A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion

Grazia Nardella, Grazia Visci, Vito Guarnieri, Stefano Castellana, Tommaso Biagini, Luigi Bisceglia, Orazio Palumbo, Marina Trivisano, Carmela Vaira, Massimo Scerrati, Davide Debrasi, Vincenzo D'Angelo, Massimo Carella, Giuseppe Merla, Tommaso Mazza, Marco Castori, Leonardo D'Agruma, Carmela Fusco

Research output: Contribution to journalArticle

Abstract

Cerebral cavernous malformation (CCM) is a capillary malformation arising in the central nervous system. CCM may occur sporadically or cluster in families with autosomal dominant transmission, incomplete penetrance, and variable expressivity. Three genes are associated with CCM KRIT1, CCM2, and PDCD10. This work is a retrospective single-center molecular study on samples from multiple Italian clinical providers. From a pool of 317 CCM index patients, we found germline variants in either of the three genes in 80 (25.2%) probands, for a total of 55 different variants. In available families, extended molecular analysis found segregation in 60 additional subjects, for a total of 140 mutated individuals. From the 55 variants, 39 occurred in KRIT1 (20 novel), 8 in CCM2 (4 novel), and 8 in PDCD10 (4 novel). Effects of the three novel KRIT1 missense variants were characterized in silico. We also investigated a novel PDCD10 deletion spanning exon 4-10, on patient's fibroblasts, which showed significant reduction of interactions between KRIT1 and CCM2 encoded proteins and impaired autophagy process. This is the largest study in Italian CCM patients and expands the known mutational spectrum of KRIT1, CCM2, and PDCD10. Our approach highlights the relevance of seeking supporting information to pathogenicity of new variants for the improvement of management of CCM.

Original languageEnglish
JournalHuman Mutation
DOIs
Publication statusE-pub ahead of print - Aug 30 2018

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Central Nervous System Cavernous Hemangioma
Penetrance
Autophagy
Computer Simulation
Genes
Virulence
Exons
Central Nervous System
Fibroblasts

Cite this

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title = "A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion",
abstract = "Cerebral cavernous malformation (CCM) is a capillary malformation arising in the central nervous system. CCM may occur sporadically or cluster in families with autosomal dominant transmission, incomplete penetrance, and variable expressivity. Three genes are associated with CCM KRIT1, CCM2, and PDCD10. This work is a retrospective single-center molecular study on samples from multiple Italian clinical providers. From a pool of 317 CCM index patients, we found germline variants in either of the three genes in 80 (25.2{\%}) probands, for a total of 55 different variants. In available families, extended molecular analysis found segregation in 60 additional subjects, for a total of 140 mutated individuals. From the 55 variants, 39 occurred in KRIT1 (20 novel), 8 in CCM2 (4 novel), and 8 in PDCD10 (4 novel). Effects of the three novel KRIT1 missense variants were characterized in silico. We also investigated a novel PDCD10 deletion spanning exon 4-10, on patient's fibroblasts, which showed significant reduction of interactions between KRIT1 and CCM2 encoded proteins and impaired autophagy process. This is the largest study in Italian CCM patients and expands the known mutational spectrum of KRIT1, CCM2, and PDCD10. Our approach highlights the relevance of seeking supporting information to pathogenicity of new variants for the improvement of management of CCM.",
author = "Grazia Nardella and Grazia Visci and Vito Guarnieri and Stefano Castellana and Tommaso Biagini and Luigi Bisceglia and Orazio Palumbo and Marina Trivisano and Carmela Vaira and Massimo Scerrati and Davide Debrasi and Vincenzo D'Angelo and Massimo Carella and Giuseppe Merla and Tommaso Mazza and Marco Castori and Leonardo D'Agruma and Carmela Fusco",
note = "{\circledC} 2018 Wiley Periodicals, Inc.",
year = "2018",
month = "8",
day = "30",
doi = "10.1002/humu.23629",
language = "English",
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issn = "1059-7794",
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TY - JOUR

T1 - A single-center study on 140 patients with cerebral cavernous malformations

T2 - 28 new pathogenic variants and functional characterization of a PDCD10 large deletion

AU - Nardella, Grazia

AU - Visci, Grazia

AU - Guarnieri, Vito

AU - Castellana, Stefano

AU - Biagini, Tommaso

AU - Bisceglia, Luigi

AU - Palumbo, Orazio

AU - Trivisano, Marina

AU - Vaira, Carmela

AU - Scerrati, Massimo

AU - Debrasi, Davide

AU - D'Angelo, Vincenzo

AU - Carella, Massimo

AU - Merla, Giuseppe

AU - Mazza, Tommaso

AU - Castori, Marco

AU - D'Agruma, Leonardo

AU - Fusco, Carmela

N1 - © 2018 Wiley Periodicals, Inc.

PY - 2018/8/30

Y1 - 2018/8/30

N2 - Cerebral cavernous malformation (CCM) is a capillary malformation arising in the central nervous system. CCM may occur sporadically or cluster in families with autosomal dominant transmission, incomplete penetrance, and variable expressivity. Three genes are associated with CCM KRIT1, CCM2, and PDCD10. This work is a retrospective single-center molecular study on samples from multiple Italian clinical providers. From a pool of 317 CCM index patients, we found germline variants in either of the three genes in 80 (25.2%) probands, for a total of 55 different variants. In available families, extended molecular analysis found segregation in 60 additional subjects, for a total of 140 mutated individuals. From the 55 variants, 39 occurred in KRIT1 (20 novel), 8 in CCM2 (4 novel), and 8 in PDCD10 (4 novel). Effects of the three novel KRIT1 missense variants were characterized in silico. We also investigated a novel PDCD10 deletion spanning exon 4-10, on patient's fibroblasts, which showed significant reduction of interactions between KRIT1 and CCM2 encoded proteins and impaired autophagy process. This is the largest study in Italian CCM patients and expands the known mutational spectrum of KRIT1, CCM2, and PDCD10. Our approach highlights the relevance of seeking supporting information to pathogenicity of new variants for the improvement of management of CCM.

AB - Cerebral cavernous malformation (CCM) is a capillary malformation arising in the central nervous system. CCM may occur sporadically or cluster in families with autosomal dominant transmission, incomplete penetrance, and variable expressivity. Three genes are associated with CCM KRIT1, CCM2, and PDCD10. This work is a retrospective single-center molecular study on samples from multiple Italian clinical providers. From a pool of 317 CCM index patients, we found germline variants in either of the three genes in 80 (25.2%) probands, for a total of 55 different variants. In available families, extended molecular analysis found segregation in 60 additional subjects, for a total of 140 mutated individuals. From the 55 variants, 39 occurred in KRIT1 (20 novel), 8 in CCM2 (4 novel), and 8 in PDCD10 (4 novel). Effects of the three novel KRIT1 missense variants were characterized in silico. We also investigated a novel PDCD10 deletion spanning exon 4-10, on patient's fibroblasts, which showed significant reduction of interactions between KRIT1 and CCM2 encoded proteins and impaired autophagy process. This is the largest study in Italian CCM patients and expands the known mutational spectrum of KRIT1, CCM2, and PDCD10. Our approach highlights the relevance of seeking supporting information to pathogenicity of new variants for the improvement of management of CCM.

U2 - 10.1002/humu.23629

DO - 10.1002/humu.23629

M3 - Article

C2 - 30161288

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

ER -