title: Genetic Screening of Pediatric Cavernous Malformations.
abstract: Cerebral cavernous malformations (CCMs) are vascular malformations mostly located within the central nervous system. Heterozygous loss of function mutations in CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 genes are identified in about 90 % of familial cases of CCMs and two thirds of sporadic cases with multiple lesions. In this study, we performed genetic screening of a cohort of 31 patients, mainly pediatric. We analyzed the CCM1, CCM2, and CCM3 genes by multiplex ligation-dependent probe amplification (MLPA) and direct sequencing of exons and intronic boundaries. A total of 9 typical pathogenic loss-of-function mutations were identified in 10 out 31 patients (32 %). The 75 % of familial cases were mutated and the percentage reached to 85 % when we consider only pediatric cases. Detection rate in sporadic cases with multiple lesions was considerably lower (16 %). We identified a novel variant of CCM3, the c.130-131insT (p.R45Efs*8), in 1 pediatric sporadic case with multiple lesions that introduced a premature termination codon into the messenger RNA (mRNA), most likely leading to mRNA decay. Similar to other CCM pediatric series, the main symptoms associated to clinical debut consisted of cerebral hemorrhage. In conclusion, the penetrance of CCM mutations in familial pediatric cases is high (85 %). The genetic workup could improve clinical and genetic counseling in CCM patients. Moreover, we confirmed the high risk of hemorrhage in children with CCMs.
authors: Istituto Giannina Gaslini, Genoa, Italy.
authors: Elisa
authors: E
authors: Merello
authors: Istituto Giannina Gaslini, Genoa, Italy.
authors: Marco
authors: M
authors: Pavanello
authors: Istituto Giannina Gaslini, Genoa, Italy.
authors: Alessandro
authors: A
authors: Consales
authors: Istituto Giannina Gaslini, Genoa, Italy.
authors: Samantha
authors: S
authors: Mascelli
authors: Istituto Giannina Gaslini, Genoa, Italy.
authors: Alessandro
authors: A
authors: Raso
authors: Istituto Giannina Gaslini, Genoa, Italy.
authors: Andrea
authors: A
authors: Accogli
authors: Istituto Giannina Gaslini, Genoa, Italy.
authors: Armando
authors: A
authors: Cama
authors: Istituto Giannina Gaslini, Genoa, Italy.
authors: Capra
authors: C
authors: Valeria
authors: Istituto Giannina Gaslini, Genoa, Italy. patriziademarco@gaslini.org.|Dipartimento Testa-Collo e Neuroscienze, UOC Neurochirurgia, Istituto Giannina Gaslini, Genoa, Italy. patriziademarco@gaslini.org.
authors: Patrizia
authors: P
authors: De Marco
mesh_terms: D000293:Adolescent; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D018388:Codon, Terminator / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D020786:Hemangioma, Cavernous, Central Nervous System / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D000075927:KRIT1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009154:Mutation; D019683:Penetrance; D011518:Proto-Oncogene Proteins / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C502544:CCM2 protein, human; D002352:Carrier Proteins; D018388:Codon, Terminator; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C495390:PDCD10 protein, human; D011518:Proto-Oncogene Proteins
keywords: CCM genes; Cerebral cavernous malformation (CCMs); Direct sequencing; Multiplex ligation-dependent probe amplification (MLPA)