A single‐center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion. Issue 12 (24th September 2018)

• Record Type: Journal Article
• Authors: Nardella, Grazia; Visci, Grazia; Guarnieri, Vito; Castellana, Stefano; Biagini, Tommaso; Bisceglia, Luigi; Palumbo, Orazio; Trivisano, Marina; Vaira, Carmela; Scerrati, Massimo; Debrasi, Davide; D'Angelo, Vincenzo; Carella, Massimo; Merla, Giuseppe; Mazza, Tommaso; Castori, Marco; D'Agruma, Leonardo; Fusco, Carmela
• Is Part Of: Human mutation. Volume 39:Issue 12(2018)
• Page Start: 1885
• Page End: 1900
• Publication Date: 2018-09-24
• Subjects: autophagy assay -- CCM2 -- cerebral cavernous malformation -- in silico analysis -- KRIT1 -- PDCD10; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23629
• Languages: English
• ISSNs: 1059-7794

Abstract

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. Abstract : Cerebral cavernous malformation is a capillary malformation with three genes associated KRIT1, CCM2 and PDCD10. From a pool of 317 CCM index patients we found germline variants in either of the three genes. Effects of the 3 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 reduction of interactions between CCM proteins and impaired autophagy process. Our approach highlights the relevance of seeking supporting information to pathogenicity of new variants for CCM management.