Adams-Oliver syndrome: genes and variants

Genes linked to Adams-Oliver syndrome

• NOTCH1: Neurogenic locus notch homolog protein 1

  Ligand-dependent cleavage releases an intracellular domain that directly controls transcriptional programs governing cell fate and differentiation. Pathogenic variants can cause congenital aortic-valve disease and left-sided heart defects, while activating or inactivating somatic changes contribute to several cancers.

  9 disease-causing and 1,311 uncertain variants in NOTCH1 are linked to Adams-Oliver syndrome.

• NOTCH3: Neurogenic locus notch homolog protein 3

  Its signaling helps maintain vascular smooth-muscle and mural-cell identity in small arteries. Pathogenic cysteine-altering variants cause CADASIL, with migraine, recurrent ischemic strokes, white-matter disease, and progressive cognitive impairment.

  1 disease-causing and 0 uncertain variants in NOTCH3 are linked to Adams-Oliver syndrome.

Where Adams-Oliver syndrome variants cluster

• NOTCH1 EGF-like 11 (positions 412–450): 3 of 9 disease-causing changes, 21.8× more than its size predicts.

Known disease-causing variants in Adams-Oliver syndrome

Which prediction tools work for Adams-Oliver syndrome

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

• CATVariant: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 88 out of 100

Same protein, different disease

• Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 is also caused by NOTCH3 variants; they fall mostly in different places as the Adams-Oliver syndrome variants (89 disease-causing).
• Lateral meningocele syndrome is also caused by NOTCH3 variants; they fall mostly in different places as the Adams-Oliver syndrome variants (12 disease-causing).
• Myofibromatosis, infantile, 2 is also caused by NOTCH3 variants; they fall mostly in different places as the Adams-Oliver syndrome variants (12 disease-causing).

Diseases related to Adams-Oliver syndrome

• Familial thoracic aortic aneurysm and aortic dissection, also linked to NOTCH1
• Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, also linked to NOTCH3
• Connective tissue disorder, also linked to NOTCH1
• Myofibromatosis, infantile, 2, also linked to NOTCH3
• Auditory neuropathy, also linked to NOTCH3
• Lateral meningocele syndrome, also linked to NOTCH3
• Aortic valve disease 2, also linked to NOTCH1
• Ischemic stroke, also linked to NOTCH3
• Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, also linked to NOTCH3

Frequently asked questions

Which genes are linked to Adams-Oliver syndrome?

In CATVariant, Adams-Oliver syndrome is linked to 2 analyzed proteins: NOTCH1 (Neurogenic locus notch homolog protein 1) and NOTCH3 (Neurogenic locus notch homolog protein 3).

How many genetic variants are linked to Adams-Oliver syndrome?

1,576 variants: 10 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,311 are of uncertain significance or have conflicting reports.

Which uncertain variants in Adams-Oliver 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 Adams-Oliver syndrome?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.88, based on 9 disease-causing and 330 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.

Download every variant as CSV · Browse all diseases · Methods · About the Center