Genetic Screening of Pediatric Cavernous Malformations

Springer Science and Business Media LLC - Tập 60 - Trang 232-238 - 2016
Elisa Merello1, Marco Pavanello1, Alessandro Consales1, Samantha Mascelli1, Alessandro Raso1, Andrea Accogli1, Armando Cama1, Capra Valeria1, Patrizia De Marco1,2
1Istituto Giannina Gaslini, Genoa, Italy
2Dipartimento Testa-Collo e Neuroscienze, UOC Neurochirurgia, Istituto Giannina Gaslini, Genoa, Italy

Tóm tắt

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.

Tài liệu tham khảo

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