Improving clinical interpretation of five KRIT1 and PDCD10 intronic variants

Carmela Fusco, Grazia Nardella, Antonio Petracca, Dario Ronchi, Nicola Paciello, Marilena Di Giacomo, Stefano Gambardella, Silvia Lanfranconi, Stefania Zampatti, Leonardo D'Agruma, Lucia Micale, Marco Castori

Research output: Contribution to journalArticlepeer-review

Abstract

Cerebral cavernous malformation (CCM) is a vascular malformation of the central nervous system which may occur sporadically or segregate within families due to heterozygous variants in KRIT1/CCM1, MGC4607/CCM2 or PDCD10/CCM3. Intronic variants are not uncommon in familial CCM, but their clinical interpretation is often hampered by insufficient data supporting in silico predictions. Here, the mRNA analysis for two intronic unpublished variants (KRIT1 c.1147-7 T > G and PDCD10 c.395 + 2 T > G) and three previously published variants in KRIT1 but without data supporting their effects was carried out. This study demonstrated that all variants can induce a frameshift with the lack of residues located in the C-terminal regions and involved in protein–protein complex formation, which is essential for vascular homeostasis. These results support the introduction of mRNA analysis in the diagnostic pathway of familial CCM and expand the knowledge of abnormal splicing patterning in this disorder.

Original languageEnglish
JournalClinical Genetics
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • cerebral cavernous malformations
  • KRIT1
  • mRNA analysis
  • PDCD10
  • splicing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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