Background:
The genetic basis of brain arteriovenous malformation (BAVM), a tangle of abnormal vessels directly shunting blood from the arterial to venous circulation, is unknown. However, there are two rare vascular disorders with known familial mutations in which a subset of patients display a BAVM phenotype: hereditary hemorrhagic telangiectasia (
ACVRL1
,
ENG
, and
SMAD4
mutations) and capillary malformation-arteriovenous malformation (
RASA1
mutations). To investigate whether variants in these four vascular malformation genes are associated with sporadic BAVM, we performed a case-control study, evaluating both single nucleotide polymorphisms (SNPs) and copy number variation (CNV).
Methods:
We used genome-wide data (Affymetrix SNP 6.0) from 319 cases and 496 healthy controls. There were 27 unlinked SNPs (r
2
<0.8) on the array with minor allele frequency >1% and in Hardy-Weinberg equilibrium (p>0.01) mapping within 20kb of the four genes:
ACVRL1
(n=16),
ENG
(n=6),
SMAD4
(n=2), and
RASA1
(n=3). Single SNP association was tested using multivariate logistic regression in PLINK, adjusting for age, gender, and top 3 principal components of ancestry (to control for population stratification). The Bonferroni method (p<0.0019) was used to correct for multiple comparisons. CNVs in these genes were called using the PennCNV algorithm.
Results:
Two SNPs located upstream and downstream of
ACVRL1
were associated with BAVM at nominal p<0.05: rs10783480 (OR=0.69, 95% CI=0.50 - 0.96, p=0.029,) and rs11169956 (OR=0.69, 95% CI=0.48 - 0.99, p=0.046). However, these SNPs were not associated with BAVM after correction for multiple testing of all SNPs. Polymorphisms in the
RASA1
,
ENG
, and
SMAD4
genes were not significantly associated with BAVM (p>0.05). We observed one CNV, a duplication that mapped to the
ACVRL1
gene, in one control. We did not observe any CNVs mapping to
RASA1
,
ENG
, or
SMAD4
.
Conclusions:
Common SNPs and CNVs in four vascular malformation genes associated with inherited disorders displaying BAVM were not significantly associated with sporadic BAVM. A previously reported
ACVRL1
intronic SNP (rs2071219) was not on the Affymetrix array and none of the existing
ACVRL1
SNPs tagged this SNP. Further, rare polymorphisms in these genes were not genotyped and may contribute to BAVM risk.
“MEDICOLEGAL MASQUERADE” A RUPTURED BRAIN ARTERIOVENOUS MALFORMATION MIMICKING HOMICIDE: A CASE REPORT
