Hereditary cerebrovascular disease is dominated by a small set of well-characterized monogenic syndromes: CADASIL (the most common), CARASIL, COL4A1/A2-related small vessel disease, hereditary cavernous malformations, hereditary hemorrhagic telangiectasia (HHT), familial moyamoya, and Fabry disease (an important treatable cause of young stroke). This page covers the highest-yield first-line test for each — and importantly, when to escalate to a small-vessel disease panel or WES. Clinical syndrome detail is in the Stroke clinical chapter; here, the focus is on the lab side.

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)

• First-line test: NOTCH3 full-gene sequencing.
• Focus on exons 2–24 — virtually all CADASIL-causing variants are cysteine-altering missense (adding or removing a cysteine within the EGF-like repeat domains).
• Yield: ~85–95% in classical CADASIL (recurrent subcortical infarcts + migraine + cognitive decline + leukoencephalopathy + family history).
• If negative or VUS in classical phenotype: skin biopsy for granular osmiophilic material (GOM) on electron microscopy — diagnostic if positive.
• Imaging clues that increase pre-test probability: anterior temporal pole white matter involvement (very specific), external capsule involvement, lacunar infarcts in basal ganglia and centrum semiovale.
• Cascade family testing is straightforward once the variant is identified.

CARASIL (Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)

• First-line test: HTRA1 sequencing.
• Inheritance: biallelic recessive variants cause classical CARASIL — early adult onset (20s–40s) of progressive cognitive decline + stroke + alopecia + spondylosis.
• Heterozygous HTRA1 variants: now recognized to cause autosomal-dominant adult-onset small vessel disease with later onset than CARASIL — order HTRA1 in CADASIL-negative small vessel disease.
• Geography: classically described in Japanese and Asian populations but now reported worldwide.

COL4A1 / COL4A2-Related Small Vessel Disease

• First-line test: COL4A1 + COL4A2 sequencing.
• Phenotype spectrum: porencephaly (in utero stroke), perinatal hemorrhage, sporadic adult ischemic stroke, leukoencephalopathy, retinal arteriolar tortuosity, intracranial aneurysms, Axenfeld-Rieger anomaly, HANAC syndrome (hereditary angiopathy with nephropathy, aneurysms, and cramps).
• When to test: small vessel disease with retinal arteriolar tortuosity, porencephalic cysts, intracranial aneurysms, or multi-system involvement.

Familial Cerebral Cavernous Malformations (CCM)

• First-line test: CCM NGS panel — KRIT1 (CCM1, most common), CCM2, PDCD10 (CCM3) — sequencing + del/dup.
• When to test: multiple cavernous malformations on MRI; family history of CCM; CCM in a young patient.
• Hispanic founder mutation: KRIT1 Q455X common in Hispanic populations of New Mexico ancestry — consider targeted testing.

Hereditary Hemorrhagic Telangiectasia (HHT / Osler-Weber-Rendu)

• First-line test: HHT NGS panel — ENG, ACVRL1, SMAD4, GDF2 — sequencing + del/dup.
• When to test: classical HHT triad (epistaxis + telangiectasias + family history); cerebral or pulmonary AVMs; high-output heart failure from AVMs.
• Neurologic relevance: cerebral AVMs (10–20% of HHT patients), paradoxical embolism via pulmonary AVMs (cause of cryptogenic stroke).
• SMAD4: HHT + juvenile polyposis overlap syndrome; surveillance for both.

Familial Moyamoya

• First-line test: RNF213 sequencing — especially East Asian background.
• RNF213 R4810K: common founder variant in Japanese / Korean / Chinese populations — disease-modifying with variable penetrance.
• If negative: moyamoya NGS panel covering additional genes (ACTA2, BRCC3, others).
• Pediatric / syndromic moyamoya: consider chromosomal microarray (Down syndrome, NF1) + WES.

Fabry Disease (Vascular Phenotype)

• Critical principle: Fabry is an important treatable cause of young stroke — do not miss it.
• First-line in males: α-galactosidase A enzyme activity (dried blood spot or whole blood).
• First-line in females: GLA sequencing — enzyme activity can be normal in heterozygous females.
• Reflex confirmation: plasma lyso-Gb3 biomarker (elevated in disease).
• When to test stroke patients:
  • Young cryptogenic stroke (especially <55 years).
  • Family history of stroke / renal failure / cardiomyopathy.
  • Classic Fabry features: angiokeratomas, hypohidrosis, neuropathic pain, corneal verticillata.
  • Renal failure + neurologic symptoms.
  • Left ventricular hypertrophy in young patient.
• Treatment relevance: confirmed Fabry → eligibility for enzyme replacement (agalsidase α / β) or chaperone therapy (migalastat, for amenable GLA mutations only).

Familial Intracranial Aneurysm

• First-line test: intracranial aneurysm NGS panel covering ANIB genes, connective tissue disorders (COL3A1, FBN1), and known aneurysm-associated genes.
• When to test: ≥2 first-degree relatives with intracranial aneurysm; aneurysm in a young patient with connective tissue features; multiple aneurysms.
• Differential genes: COL3A1 (vascular Ehlers-Danlos), FBN1 (Marfan), LOX, FOXE3, THSD1, RNF213 (overlap with moyamoya).

Cerebral Amyloid Angiopathy (Hereditary)

• Sporadic CAA: clinical / imaging diagnosis (Boston criteria); no genetic test routinely needed.
• Hereditary CAA forms: rare — Dutch / Iowa / Flemish CAA (mutations in APP), British / Danish familial dementia (ITM2B), Icelandic CAA (CST3 / cystatin C), Finnish hereditary amyloidosis (GSN / gelsolin).
• When to test: very early-onset CAA + strong family history + unusual ethnic background → targeted gene by ancestry.

Hereditary Stroke / Young Stroke Workup Strategy

For an unexplained young stroke (<55 years) with no obvious cause after standard workup, consider genetic testing in the following order:

1. Fabry disease first: α-Gal A enzyme (males) + GLA sequencing (females). It is treatable and shouldn’t be missed.
2. Family history of stroke + subcortical white matter disease → NOTCH3 sequencing (CADASIL).
3. Suggestive imaging (e.g., porencephaly, retinal arteriolar tortuosity) → COL4A1 / COL4A2.
4. Multiple cavernous malformations → CCM panel.
5. AVMs + epistaxis + family history → HHT panel.
6. Moyamoya on imaging → RNF213.
7. Multiple aneurysms + young patient + family history → aneurysm / connective tissue NGS panel.
8. Compatible CADASIL-like phenotype but NOTCH3 negative → HTRA1, COL4A1/A2, or small vessel disease NGS panel.

Disease → Test Quick Reference Table

Pitfalls and Pearls

• CADASIL → NOTCH3: focus on cysteine-altering variants in exons 2–24. Yield 85–95% in classical phenotype.
• NOTCH3 VUS with classical CADASIL phenotype → skin biopsy for GOM is diagnostic.
• CADASIL imaging clue: anterior temporal pole + external capsule white matter — very specific.
• HTRA1: classical CARASIL is biallelic recessive; heterozygous HTRA1 now recognized as autosomal-dominant adult-onset SVD.
• COL4A1/A2: think about it with porencephaly, retinal arteriolar tortuosity, or aneurysms.
• Fabry in young stroke: do NOT miss. α-Gal A in males; GLA sequencing mandatory in females (enzyme can be normal).
• HHT + cerebral AVMs: paradoxical embolism via pulmonary AVMs is a cause of cryptogenic stroke.
• Moyamoya + East Asian: targeted RNF213 R4810K.
• Family history of intracranial aneurysm: counsel about Ehlers-Danlos vascular type (COL3A1) — surgical / endovascular implications.
• Cascade family testing: facilitate after any positive diagnosis.
• Treatment-driven testing: Fabry → enzyme replacement / chaperone; hATTR also relevant (covered on peripheral neuropathy page).

References

1. Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. 1996;383(6602):707-710.
2. Hara K, Shiga A, Fukutake T, et al. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med. 2009;360(17):1729-1739.
3. Verdura E, Hervé D, Scharrer E, et al. Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease. Brain. 2015;138(Pt 8):2347-2358.
4. Lanfranconi S, Markus HS. COL4A1 and COL4A2 mutations and disease. Stroke. 2010;41(8):e513-e518.
5. Sciacca FL, Ciusani E, Silvani A, Corsini E. Genetics of cerebral cavernous malformations. J Neurosurg Sci. 2014;58(3):137-146.
6. Kamimura T, Okazaki S, Morimoto T, et al. Prevalence of RNF213 p.R4810K variant in early-onset stroke with intracranial arterial stenosis. Stroke. 2019;50(6):1561-1563.
7. Mehta A, Beck M, Eyskens F, et al. Fabry disease: a review of current management strategies. QJM. 2010;103(9):641-659.
8. Faughnan ME, Mager JJ, Hetts SW, et al. Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. Ann Intern Med. 2020;173(12):989-1001.