human genetics and molecular mechanisms of vein of galen

LITERATURE REVIEWJ Neurosurg Pediatr 21:367–374, 2018

Vein of Galen malformations (VOGMs) are develop-mental arteriovenous malformations (AVMs) that abnormally connect the choroidal circulation to a

single median venous sac. In the mid-20th century, Jaeger et al.28 described the first case of an “aneurysm of the vein of Galen.” A deeper understanding of the developmental

cerebrovascular anatomy further refined this concept by demonstrating that true VOGMs are, in fact, fistulous con-nections to the median prosencephalic vein, which is the embryonic precursor of the mature vein of Galen.47 Hence, a true VOGM does not affect the vein of Galen proper, lead-ing to a semantic misconception that persists in modern

ABBREVIATIONS AVM = arteriovenous malformation; CM-AVM = capillary malformation–AVM; GAP = GTPase-activating protein; GTP = guanosine-triphosphate; HHT = hereditary hemorrhagic telangiectasia; OMIM = Online Mendelian Inheritance in Man; RASA1 = Ras GTPase-activating protein 1; TGF-β = transforming growth factor–β; VOGM = vein of Galen malformation.SUBMITTED July 3, 2017. ACCEPTED September 20, 2017.INCLUDE WHEN CITING Published online January 19, 2018; DOI: 10.3171/2017.9.PEDS17365.

Human genetics and molecular mechanisms of vein of Galen malformationDaniel Duran, MD,1 Philipp Karschnia, BS,1 Jonathan R. Gaillard, BS,1 Jason K. Karimy, MS,1 Mark W. Youngblood, MPhil,1,7 Michael L. DiLuna, MD,1 Charles C. Matouk, MD,1 Beverly Aagaard-Kienitz, MD,2 Edward R. Smith, MD,3 Darren B. Orbach, MD, PhD,4 Georges Rodesch, MD, PhD,5 Alejandro Berenstein, MD,6 Murat Gunel, MD,1,7,8 and Kristopher T. Kahle, MD, PhD1,8,9

1Department of Neurosurgery, 7Department of Genetics, 8Centers for Mendelian Genomics and Yale Program on Neurogenetics, and 9Department of Pediatrics and Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut; 2Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin; Departments of 3Neurosurgery and 4Neurointerventional Radiology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts; 5Service de Neuroradiologie Diagnostique et Thérapeutique, Hôpital Foch, Suresnes, France; and 6Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York

Vein of Galen malformations (VOGMs) are rare developmental cerebrovascular lesions characterized by fistulas be-tween the choroidal circulation and the median prosencephalic vein. Although the treatment of VOGMs has greatly benefited from advances in endovascular therapy, including technical innovation in interventional neuroradiology, many patients are recalcitrant to procedural intervention or lack accessibility to specialized care centers, highlighting the need for improved screening, diagnostics, and therapeutics. A fundamental obstacle to identifying novel targets is the limited understanding of VOGM molecular pathophysiology, including its human genetics, and the lack of an adequate VOGM animal model. Herein, the known human mutations associated with VOGMs are reviewed to provide a framework for future gene discovery. Gene mutations have been identified in 2 Mendelian syndromes of which VOGM is an infrequent but associated phenotype: capillary malformation–arteriovenous malformation syndrome (RASA1) and hereditary hem-orrhagic telangiectasia (ENG and ACVRL1). However, these mutations probably represent only a small fraction of all VOGM cases. Traditional genetic approaches have been limited in their ability to identify additional causative genes for VOGM because kindreds are rare, limited in patient number, and/or seem to have sporadic inheritance patterns, attribut-able in part to incomplete penetrance and phenotypic variability. The authors hypothesize that the apparent sporadic occurrence of VOGM may frequently be attributable to de novo mutation or incomplete penetrance of rare transmitted variants. Collaboration among treating physicians, patients’ families, and investigators using next-generation sequencing could lead to the discovery of novel genes for VOGM. This could improve the understanding of normal vascular biology, elucidate the pathogenesis of VOGM and possibly other more common arteriovenous malformation subtypes, and pave the way for advances in the diagnosis and treatment of patients with VOGM.https://thejns.org/doi/abs/10.3171/2017.9.PEDS17365KEY WORDS vein of Galen malformation; VOGM; pediatric; genetics; AVM; arteriovenous malformation; vasculogenesis; endovascular; vascular disorders

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medical literature. VOGMs represent < 1% of all vascular malformations; however, they account for approximately 30% of all pediatric cerebrovascular malformations.14,35

VOGMs demonstrate 2 distinct angioarchitectural pat-terns (Fig. 1). Choroidal malformations are characterized by numerous feeder vessels and “pseudoniduses” that communicate with the medial prosencephalic vein. In contrast, mural VOGMs present a small number of larger-caliber fistulas into this structure.32 True VOGMs must be carefully differentiated from other lesions that can mimic them angiographically, such as tectal AVMs draining into a dilated, but mature, vein of Galen.

Clinical repercussions of VOGMs result from elevated shunt fractions that often produce high-output cardiac fail-ure or communicating hydrocephalus secondary to venous congestion and an imbalance in CSF reabsorption.5,32 Al-though cardiac failure may be devastating and may ensue early in the clinical course of the disease, VOGMs can also present with less obvious clinical features, including dilat-ed scalp veins (Fig. 2A) or slow progressive macrocephaly (Fig. 2C). Cutaneous stigmata are also frequently encoun-tered in patients and other family members (Fig. 2B).

Historically, treatment for VOGM was attempted with surgical clipping of the fistulous connections, leading to an unacceptably high perioperative mortality rate of close to 100%.26 The advent of microsurgery did not significantly improve outcomes in the surgical management of VOGM, slightly reducing perioperative mortality to an unaccept-ably high rate of approximately 80%.30 However, since the late 1980s, endovascular embolization of VOGMs has become the therapeutic standard of care, markedly lower-ing the mortality rate to approximately 15%30 and greatly reducing neurological morbidity.

Patient selection plays an important role in therapeu-tic decision making, as demonstrated by the implementa-tion of the Bicêtre score in the mid-2000s.32 In addition, the implementation of a multidisciplinary diagnostic and therapeutic strategy (involving prenatal detection and ade-quate risk stratification leading to proper patient selection and timing of intervention) has demonstrated significant improvement in patient outcomes.7 In the experience of a single high-volume center, the introduction of this ap-proach has reduced the neonatal mortality rate from 50% to 11% in less than 2 decades.7,19

Despite advances in clinical treatment, our understand-ing of the human genetics and molecular mechanisms of VOGMs remains rudimentary. However, some insight has been gathered from the study of Mendelian forms of vas-cular dysplasias that are rarely associated with VOGMs and other types of high-flow cerebral AVMs. For example, mutations in Ras GTPase-activating protein 1 (RASA1) are responsible for the autosomal dominant capillary mal-formation–arteriovenous malformation syndrome (CM-AVM; Online Mendelian Inheritance in Man [OMIM] no. 605384). This is a phenotypically heterogeneous disease characterized by the presence of atypical CMs with or without central or peripheral AVMs.15

More than 50 CM-AVM–associated RASA1 mutations have been described in the literature.48 Of these, only 8 variants were associated with patients with CM-AVM in which VOGM was the presenting AVM,10,25,48 explaining

a small percentage of total cases. To date, 2 other single-case reports have described the presence of mutations in known hereditary hemorrhagic telangiectasia–causing genes (activin A receptor type II–like 1 [ACVRL1] and endoglin [ENG]) in patients with VOGM.

FIG. 1. Representative images of VOGMs. Lateral representative projec-tions of digital subtraction angiography vertebral artery contrast injec-tions depicting choroidal VOGM (A) and mural VOGM (B). 3-T time-of-flight MR angiography 3D renderings depicting choroidal VOGM (C) and mural VOGM (D). Fetal T2-weighted MR images depicting a dilated vein of Markowski in a patient with VOGM, axial projection (E) and sagittal projection (F). 3D reconstructions from 3-T time-of-flight MR angiogra-phy of a choroidal VOGM, lateral projection (G) and oblique projection (H). Note the persistent limbic arch between the anterior cerebral ves-sels and the choroidal circulation. Figure is available in color online only.


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Herein, we present the first comprehensive report of known genetic alterations associated with VOGMs. Fur-ther understanding of the genetic basis of VOGM is criti-cal to deciphering the complex pathophysiological impli-cations of this disease and may lead to improvements in early diagnosis and the identification of actionable thera-peutic targets.

Genes Associated With Syndromes in Which VOGM Is an Uncommon Associated FindingVOGM in CM-AVM Syndrome: RASA1 Mutations

The RAS gene family encodes membrane-associated, guanine nucleotide–binding proteins that cycle between an active guanosine-triphosphate (GTP)–bound species and an inactive guanosine-diphosphate (GDP)–bound species.13,18 GTPase-activating proteins (GAPs) greatly en-hance the weak intrinsic GTPase activity of RAS proteins, affecting critical RAS functions in the control of cellular proliferation and differentiation.18

RASA1 encodes Ras GTPase-activating protein 1 (RASA1), the canonical function of which is to inhibit activity of the RAS-cyclic AMP pathway.51,55,57 RASA1 is ubiquitously expressed, with particularly high levels in brain and other ectoderm-derived tissues, such as cutane-ous fibroblasts.43 RASA1 enhances the intrinsic GTPase activity of RAS, yielding GDP-bound (inactive) RAS.2,8 Hence, impaired RASA1 activity leads to RAS remaining locked in a GTP-bound configuration, thereby leading to constitutive RAS activation.54,59

Rasa1 inactivation in mice provided early insight into the role of this gene in vascular development. Global bial-lelic Rasa1 knockout mice (Rasa1−/−) exhibited develop-mental arrest by E9.25 and death by E10.5.24 Assessment of the Rasa1−/− embryonic vascular system revealed mul-

tiple vascular abnormalities, which included the follow-ing: 1) aberrant yolk sac angioarchitecture characterized by the formation of a honeycomb pattern of ectatic ves-sels at E.9.5; 2) reduced caliber of the dorsal aorta; and 3) sprouting of aberrant ventral dorsal aortic branches, denoting delayed primitive endothelial cell reorganization that eventually led to embryonic lethality.24 Of note, no apparent abnormal vascular phenotypes were identified in heterozygous knockout (Rasa1+/−) mice.

By performing genome-wide linkage analysis in 13 kindreds harboring familial port wine stains (OMIM no. 16300), Eerola et al. reported the discovery of a suscep-tibility locus on 5q,16 which was subsequently narrowed down to a 5-centiMorgan region containing the posi-tional candidates EDIL3, MEF2C, and RASA1.15 Subse-quent targeted screening for mutations in RASA1 across 17 kindreds was performed. Six of these included fam-ily members with atypical CMs associated with AVMs, arteriovenous fistulas, or characteristics of Parkes Weber syndrome (OMIM no. 608355). Affected family mem-bers were found to harbor heterozygous loss-of-function RASA1 mutations, leading to the description of CM-AVM syndrome (OMIM no. 608354).

Further characterization of this syndrome led to refined observations on the heterogeneity of the presenting AVMs in CM-AVM.9 Revencu et al.48 reported a comprehensive description of sequencing findings in a large cohort of 68 families with CM-AVM syndrome and combined these data with those previously reported by their group. A total of 314 individuals across 132 kindreds harbored RASA1 mutations. Of these, 97% demonstrated cutaneous mani-festations (CMs), whereas only 23% (73 individuals) pre-sented with a total of 75 AVMs. Of all the AVMs in this cohort, 32 (42.6%) occurred in the CNS. Among these, only 3 (4%) were true VOGMs.48 The involvement of

FIG. 2. Photographs of clinical manifestations encountered in patients with VOGM. A: Dilated scalp veins. B: Atypical CMs in a patient with VOGM harboring a maternally-inherited RASA1 mutation (left) and her mother (right). C: Progressive macrocephaly in an infant harboring a mural VOGM. Figure is available in color online only.


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p120-RasGAP in multiple different growth factor receptor signaling cascades that regulate endothelial proliferation, migration, and survival may account for the phenotypic variability of patients with RASA1 mutations.15

Heuchan et al.25 published an abstract describing target-ed sequencing of RASA1 in 11 individuals with VOGMs. Four of 11 individuals (36.4%) harbored coding mutations in RASA1, 3 of which were missense variants and 1 of which was a stop-gain variant. The latter was associated with typical CM-AVM cutaneous manifestations.25 To date, a total of 10 germline variants in 3 different genes have been reported in patients with VOGMs (Table 1). The repercussions of these variants on the canonical transcript of RASA1 protein are depicted in Fig. 3. Of note, 7 of the 8 RASA1 variants cluster to exons 16–24, which code for the RAS GAP (RAS GTPase-activating) domain and its peripheral amino acid sequence, suggesting functional significance of this region for VOGM development.

Interestingly, a RASA1 somatic mutation in the CM of a patient with CM-AVM who also harbored a germline variant in the gene has been reported.36 In addition to this report, several others have described the influence of so-matic second hits as critical initiators of several different types of congenital vascular malformations. The autoso-mal dominant venous cutaneous and mucosal malforma-tion syndrome (OMIM no. 600195) is known to be caused by heterozygous germline mutations with additional so-matic mutations in TEK (TIE2).44

Moreover, capillary infantile hemangiomas, which also follow an autosomal dominant inheritance pattern (OMIM no. 602089), are caused by somatic mutations in the af-fected tissue in patients with predisposing germline KDR or FLT4 mutations.60 This phenomenon has also been described in other intracranial vascular lesions, namely familial autosomal dominant cavernous malformations (OMIM no. 116860). Somatic mutations in patients har-boring germline mutations in CCM1, CCM2, and CCM3 have been widely reported.3,20,45

Collectively, these data suggest that germline mutations may act as a predisposing factor for the development of specific cerebrovascular syndromes; the appearance of VOGM in these syndromes could be due to additional

somatic mutations arising in specific cerebrovascular cell types during intracranial vasculogenesis.36

VOGM in Hereditary Hemorrhagic Telangiectasia Syndrome: Mutations in ENG and ACVRL1 (ALK1)

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant disorder with an estimated incidence of approx-imately 1 per 100,000 persons.22,39 Commonly observed vascular abnormalities include telangiectasias on skin and mucosae, which often lead to epistaxis, and AVMs in the lungs, liver, and CNS. CNS vascular malformations in the context of HHT are heterogeneous and relatively infrequent. Maher et al.37 reported an incidence of 12 pa-tients who harbored CNS vascular malformations among a cohort of 321 patients with HHT (3.7%). Dural AV fis-tulas, cavernous malformations, and parenchymal AVMs were among the CNS vascular lesions described in this cohort.37 Variants in ENG and ACVRL1 (ALK1) have been associated with HHT types 1 (OMIM no. 187300) and 2 (OMIM no. 600376), respectively.1,6,40 Several reports48,56 of VOGMs in patients with diagnosed HHT or with a pos-itive family history strengthen the anecdotal connection between these conditions. However, reports of patients with genotyped HHT or families harboring a member with angiographically-confirmed VOGM are rare.10

For example, Tsutsumi et al.56 reported a child (born from a mother with clinical HHT harboring a choroidal VOGM) who presented with high-output cardiac failure. Sequencing revealed a maternally-inherited frameshift mutation in the ENG gene (p.Gln558fs; Table 1, no. 10). The same group later reported a case of a male newborn with subarachnoid hemorrhage secondary to VOGM.10 In this study, germline DNA from 4 patients with VOGM un-derwent polymerase chain reaction–based targeted screen-ing of exons and intron-exon boundaries for RASA1, ENG, ACVRL1, and SMAD4. This screen revealed a missense variant in ACVRL1 (p.Arg218Trp; Table 1, no. 9). Segrega-tion analysis confirmed the presence of the variant in the patient’s mother and sister, both of whom lacked features of HHT. Of note, upon careful examination of the imag-

TABLE 1. VOGM-associated genetic variants

No. Gene Coding Variant Exon Type of Mutation Protein Variant Year of Publication Authors & Year

1 RASA1 c.2977del 24 Frameshift deletion p.Arg993Valfs 2013 Revencu et al., 20132 RASA1 c.2125C>T† 16 Stop gain p.Arg709* 2013 Revencu et al., 2013; Heuchan et al., 20133 RASA1 c.3024del 24 Frameshift deletion p.Glu1008Aspfs 2013 Revencu et al., 20134 RASA1 c.2288A>T 17 Missense p.Glu763Val 2008 Revencu et al., 20135 RASA1 c.2532_2536del 19 Frameshift deletion p.Leu845Thrfs 2008 Revencu et al., 20136 RASA1 c.2119C>T 16 Missense p.Arg707Cys 2013 Heuchan et al., 20137 RASA1 c.2912T>C 23 Missense p.Leu971Ser 2013 Heuchan et al., 20138 RASA1 c.1678G>T 12 Stop gain p.Glu560* 2013 Chida et al., 20139 ACVRL1‡ c.652C>T 6 Missense p.Arg218Trp 2013 Chida et al., 2013

10 ENG c.1672_1684del 12 Frameshift deletion p.Gln558fs 2011 Tsutsumi et al., 2011

† Reported separately by 2 publications.‡ Although the case in this report is presented as a true VOGM, imaging in this report does not demonstrate clear fistulas to the vein of Markowski.



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ing findings in the ACVRL1-mutant patient in this report, no clear evidence of fistulas to the vein of Markowski was presented. No other vascular phenotypes were reported for these 2 carriers. Protein modifications of VOGM-associat-ed mutations in ENG and ACVRL1 are depicted in Fig. 3.

ACVRL1, also known as ALK1, codes for the serine/threonine-protein kinase receptor R3, which is highly ex-pressed in human endothelium.29 This molecule functions as a transforming growth factor–b (TGF-b) type I receptor, selectively binding bone morphogenetic proteins (BMPs) 9 and 10.38 ENG codes for a homodimeric membrane gly-coprotein, which is also highly expressed in the vascular endothelium and acts as a TGF-b coreceptor, binding to TGF peptides b-1 and b-3 with high affinity.4,33,42 Inter-estingly, the structure of ENG harbors an orphan domain on the N-terminal region, which mediates binding to the serine/threonine-protein kinase receptor R3.1

The downstream phenotypic effects of ENG and ACVRL1 mutations are thought to be mediated by acti-vation of SMAD transcription factors, either directly or through intercalated scaffolding proteins,34 leading to nu-clear translocation and changes in transcriptional regula-tion.61 Homozygous knockout of either ENG or ACVRL1 in mice produces embryonically lethal phenocopies and lacks clear arteriovenous differentiation,52,58 a hallmark of HHT and AVMs in general. Taken together, these data suggest abnormal TGF-b–SMAD-BMP endothelial in-teractions as a mechanism to explain VOGM and other AVMs in the context of HHT.49

Of note, both CM-AVM and HHT demonstrate auto-somal dominant inheritance with incomplete penetrance and expressivity.15,22 Additional associated vascular phe-notypes, especially cutaneous manifestations, can be mild and thus are often easily overlooked. Together, these fac-tors may result in underreporting of VOGM in these syn-dromes.

Familial VOGMThe presence of VOGM in 2 successive generations of

the same family—with or without other syndromic fea-tures of CM-AVM or HHT—has been reported once. Xu et al.62 presented the case of a 44-year-old woman who presented with nonspecific neurological symptoms of pos-tural instability and lightheadedness, with no significant history, who was incidentally diagnosed with a VOGM. Upon further interrogation, the patient revealed that she had miscarried a fetus harboring a VOGM. Of note, this group also performed a rigorous literature review of pa-tients presenting with VOGM as adults and found 16 cas-es, highlighting the rarity of such an occurrence.62

There have also been reports of 2 families with mul-tiple cases of VOGM in the same generation. Heuchan et al.25 reported 2 siblings with VOGM who carried the same RASA1 mutation (p.Arg707Cys; Table 1, no. 6). In addi-tion, a suspected case of 2 affected siblings was reported by Chida et al.10 One of the 4 index cases screened for mu-tations by their group had a sibling who died 1 day after birth. The index case was not found to harbor mutations in RASA1, ENG, ACVRL1, or SMAD4. A postmortem trans-fontanellar ultrasound showed “an abnormal vessel like VGAM.”10

Finally, phenotypic discordance in monozygotic twins, in which one of the individuals presents with a VOGM, has been reported twice.31,53 Interestingly, twin-to-twin transfusion syndrome ensued in both instances, which is probably explained by a high shunt fraction caused by the VOGM in the affected fetus.

Together, these data show that the occurrence of VOGMs is most often called sporadic due to the paucity of reported cases of familial aggregation. This most likely corresponds to the combination of historically high mor-tality, incomplete penetrance, and phenotypic variability.

FIG. 3. Schematic representation of protein alterations secondary to RASA1, ENG, and ACVRL1 mutations in VOGM. Truncating mutations (stop gains and frameshifts) are depicted in red. Missense mutations are depicted in blue. Protein structure is depicted as a gray line, with dark gray boxes representing mapped functional domains. GS = glycine-serine–rich domain; PH = Pleckstrin homology; RasGAP = RAS GTPase-activating; SH2 = Src homology 2; SH3 = Src homology 3; TM = transmembrane segment. Figure is available in color online only.


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Future Directions: Toward an Improved Understanding of VOGM Genetics

Advances in our understanding of the complex gross, histological, anatomical, and radiographic pathophysiolo-gy of VOGM have been achieved over the past 4 decades.32 This, in turn, has helped guide the development of effective endovascular therapies that have significantly improved the survival and neurological outcomes of children.17,27,63 Indeed, individuals harboring a once fatal or highly mor-bid condition now have functional and productive lives. The first representatives of this new and growing wave of VOGM survivors are currently reaching early adulthood.

However, many patients with VOGMs can be recal-citrant to procedural intervention or lack accessibility to specialized treatment centers,63 highlighting the need for improved screening and therapeutic strategies. A funda-mental obstacle to identifying novel preventive, early diag-nostic, and therapeutic strategies is our limited understand-ing of VOGM human genetics and the lack of development of associated animal models. Mutations in RASA1, ENG, and ACVRL1 have been identified in syndromes of which VOGM is an infrequent but associated phenotype. These genes are critical control nodes in the RAS and TGF-b signaling pathways in normal vascular development,21,41 and mutations of these genes probably contribute to the pathogenesis of VOGMs.

Traditional genetic approaches have been limited in their ability to identify additional VOGM-associated genes because kindreds are few, limited in patient number, and/or seem to have sporadic inheritance patterns attribut-able to such factors as phenotypic variability and incom-plete penetrance.15 Due to improvements in endovascular therapy, a growing number of VOGM survivors reaching reproductive age may result in the detection of additional inherited forms of VOGM.30

Knowledge of underlying molecular mechanisms of disease is often the first step in designing targeted thera-peutic approaches for rare diseases.46 However, the narrow developmental window, during which altered molecular signaling likely interferes with the normal embryologic re-gression of the vein of Markowski and subsequently leads to arteriovenous fistula formation in VOGM, could pose a formidable challenge for actionable early diagnosis and therapeutics. For example, screening attempts through bio-markers in amniotic fluid can be safely accomplished only after the aberrant angioarchitectural pattern of VOGM is instated during weeks 6–11 of embryologic development.47 Similarly, attempting to pharmacologically interfere with the genesis of VOGM would necessarily be limited by this narrow developmental window.

Critically, recent studies of de novo sequence varia-tion using whole-exome capture and massively parallel DNA sequencing have proven to be a powerful approach to systematic gene discovery in genetically complex neu-rodevelopmental disorders such as epilepsy,23 intellectual disability,12 and autism.50 We hypothesize that the apparent sporadic occurrence of VOGM may frequently be attribut-able to de novo mutation or incomplete penetrance of rare transmitted variants and therefore amenable to discovery using whole-exome or whole-genome sequencing.11

Our group and others have embarked on multicenter collaborative efforts involving treating physicians, fami-lies of patients, and investigators with expertise in these techniques, in an attempt to answer outstanding questions pertaining to VOGM molecular pathogenesis. These ef-forts are motivated by the severe and frequently devastat-ing consequences of VOGM, as well as by the paucity of basic molecular knowledge of the disease. By means of concerted, multidisciplinary efforts such as these, we may gain insight into the molecular mechanisms underlying VOGMs, which may prove to harbor preventive, diagnos-tic, and therapeutic value for patients and their families.

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DisclosuresThe authors report no conflict of interest concerning the materi-als or methods used in this study or the findings specified in this paper.

Author ContributionsConception and design: Kahle. Acquisition of data: Kahle, Duran, Karschnia, Gaillard, Karimy, Youngblood, DiLuna, Matouk, Aagaard-Kienitz, Smith, Orbach, Rodesch, Gunel. Analysis and interpretation of data: Kahle, Berenstein. Drafting the article: all authors. Critically revising the article: Kahle, Karimy, DiLuna, Matouk, Aagaard-Kienitz, Smith, Orbach, Rodesch, Berenstein, Gunel. Reviewed submitted version of manuscript: Duran, Gail-lard, DiLuna, Matouk, Rodesch, Berenstein, Gunel. Approved the final version of the manuscript on behalf of all authors: Kahle. Study supervision: Kahle, Berenstein. Conducted review of litera-ture: Duran, Karschnia, Gaillard, Karimy, Youngblood. Created/revised figures: Gaillard, Rodesch.

CorrespondenceKristopher T. Kahle: Yale School of Medicine, New Haven, CT. [email protected].


human genetics and molecular mechanisms of vein of galen

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