Mechanism of pathogenicity
We’ll show below you the main pathogenic mechanisms by which deep intronic mutation may cause disease. In addition, we’ll give you some examples.
1) Inclusion of pseudoexons
– Beta-Thalassemia: IVS2+705G>T in the HBB gene
– Leber congenital amaurosis: c.2991+1655A>G in the CEP290 gene
– Duchenne muscular dystrophy: c.3787-843C>A in the DMD gene
– Breast cancer: c.6937+594T>G in the BRCA2 gene
2) Competition with natural splices sites
– Pompe disease: c.2190-345A>G in the GAA gene
– Barth syndrome: IVS3+110G>A in the TAZ gene
– Menkes disease: c.2406+1117A>G in the ATP7A gene
3) Disruption of the transcription regulatory pattern
– Charcot-Marie-Tooth disease type 1B: c.126-1086T>A in the MPZ gene
– Lethal Lung Developmental Disorder: 0.8 Kb large deletion in intron 1 of the FOXF1 gene
4) Inactivation of non-coding RNA genes (ncRNA gene)
– Lowry-Wood syndrome/Taybi-Linder syndrome: various point mutations in the RNU4ATAC ncRNA gene, which is located in intron 2 of the CLASP1 gene
5) Genomic rearrangements (rarely associated with monogenic diseases)
– Duchenne muscular dystrophy: 90kb insertion of non-coding DNA from chromosome 4 into intron 43 of the DMD gene
– X-linked intellectual developmental disorder-1: the last six duplicated exons of the TENM3 gene inserted in inverted orientation into intron 2 of the IQSEC2 gene
If NGS-based tests (like WES or multigene panels) and large deletion/duplication analyses fail to identify a causative mutation, the presence of a deep intronic mutation should be taken into account, and its possible pathogenicity should be analysed by mRNA studies in affected tissue from patients.
Definition
