Arteriovenous Cerebral High Flow Shunts: genetic analysis of patients from a pediatric tertiary care center

Ferruccio Romano ¹ Patrizia De Marco ² Giulia Amico ³ Marisa Mallamaci ⁴ Marco Pavanello ⁵ Gianluca Piatelli ⁵ Marcello Scala ² Federico Zara ² Francesca Faravelli ¹ Mariasavina Severino ⁶ Domenico Tortora ⁶ Francesco Pasetti ⁷ Lucio Castellan ⁸ Silvia Buratti ⁴ Valeria Capra ^2*

• ¹ Giannina Gaslini Institute (IRCCS), Genoa, Liguria, Italy
• ² Department of Medical Genetics, Giannina Gaslini Institute (IRCCS), Genova, Italy
• ³ Laboratory of Human Genetics, Giannina Gaslini Institute (IRCCS), Genoa, Italy
• ⁴ Neonatal and Pediatric Intensive Care Unit, Giannina Gaslini Institute (IRCCS), Genova, Italy
• ⁵ Department of Neurosurgery, Giannina Gaslini Institute (IRCCS), Genoa, Italy
• ⁶ Center for Neuroradiology and Interventional Radiology, Giannina Gaslini Institute (IRCCS), Genoa, Italy
• ⁷ Department of Radiology, Giannina Gaslini Institute (IRCCS), Genoa, Italy
• ⁸ San Martino Hospital (IRCCS), Genova, Liguria, Italy

Arteriovenous Cerebral High Flow Shunts include Vein of Galen aneurysmal malformation (VGAM) and Vein of Galen dilatation (VGD), that can be secondary to arteriovenous malformations (AVMs), or arteriovenous fistulas (AVFs). These entities are often sporadic, but can be found in association with variants in genes like RASA1 and EPHB4 (capillary malformation-arteriovenous malformation, CM-AVM, OMIM # 608354), or ACVRL1, ENG, and SMAD4 (hereditary hemorrhagic telangiectasia, HHT, OMIM # 187300). Clinical phenotypes associated with these syndromes are highly variable, with incomplete penetrance and mostly depend on the hemodynamic consequences (including heart failure and cerebral hemorrhage) or complications of management, rather than the anatomic vascular variation per se. This paper has the purpose of genetically characterizing a cohort of 29 patients affected by Arteriovenous Cerebral High Flow Shunts, treated at a pediatric referral center. The employed genetic techniques include: next generation sequencing, multiplex ligation-dependent probe amplification, and whole exome sequencing. 11 patients out of 29 were found with variants in genes with vascular functions: 5 received a genetic diagnosis, one presented with a VUS in EPHB4, and 5 harbored variants in novel genes possibly linked with cerebrovascular disorders. We provide extensive case descriptions, attempting to infer genotype-phenotype correlations: variants in all known genes associated with arteriovenous cerebral shunts were reported in VGAM patients, while cutaneous angiomas were specific for RASA1 mutations. Genotypic and phenotypic description of affected individuals may have relevant implications in terms of better pathophysiological understanding, genotype-phenotype correlations, treatment strategies and outcomes.