Deep intronic mutations


Deep intronic variants are those genetic variants  falling more than 100bp away from the closest exon-intron boundary.

Of course, like all other type of variants, deep intronic variants may be be pathogenic, but their pathogenicity is hard to be confirmed. They can be considered as the ‘dark side’ of the mutational spectrum of a gene, because they’re (1) hard to be identified and (2) difficult to be correctly evaluated.

By the introduction of whole genome sequencing in clinical studies, an increasing number of deep intronic mutations are continuously identified. Recent evidences show the a vast set of intronic regions in the human genome should some some sort of complex functionality, that must be elucidated.

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.


Vaz-Drago et al. Deep intronic mutations and human disease. Hum Genet 2017 Sep; 136(9):1093-1111. PMID: 28497172

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