Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1: genes and variants

Genes linked to Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

• 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.

  89 disease-causing and 138 uncertain variants in NOTCH3 are linked to Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1.

Where Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 variants cluster

• NOTCH3 EGF-like 1 (positions 40–77): 12 of 89 disease-causing changes, 8.2× more than its size predicts.
• NOTCH3 EGF-like 4 (positions 158–195): 11 of 89 disease-causing changes, 7.5× more than its size predicts.
• NOTCH3 EGF-like 3 (positions 119–156): 10 of 89 disease-causing changes, 6.9× more than its size predicts.
• NOTCH3 EGF-like 13 (positions 507–543): 6 of 89 disease-causing changes, 4.2× more than its size predicts.
• NOTCH3 EGF-like 5 (positions 197–234): 6 of 89 disease-causing changes, 4.1× more than its size predicts.

Known disease-causing variants in Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Showing 60 of 89.

Uncertain variants in Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 that look disease-causing

Which prediction tools work for Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

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

• MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 82 out of 100
• SIFT: 79 out of 100
• phyloP: 61 out of 100

Same protein, different disease

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

Diseases related to Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

• Myofibromatosis, infantile, 2, also linked to NOTCH3
• Auditory neuropathy, also linked to NOTCH3
• Lateral meningocele syndrome, also linked to NOTCH3
• Adams-Oliver syndrome, also linked to NOTCH3
• 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 Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1?

In CATVariant, Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 is linked to 1 analyzed protein: NOTCH3 (Neurogenic locus notch homolog protein 3).

How many genetic variants are linked to Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1?

300 variants: 89 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 138 are of uncertain significance or have conflicting reports.

Which uncertain variants in Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example NOTCH3 C597S. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.82, based on 36 disease-causing and 84 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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