PDCD10 Gene Mutations in Multiple Cerebral Cavernous Malformations

Abstract

Cerebral cavernous malformations (CCMs) are vascular abnormalities that may cause seizures, intracerebral haemorrhages, and focal neurological deficits. Familial form shows an autosomal dominant pattern of inheritance with incomplete penetrance and variable clinical expression. Three genes have been identified causing familial CCM: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3. Aim of this study is to report additional PDCD10/CCM3 families poorly described so far which account for 10-15% of hereditary cerebral cavernous malformations. Our group investigated 87 consecutive Italian affected individuals (i.e. positive Magnetic Resonance Imaging) with multiple/familial CCM through direct sequencing and Multiplex Ligation-Dependent Probe Amplification (MLPA) analysis. We identified mutations in over 97.7% of cases, and PDCD10/CCM3 accounts for 13.1%. PDCD10/CCM3 molecular screening revealed four already known mutations and four novel ones. The mutated patients show an earlier onset of clinical manifestations as compared to CCM1/CCM2 mutated patients. The study of further families carrying mutations in PDCD10/CCM3 may help define a possible correlation between genotype and phenotype; an accurate clinical follow up of the subjects would help define more precisely whether mutations in PDCD10/CCM3 lead to a characteristic phenotype.

Cerebral Cavernous Malformations: An Update on Prevalence, Molecular Genetic Analyses, and Genetic Counselling

“…While 24 CCM1 mutation carriers are listed here, only a single proband with a heterozygous CCM3 splice site mutation was identified ( Table 1 ). This uneven distribution between pathogenic variants in CCM1 , CCM2 , and CCM3 demonstrates that the latter is less tolerant to mutations and supports the observation that CCM3 mutation carriers often manifest earlier in life with a more severe phenotype [Denier et al, 2006, Cigoli et al, 2014, Shenkar et al, 2015.…”

“…In addition, inter-and intrafamilial phenotypic variability is high and fulminant clinical courses of CCM are rather rare. An earlier and more severe disease manifestation has been reported for CCM3 mutation carriers when compared to CCM1 and CCM2 mutation carriers [Denier et al, 2006;Cigoli et al, 2014;. In a cohort of 18 CCM3 mutation carriers, the mean age at symptom onset was 12.6 years (range 0.25-52 years) as opposed to a mean age at first overt haemorrhage of 30 years for familial cases carrying a CCM1 or CCM2 mutation (range 1-52 years) [Shenkar et al, 2015].…”

“…Targeted sequencing of DNA samples of both parents should be offered as part of the diagnostic work-up for apparently isolated CCM cases. Since parents do not always consent to predictive genetic testing, de novo mutations in CCM1-3 might not be as rare as previously thought [Lucas et al, 2001;Bergametti et al, 2005;Liquori et al, 2006;Stahl et al, 2008;Riant et al, 2013;Cigoli et al, 2014;Shenkar et al, 2015;. NGS data may indicate mosaicism, but high coverage and a sophisticated validation are necessary for reliable clinical conclusions [Acuna-Hidalgo et al, 2015].…”

“…Pathogenic variants can be identified in 87-98% of all cases with a positive family history [Denier et al, 2006;Stahl et al, 2008;Cigoli et al, 2014;Spiegler et al 2014]. For apparently mutation-negative familial cases, pathogenic variants outside of the immediate diagnostic target region have been discussed.…”

Constitutional de novo and postzygotic mutations in isolated cases of cerebral cavernous malformations

“…Following the established criteria, pathogenic variants can be found in up to 87% of familial and 57% of isolated cases (Spiegler et al 2014). De novo mutations have occasionally been reported previously, but their precise prevalence is still unknown (Bergametti et al 2005;Liquori et al 2006;Stahl et al 2008;Riant et al 2013;Cigoli et al 2014).…”