Genetic Screening of Pediatric Cavernous Malformations

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)232-238
Number of pages7
JournalJournal of Molecular Neuroscience
Volume60
Issue number2
DOIs
Publication statusPublished - Oct 1 2016

Fingerprint

Central Nervous System Cavernous Hemangioma
Genetic Testing
Pediatrics
Mutation
Messenger RNA
Vascular Malformations
Penetrance
Nonsense Codon
Multiplex Polymerase Chain Reaction
Genetic Counseling
RNA Stability
Cerebral Hemorrhage
Genes
Exons
Central Nervous System
Hemorrhage

Keywords

  • CCM genes
  • Cerebral cavernous malformation (CCMs)
  • Direct sequencing
  • Multiplex ligation-dependent probe amplification (MLPA)

ASJC Scopus subject areas

  • Medicine(all)
  • Cellular and Molecular Neuroscience

Cite this

Genetic Screening of Pediatric Cavernous Malformations. / Merello, Elisa; Pavanello, Marco; Consales, Alessandro; Mascelli, Samantha; Raso, Alessandro; Accogli, Andrea; Cama, Armando; Valeria, Capra; De Marco, Patrizia.

In: Journal of Molecular Neuroscience, Vol. 60, No. 2, 01.10.2016, p. 232-238.

Research output: Contribution to journalArticle

@article{51161d14232749dd921adc5bdf7774df,
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.",
keywords = "CCM genes, Cerebral cavernous malformation (CCMs), Direct sequencing, Multiplex ligation-dependent probe amplification (MLPA)",
author = "Elisa Merello and Marco Pavanello and Alessandro Consales and Samantha Mascelli and Alessandro Raso and Andrea Accogli and Armando Cama and Capra Valeria and {De Marco}, Patrizia",
year = "2016",
month = "10",
day = "1",
doi = "10.1007/s12031-016-0806-8",
language = "English",
volume = "60",
pages = "232--238",
journal = "Journal of Molecular Neuroscience",
issn = "0895-8696",
publisher = "Humana Press",
number = "2",

}

TY - JOUR

T1 - Genetic Screening of Pediatric Cavernous Malformations

AU - Merello, Elisa

AU - Pavanello, Marco

AU - Consales, Alessandro

AU - Mascelli, Samantha

AU - Raso, Alessandro

AU - Accogli, Andrea

AU - Cama, Armando

AU - Valeria, Capra

AU - De Marco, Patrizia

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

KW - CCM genes

KW - Cerebral cavernous malformation (CCMs)

KW - Direct sequencing

KW - Multiplex ligation-dependent probe amplification (MLPA)

UR - http://www.scopus.com/inward/record.url?scp=84983458326&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84983458326&partnerID=8YFLogxK

U2 - 10.1007/s12031-016-0806-8

DO - 10.1007/s12031-016-0806-8

M3 - Article

VL - 60

SP - 232

EP - 238

JO - Journal of Molecular Neuroscience

JF - Journal of Molecular Neuroscience

SN - 0895-8696

IS - 2

ER -