KRIT1 Gene in Patients with Cerebral Cavernous Malformations: Clinical Features and Molecular Characterization of Novel Variants

Abstract

Cerebral cavernous malformations (CCMs) are vascular malformations that may result in headaches, seizures, focal neurological deficits, and hemorrhage. CCMs occur sporadically (80%) or in familial form (20%), with autosomal dominant inheritance. Among the three CCM-related genes, mutations in KRIT1 account for 53-65% of familial cases and more than 100 different mutations have been identified so far. In the present work, we describe the clinical, neuroradiological, and genetic findings of sixteen CCM Italian patients, 13 belonging to 4 unrelated families and 3 sporadic cases. Six distinct KRIT1 gene variants, two novel (c.1730+1_1730+3del, c.1664 C>T) and four previously described (c.966G>A, c.1255-1G>A c.1197_1200del, c.1255-1_1256del), were identified, including a possible de novo mutation. All the variants resulted in a premature stop codon. Cerebral 1.5 T magnetic resonance imaging showed multiple CCMs in all the mutation carriers for whom it was available, including sporadic cases. One patient had also cutaneous angiomas. Among the mutation carriers, symptomatic patients constituted 66% and a variable phenotypic expression was observed. Our data confirms phenotypic variability and incomplete penetrance of neurological symptoms in KRIT1-positive families, expands the mutational spectrum of this gene, and highlights how sporadic cases with multiple lesions need an approach similar to individuals with familial CCM.

Keywords: CCM; Cutaneous angioma; De novo mutation; Functional studies; KRIT1 gene; Novel variants.

Fig. 1

a Pedigrees of the four CCM families. Squares represent males and circles represent females. Full black symbols: symptomatic individuals with CCMs on MRI; white symbols: unaffected individuals; black half symbols: asymptomatic individuals with CCMs on MRI; gray symbols: individuals with epilepsy in whom MRI has not been performed; diagonal line symbols: deceased subjects; arrow: proband; “?”: MRI not performed, “*”: presence of a mutated allele; “°”: genetic analysis not carried out, “§”: mutation carriers (genetic analysis performed elsewhere). b Electropherograms of DNA and cDNA and corresponding amino acid sequences of variants identified in CCM patients. Arrows indicate the sites of mutation; red dotted line arrow indicates the boundary between exon 14 and exon 16. c Brain MRI findings in CCM patients. Susceptibility-weighted (a) and gradient echo (b) images showing multiple CCMs. Arrows indicate CCMs (in the case of sporadic patient 6, arrows are not shown due to the high number of lesions). In patient II: 1 from family 2, in addition to cerebral cavernous malformations, deep blue nodules are also noted in the subcutaneous tissue of upper limbs and neck (c)