AUTHOR=Scimone Concetta , Donato Luigi , Katsarou Zoe , Bostantjopoulou Sevasti , D'Angelo Rosalia , Sidoti Antonina 

TITLE=Two Novel KRIT1 and CCM2 Mutations in Patients Affected by Cerebral Cavernous Malformations: New Information on CCM2 Penetrance

JOURNAL=Frontiers in Neurology

VOLUME=Volume 9 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2018.00953

DOI=10.3389/fneur.2018.00953

ISSN=1664-2295

ABSTRACT=Wide comprehension of genetic features of Cerebral Cavernous Malformations (CCM) represents the starting point to better manage patients and risk rating in their relatives. Causative mutations spectrum is constantly growing. KRIT1, CCM2 and PDCD10 are the three loci to date linked to familial CCM development although germline mutations were also detected in patients affected by sporadic forms. In this context, the main challenge is to draw up criteria to formulate genotype;phenotype correlations. Clearly, genetic factors determining incomplete penetrance of CCM are to be identified. 
Here we report two novel intronic variants probably affecting splicing. Molecular screening of CCM genes was performed on DNA purified by peripheral blood. Coding exons and intron-exon boundaries were sequenced by Sanger method.
The first was detected in a sporadic patient and involves KRIT1. The second one affects CCM2 and it is harboured by a woman with familial CCM. 
Interestingly, molecular analysis extended on both healthy and ill relatives allowed to estimate, for the first time, a penetrance for CCM2lower than 100%, as to date reported. Moreover, heterogeneity of clinical manifestations among affected carrying the same genotype further confirms involvement of modifiers factors in CCM development.