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Improving clinical interpretation of five KRIT1 and PDCD10 intronic variants
Author(s) -
Fusco Carmela,
Nardella Grazia,
Petracca Antonio,
Ronchi Dario,
Paciello Nicola,
Di Giacomo Marilena,
Gambardella Stefano,
Lanfranconi Silvia,
Zampatti Stefania,
D'Agruma Leonardo,
Micale Lucia,
Castori Marco
Publication year - 2021
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13944
Subject(s) - in silico , frameshift mutation , rna splicing , genetics , biology , messenger rna , intron , exon , gene , rna
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 Here, the mRNA analysis for two intronic unpublished variants ( KRIT1 c.1147‐7 T 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.