Genetic Insights into Cerebrovascular Disorders: a Comprehensive Review 1,2 3 4 5 Fawaz Al-Mufti, MD *, Ahmed Alkanaq, MD , Krishna Amuluru, MD , Rolla Nuoman, MD , 6 7 7 Ahmed Abdulrazzaq, DDS , Tamarah Sami, DDS , Halla Nuoaman, MD , Caroline Hayes- 5 2 8 Rosen, MD , Charles J. Prestigiacomo, MD , and Chirag D. Gandhi, MD 1 Rutgers University - Robert Wood Johnson Medical School, Department of Neurology, Division of Neuroendovascular Surgery and Neurocritical Care, New Brunswick, New Jersey, USA 2 Rutgers University - New Jersey Medical School, Department of Neurosurgery, Newark, New Jersey, USA 3 Rutgers University - Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA Journal of Vascular and Interventional Neurology, Vol. 5 Vol. and Interventional Neurology, Journal of Vascular 4 University of Pittsburgh Medical Center- Hamot, Department of Neurointerventional Radiology, Erie, Pennsylvania, USA 5 Rutgers University - New Jersey Medical School, Department of Neurology, Division of Child Neurology, Newark, New Jersey, USA 6 Rutgers University - School of Dental Medicine, Newark, New Jersey, USA 7 Rutgers University - Robert Wood Johnson Medical School, Department of Neurology, New Brunswick, New Jersey, USA 8 Westchester Medical Center, New York Medical College, Department of Neurosurgery, Valhalla, New York, USA Keywords Cerebrovascular malformations; hereditary diseases Introduction Genetic vascular disorders are usually present at birth; The prevalence of intracranial vascular malformation structurally, they tend to grow proportionately with the has been shown to be increasing over time. This is child, and do not regress spontaneously. The malforma- believed to be due to the advancement in radiological tions vary greatly in number, size, and location, and can procedures. Many studies examining neurological syn- also occur in the context of syndromes. Cerebrovascular dromes have aimed at early identification of intracranial malformations are defined as localized structural defects malformations, to prevent possible complications. With of the vasculature, named after the type of vessel affec- the advancement of medical genetics, represented by the ted [1]. Although the majority of vascular malformations recent breakthrough of whole exome sequencing, the are sporadic, a small proportion may be inherited. proportion of neurological disorders that can be attrib- uted to identifiable genetic mutations is increasing. Due to the relative rarity of cerebrovascular malforma- tions and the broad spectrum of possible complications, Vascular malformations are believed to result from a much of the evidence for genetic etiology comes from somatic mutation creating a mosaic clinical phenotype, single studies conducted in small and homogenous pop- in which two genetically distinct populations of cells ulations. exist within the same individual [2]. In this review, we reviewed published English language medical literature, With the advances of molecular technologies and medi- describing genes related to the development of intracra- cal research, genetic testing for a more proactive and nial vascular disorders, with their perspective malforma- precise clinical management is becoming a cornerstone tions. Since these genes play vital roles in the embryonic in the diagnostic workup for patients, especially for neu- process of vasculogenesis, as well as the post-embryonic rological diseases. processes of angiogenesis and arteriogenesis, it is very Vol. 9, No. 5, pp. 21–32. Published October, 2017. All Rights Reserved by JVIN. Unauthorized reproduction of this article is prohibited *Corresponding Author: Fawaz Al-Mufti, MD. Financial Disclosures: None. This work has not been previously presented or published. 22 difficult to assign genes to a specific anatomical or his- tological category. Therefore, we classified the genetic information in relation to the underlying histopathologi- cal manifestations. To simplify the classification process, and to make it more attributable to clinical practice, we categorized the intracranial malformations based on their pathology, which can be histologically differentiated from one another based on the underlying molecular genetics. Methods The objective of this review was to provide a primarily Journal of Vascular and Interventional Neurology, Vol. 5 Vol. and Interventional Neurology, Journal of Vascular descriptive overview on the genetic basis of neurovascu- lar disorders. An electronic Medline (PubMed) search was performed using the following terms in varied combinations: “cere- brovascular malformations,” “inherited mutations,” and Figure 1. “pathogenic variants,” followed by genetic variants search of National Center for Biotechnology Informa- tion genetics databases without language restrictions. We screened for clinical, human studies in adult patients published in the following designs: prospective random- ized, or observational, or case–control designs, retro- spective analyses, and case series. Due to increasing number of publications describing genetic basis of neurovascular disorders, it has become pertinent to perform a review of genes linked to neuro- vascular disorder and to delineate the implications that these genes can have on the clinical presentation and subsequently management, when it comes to genetic testing and identification of genetic variants carriers. Intracranial Aneurysms Aneurysmal subarachnoid hemorrhage (aSAH) contin- ues to be associated with high morbidity and mortality despite advances in management [3]. The natural history of aSAH suggests an overall mortality of approximately 50%, with 10% of patients dying prior to reaching the hospital, 25% dying within 24 h of SAH onset, 45% dying within 30 days, and approximately two-thirds of patients developing a cognitive impairment in one Figure 2. domain [4–6]. United States), most commonly in people between ages The worldwide prevalence of intracranial aneurysms is of 30 and 60 years [7,8]. estimated to be between 5% and 10%, and the incidence of ruptured aneurysms is about 10 in every 100,000 per- Therefore, it becomes very important to rely on sensitive sons per year (about 30,000 individuals per year in the screening methods, where information from clinical and Al-Mufti et al. 23 Journal of Vascular and Interventional Neurology, Vol. 5 Vol. and Interventional Neurology, Journal of Vascular Figure 3. Figure 4. family histories can be used to pursue specific clinical genetic testing towards an early discovery of aneurysms and prevention of intracranial hemorrhage. COL4A1-related disorders are also associated with cere- bral aneurysms, as part of the hereditary angiopathy with On the molecular level, several genes have been identi- nephropathy, aneurysms, and muscle cramps (HANAC) fied which are responsible for the underlying connective syndrome [11]. It is recommended that affected individ- tissue, and vascular dysplasia which predispose the his- uals undergo molecular testing of the COL4A1 gene to topathological development of aneurysms [9]. identify the responsible mutation. Parents, siblings, and the offspring of affected individuals can be tested for the The following genes have been described in the litera- same mutation. However, not all individuals have ture as being linked to intracranial aneurysms, some of parents who are carriers for the mutation, since some of which are responsible for other syndromic clinical pre- these mutations are de novo mutations [12,13]. sentations. Ulimately this will help in the early clinical A positive genetic test of this gene can help in the man- diagnoses and prevention of aneurysmal complications. agement and prevention of related disorders, which have overlapping clinical manifestations, and can be easily COL4a1-Related Disorders attributed to different possible pathologies. COL4A1 is a gene that codes for the collagen alpha‑1 (IV) chain, which is expressed in the basement mem- Autosomal Dominant Polycystic Kidney branes of cerebral vasculature. Pathological variants of Disease (ADPKD) this gene can lead to diminished tensile strength of ves- It is estimated that 6.9% of patients with ADPKD have sels and increased fragility, manifesting as a spectrum of intracranial aneurysms [14]. This syndrome is associated disorders that involve the brain and intracranial circula- with the lae onset cysts, in both kidneys, in addition to tion [10]. These disorders include porencephaly, which other organs like the liver. Individuals with positive fam- may present with a myriad of neurological manifesta- ily history of intracranial hemorrhages or aneurysms, tions at different ages, including mental disability, seiz- usually have higher probability of developing intracra- ures, and migraine. nial aneurysms. 24 Two genes, PKD1 and PKD2, were found to be respon- been linked to the different types of this syndrome. In sible for the autosomal dominant inheritance of this dis- type IV, or vascular EDS, a mutation in COL3A1 causes ease. Due to the 50% chance of inheriting the gene from molecular pathology of procollagen III synthesis, a an affected parent, and the late onset of cystic forma- major component of the connective tissue of blood ves- tions, the genetic diagnosis of this disease in family sels, viscera, and uterine wall [16]. Therefore, life- members at risk can help in preventing the catastrophic threatening complications can result from the fragility of consequences of possible intracranial aneurysms, espe- these tissues, including the possibility of fusiform aneur- cially