Purpose of review: To review recent publications concerning the functional assessment on pre-mRNA splicing of genomic variants found in some monogenic dyslipidemias. Examples are derived from familial hypercholesterolemia, familial HDL deficiency/Tangier disease and familial hypobetalipoproteinemia.
Recent findings: About 5-10% of genomic variants found in familial hypercholesterolemia, FHD/Tangier disease and familial hypobetalipoproteinemia are located in the introns of the candidate genes and are classified as splicing mutations. Although variants affecting highly conserved GT/AG dinucleotides at the splice sites are likely to be pathogenic, it is difficult to predict the effects of variants located deep in the introns. Algorithms were developed to predict the effect of these variants and to provide the rationale for functional studies. Combined in-silico and wet bench analysis revealed that some intronic variants classified as pathogenic have no effect, whereas others generated abnormal transcripts. Nucleotide substitutions at the 5' and the 3' of exons might change the splice site consensus sequence, causing splicing defects. Rare silent mutations were identified which create new splice sites within exons, with the consequent production of abnormal transcripts.
Summary: Intronic variants, even if located deep in introns, as well as exonic variants could affect splicing with the formation of abnormal transcripts encoding structurally abnormal proteins.