Presentation: Patient with a cerebral vascular malformation

A young man presents with new focal-onset seizures. His history and neurological features on examination are otherwise normal. A brain MRI reveals a cerebral cavernous angioma in the right temporal lobe. When you take a family history, he mentions that his mother has had surgery for a similar brain lesion.

• Most cerebral vascular malformations are sporadic and occur in people without a known family history. Clues that point to a genetic cause include:
  • multiple affected family members: penetrance of genetic causes of cerebral vascular malformations can be highly variable, and a clearly autosomal dominant family history may not be immediately evident;
  • early onset symptoms in the context of typical imaging findings;
  • multiple or bilateral malformations: repeat imaging or a specialist opinion may be required to differentiate alternate diagnoses before deciding on genomic testing options; and
  • associated symptoms such as recurrent nosebleeds and/or vascular malformations in other organs (such as the retina or the skin), which are common and can be useful in the identification of a clinical syndrome.
• Unaffected individuals may present with a family history of an adult-onset genetic condition. Where signs and/or symptoms suggestive of that condition are not present in the patient, they should be offered referral to a local clinical genetics service to discuss testing as part of a predictive (presymptomatic) testing pathway.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• For information about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the tests best suits the needs of your patient and/or their family. For patients whose identified malformation is likely to have a genetic cause, there are a number of available panels.
  • R336 Cerebral vascular malformations: This panel should be used for patients presenting with multiple cerebral vascular malformations, as well as for patients with a single cerebral vascular malformation and a relevant family history. It includes whole exome sequencing or a panel of genes known to cause cerebral vascular malformations. It identifies small variants and exon-level copy number variants.
  • R186 Hereditary haemorrhagic telangiectasia: This panel should be used if a patient’s cerebral vascular malformation is associated with a concern of underlying hereditary haemorrhagic telangiectasia (HHT). It includes a small panel of genes known to cause HHT, to identify small variants and exon-level copy number variants. Diagnostic testing should be considered if three of the following are present but we recommend that you consult the National Genomic Test Directory, as the broader criteria (not listed here) reflect the variability of patient presentation:
    • recurrent epistaxis;
    • mucocutaneous telangiectases;
    • visceral (including cerebral) lesions; and
    • family history.
• None of the tests outlined above use whole genome sequencing, so you should use your local Genomic Laboratory Hub test order form and consent (record of discussion, or RoD) form.
  • When testing in children, parental samples may be helpful for interpretation of the proband’s result. Parental samples can be taken alongside that of the proband, and their DNA stored, or can be requested at a later date if needed.
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• GeneReviews: Familial cerebral cavernous malformations
• GeneReviews: Hereditary hemorrhagic telangiectasia
• Genomics England: NHS GMS Signed Off Panels Resource
• Imperial College Healthcare NHS Trust: Refer to the HHT and PAVM service
• NHS England: National Genomic Test Directory

References

• Faughnan ME, Mager JJ, SW Hetts and others. ‘Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia’. Annals of Internal Medicine 2020: volume 173, issue 12, pages 989–1,001. DOI: 10.7326/M20-1443
• Hermann R, Shovlin CL, Kasthuri RS and others. ‘Hereditary haemorrhagic telangiectasia‘. Nature Reviews Disease Primers 2025: volume 11, article number 1. DOI: 10.1038/s41572-024-00585-z
• Hongo H, Miyawaki S, Teranishi Y and others. ‘Genetics of brain arteriovenous malformations and cerebral cavernous malformations’. Journal of Human Genetics 2022: volume 68, issue 3, pages 157–167. DOI: 1038/s10038-022-01063-8
• Rahmani R, Scherschinski L, Srinivasan VM and others. ‘Genetics and emerging therapies for brain arteriovenous malformations’. World Neurosurgery 2022: volume 159, pages 327–337. DOI: 10.1016/j.wneu.2021.10.127

For patients

• Brain & Spine Foundation: Vascular malformations of the brain (PDF, 44 pages)
• Cavernoma Alliance UK
• NHS Health A to Z: Hereditary haemorrhagic telangiectasia