Somatic mutations in intracranial arteriovenous malformations

Autoři: Jeremy A. Goss aff001;  August Y. Huang aff002;  Edward Smith aff003;  Dennis J. Konczyk aff001;  Patrick J. Smits aff001;  Christopher L. Sudduth aff001;  Christopher Stapleton aff004;  Aman Patel aff004;  Sanda Alexandrescu aff002;  Matthew L. Warman aff005;  Arin K. Greene aff001
Působiště autorů: Department of Plastic & Oral Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States of America aff001;  Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States of America aff002;  Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States of America aff003;  Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America aff004;  Department of Orthopedic Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States of America aff005
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article



Intracranial arteriovenous malformation (AVM) is a common cause of primary intracerebral hemorrhage in young adults. Lesions typically are sporadic and contain somatic mutations in KRAS or BRAF. The purpose of this study was to identify somatic mutations in a cohort of participants with brain AVM and to determine if any genotype-phenotype associations exist.


Human brain AVM specimens (n = 16) were collected during a clinically-indicated procedure and subjected to multiplex targeted sequencing using molecular inversion probe (MIP-seq) for mutations in KRAS, BRAF, HRAS, NRAS, and MAP2K1. Endothelial cells (ECs) were separated from non-ECs by immune-affinity purification. Droplet digital PCR (ddPCR) was used to confirm mutations and to screen for mutations that may have been missed by MIP-seq. Patient and AVM characteristics were recorded.


We detected somatic mutations in 10 of 16 specimens (63%). Eight had KRAS mutations [G12D (n = 5), G12V (n = 3)] and two had BRAF mutations [V600E (n = 1), Q636X (n = 1)]. We found no difference in age, sex, presenting symptom, AVM location, or AVM size between patients with a confirmed mutation and those without. Nor did we observe differences in these features between patients with KRAS or BRAF mutations. However, two patients with BRAF mutations presented at an older age than other study participants.


Somatic mutations in KRAS and, less commonly in BRAF, are found in many but not all intracranial AVM samples. Currently, there are no obvious genotype-phenotype correlations that can be used to predict whether a somatic mutation will be detected and, if so, which gene will be mutated.

Klíčová slova:

DNA extraction – Endothelial cells – Gene sequencing – Headaches – Mutation databases – Mutation detection – Nonsense mutation – Somatic mutation


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2019 Číslo 12
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