and 11 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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