Improving clinical interpretation of five KRIT1 and PDCD10 intronic variants

Area of Science:

• Genetics
• Molecular Biology
• Neurology

Background:

• Cerebral cavernous malformation (CCM) is a central nervous system vascular disorder.
• Familial CCM arises from variants in KRIT1, MGC4607, or PDCD10.
• Interpreting intronic variants for CCM diagnosis is challenging due to limited data.

Purpose of the Study:

• To investigate the functional impact of specific intronic and previously reported KRIT1 variants in familial CCM.
• To assess the utility of mRNA analysis in the diagnostic workflow for CCM.

Main Methods:

• mRNA analysis was performed on two novel intronic variants (KRIT1 c.1147-7 T>G, PDCD10 c.395+2 T>G) and three published KRIT1 variants.
• In silico predictions were used to support mRNA analysis findings.

Main Results:

• All analyzed variants induced frameshifts, leading to the loss of C-terminal residues crucial for protein-protein interactions.
• These protein alterations disrupt vascular homeostasis.

Conclusions:

• mRNA analysis is a valuable tool for interpreting genetic variants in familial CCM diagnosis.
• The study expands understanding of aberrant splicing in CCM pathogenesis.