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

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

doi:10.3389/fneur.2018.00953

Abstract

Wide comprehension of genetic features of cerebral cavernous malformations (CCM) represents the starting point to better manage patients and risk rating in relatives. The causative mutations spectrum is constantly growing. KRIT1, CCM2, and PDCD10 are the three loci to date linked to familial CCM development, although germline mutations have also been 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 need 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 the Sanger method. The first was detected in a sporadic patient and involves KRIT1. The second affects CCM2 and it is harbored by a woman with familial CCM. Interestingly, molecular analysis extended to both healthy and ill relatives allowed to estimate, for the first time, a penetrance for CCM2 lower than 100%, as to date reported. Moreover, heterogeneity of clinical manifestations among those affected carrying the same genotype further confirms involvement of modifier factors in CCM development.

Highlights

Cerebral cavernous malformations (CCM, OMIM #116860) are vascular lesions affecting brain capillaries
The first patient affected by the sporadic form of cerebral cavernous malformations (CCM) carries the nucleotide substitution IVS15-66A>T(c.2026-66A>T), located in the intron between coding exon 14 and 15 [10], affecting the adenine located 66 nucleotide upstream of the exon junction (Figure 3); the nomenclature refers to coding exons only
Rs17164451 and rs2027950 are intronic, while rs11542682is a synonymous substitution known to lead splicing impairment and, associated to CCM lesion development [11]. Another five single nucleotide polymorphisms (SNPs) were identified in the CCM2 gene and, among these, c.358G>A is reported in Human Gene Mutation Database (HGMD) as associated to CCM development [12]

Summary

Introduction

Cerebral cavernous malformations (CCM, OMIM #116860) are vascular lesions affecting brain capillaries. Due to the enlarged, tangled vessels which form them. The single layer of endothelial cells is really inhomogeneous as a result of pericyte absence and defective tight and adherens junctions [1] with consequent impairment of the blood-brain barrier. This condition leads to an increased bleeding risk of lesions. Intracerebral hemorrhage (ICH), together with seizures, are the main clinical manifestations appearing in up to 70% of symptomatic patients.

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Conclusion