European Journal of Medical Genetics 63 (2020) 104030 Available online 18 August 2020 1769-7212/© 2020 Elsevier Masson SAS. All rights reserved. Targeted re-sequencing in pediatric and perinatal stroke Alice Grossi a, 1 , Mariasavina Severino b, 1 , Marta Rusmini a , Domenico Tortora b , Luca A. Ramenghi c , Armando Cama d , Andrea Rossi b , Maja Di Rocco e, 2 , Isabella Ceccherini a, *, 2 , Marta Bertamino f , on behalf of theGaslini Stroke Study Group a U.O.S.D. Laboratorio di Genetica e Genomica Delle Malattie Rare, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy b U.O.C. Neuroradiologia, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy c U.O.C. Patologia Neonatale, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy d U.O.C. Neurochirurgia, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy e U.O.S.D. Malattie Rare, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy f U.O.C. Medicina Fisica e Riabilitazione, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy A R T I C L E INFO Keywords: Perinatal stroke Pediatric stroke Arteriopathy Porencephaly Magnetic resonance imaging Next-generation sequencing ABSTRACT Pediatric and perinatal stroke can present as an early symptom in undiagnosed syndromes characterized by simple Mendelian inheritance. In order to diagnose those patients affected with a monogenic disorder in which an arterial cerebrovascular event or arteriopathy may have preceded any other specifc symptom, we aimed to establish and validate a targeted gene panel, and to determine its diagnostic yield and clinical utility. To this end, thirty-eight patients were selected with heterogeneous cryptogenic stroke phenotypes, mostly including multiple and recurrent ischemic or hemorrhagic arterial strokes and porencephalies, variably associated with calcifca- tions, intracranial or systemic steno-occlusive arteriopathies, positive family history, and syndromic conditions. Clinical and neuroradiological data were collected for every patient enrolled in the study, and DNA samples were tested by means of a customized gene panel including 15 genes associated with known genetic diseases related to pediatric stroke. In four patients (10.5%) the analyses unraveled pathogenetic variants in ABCC6 and COL4A1 genes, leading to a defnite genetic diagnosis with a great benefcial impact on patients management, while results were null in the remaining patients. These fndings suggest a high complexity and variability of the included stroke phenotypes, that could not be fully accounted for by the genes tested in the present study. A wider gene panel or an unbiased genomic approach may be better suited and advisable to explain a greater proportion of pediatric and perinatal stroke events. 1. Introduction Stroke and cerebrovascular disorders are an important cause of morbidity and mortality not only in elderly but also in children, being among the top 10 causes of death in the pediatric population, with a reported mortality ranging from 7% to 28%. Pediatric arterial ischemic stroke (AIS) occurs after one month of age, with an incidence of 1–2 cases per 100,000 children per year (deVeber, 2003; Tsze and Valente, 2011; Mallick and O’Callaghan, 2010; Numis and Fox, 2014). Of note, 6–35% of affected children experience recurrent stroke episodes, and up to 75% lives with persistent neurological defcits or develop epilepsy (deVeber, 2003; Tsze and Valente, 2011; Kolk et al., 2011; Numis and Fox, 2014; deVeber et al., 2017; Beslow et al., 2018). Conversely, perinatal stroke occurs between 20 weeks of fetal life and 28 days postnatal life, with an estimated incidence between one in 1600 and one in 3000 livebirths (Dunbar and Kirton, 2018). Roughly half of all peri- natal strokes present in the frst days of life, typically with seizures, and are defned acute symptomatic perinatal stroke. The remainder typically present in infancy as hemiparetic cerebral palsy, with imaging confr- mation of remote stroke, and are named presumed perinatal stroke * Corresponding author. U.O.S.D. Laboratorio di Genetica e Genomica Delle Malattie Rare, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini, 5 - 16147 Genoa, Italy. E-mail addresses: majadirocco@gaslini.org (M. Di Rocco), isa.c@unige.it (I. Ceccherini). 1 These authors equally contributed to the study. 2 Reprint request authors: Isabella Ceccherini; U.O.S.D Laboratorio di Genetica e Genomica delle Malattie Rare. Maja Di Rocco; U.O.S.D. Malattie Rare, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini, 5 - 16147 Genova, Italy. Contents lists available at ScienceDirect European Journal of Medical Genetics journal homepage: www.elsevier.com/locate/ejmg https://doi.org/10.1016/j.ejmg.2020.104030 Received 22 January 2020; Received in revised form 20 July 2020; Accepted 31 July 2020