Stroke, Cerebral Hemorrhage, Hemiplegia, and Migraine Panel

This test is aimed at identifying causative variants in genes associated with stroke, cerebral hemorrhage, hemiplegia, and migraine. The main feature that can make disorders associated with these phenotypes difficult to differentiate without additional tests is the potential for weakness and loss of control of one side of the body (either hemiplegia or hemiparesis). These phenotypes may also be co-morbidities in diseases such as brain small vessel disease.

Stroke is one of the foremost causes of long-term disability and mortality worldwide. About 2.5% of adult Americans have reported having a stroke at least once (Benjamin et al. 2019. PubMed ID: 30700139). While several methods have been described to classify strokes and there are several sub-types, the major types can be summarized as ischemic or hemorrhagic (Amarenco et al. 2009. PubMed ID: 19342825). Ischemic stroke occurs when there is some sort of blockage of an artery that prevents blood flow to the brain, resulting in oxygen deprivation. Hemorrhagic stroke results when a blood vessel ruptures in the brain, resulting in damage to the surrounding brain tissue. The vast majority of strokes reported in the United States are ischemic, and in many of these cases, onset of stroke can be attributed to modifiable risk factors (Benjamin et al. 2019. PubMed ID: 30700139).

Mendelian strokes, a group of disorders caused by a single gene, are significantly rarer. The exact incidence for all Mendelian stroke disorders is unknown overall, though the most common of these, CADASIL (cerebral autosomal dominant arteriopathies with subcortical infarcts and leukoencephalopathies) has an average estimated prevalence of 0.0015% in the general population and 0.825% among small-vessel ischemic stroke patients (Chong et al. 2017. PubMed ID: 28679849). Typically, autosomal dominant conditions associated with stroke have adult onset and autosomal recessive conditions have onset in childhood (Dichgans et al. 2019. PubMed ID: 30975520).

Although stroke has rarely been associated with familial hemiplegic migraine (FHM), there is significant phenotypic overlap between stroke and FHM (Jen. 2021. PubMed ID: 20301562). Genetic testing can aid in the differential diagnosis between these disorders. Genetic testing of individuals with a family history or who are known or suspected to have clinical features consistent with hemiplegia, migraine, cerebral hemorrhage, or stroke may help determine risk of an attack, establish preventative measures, guide treatment plans, and estimate prognosis.

This panel focuses on genes associated with Mendelian forms of stroke (strokes with a clear genetic component), cerebral hemorrhage, migraine, and hemiplegia. Notably, it includes genes associated with CADASIL (NOTCH3), CARASIL (HTRA1), COL4A1/2-related angiopathies (COL4A1, COL4A2), cerebral amyloid angiopathy (APP, CST3), HERNS (TREX1), and familial hemiplegic migraine (ATP1A2, CACNA1A, SCN1A) amongst others (Jen. 1993. PubMed ID: 20301562; de Boer et al. 1993. PubMed ID: 31536185; Hack et al. 1993. PubMed ID: 20301673; Onodera et al. 1993. PubMed ID: 20437615; Dichgans et al. 2019. PubMed ID: 30975520). The inheritance for the genes varies, and both familial and sporadic (de novo) cases have been reported (Dichgans et al. 2019. PubMed ID: 30975520). Although not determined for all forms of Mendelian stroke, in the case of CADASIL, most cases causative variants in NOTCH3 are found more often in individuals with a family history of stroke rather than sporadic cases, indicating that inherited variants are more common for this disease (Chong et al. 2017. PubMed ID: 28679849). In addition, incomplete penetrance was noted in these families as well, suggesting environmental factors may contribute to disease onset even in Mendelian stroke. To our knowledge, copy number variants have not been conclusively linked with Mendelian forms of stroke.

Function of the gene products for this group of genes varies greatly. The most common biological processes for these genes are blood coagulation, integrin signaling, angiogenesis, and the TGF-beta signaling pathway (PANTHER 16.0). See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Due to the genetic heterogeneity and the significant contribution of environmental factors to complex disease manifestation, it is difficult to estimate the clinical sensitivity of this test. Although the disorders caused by the genes evaluated in this panel are rare, analytical sensitivity should be high because all known pathogenic variants reported in the literature are detectable by sequencing.

This test is performed using Next-Generation Sequencing with additional Sanger sequencing as necessary.

This panel typically provides 95.6% average coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

This testing will NOT detect commonly found inversions in intron 1 and 22 of F8.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).