Researchers detected a complex and novel mutation in an infantile-onset Pompe disease patient that was caused by the insertion of a transposable element (TE) deep into intron 15 of the GAA gene, according to a new study published in the International Journal of Molecular Science.

“This study draws the attention of researchers to the need for detailed analysis of genome sequencing data for the presence of footprints of TE insertions,” the authors said.

The mutation was identified to be caused by the insertion of a homozygous 3394 base pair (b.p.) TE composed of SVA_D and SVA_E elements in the forward orientation, and an L1ME3 element in the reverse orientation. The insertion resulted in the exonization of roughly 3137 b.p. of the TE sequence causing the termination of transcription and the almost complete absence (~1%) of full-length GAA mRNA isoform. This ultimately resulted in a reduction of the acid alpha-glucosidase (GAA) protein.

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Sanger sequencing of all exons with roughly 200 b.p. of adjacent introns did not reveal any disease variants. The whole coding sequence of the GAA mRNA obtained from the patient’s white blood cells were also analyzed and revealed no abnormalities. The amount of GAA expression was then analyzed using quantitative polymerase chain reaction (qPCR) primers targeting the 5’ region (exons 3-4) and the 3’ region (exons 15-16).

The results revealed that the gene expression was only 15% compared to healthy controls in the 5’ direction and only 1% in the 3’ direction. qPCR analysis was also performed on the mother’s mRNA and revealed expression of only 52% in the 5’ direction and 63% in the 3’ direction. Further analysis then found a TE in intron 15 of GAA which appeared to be retrotransposition of the SVA element from chromosome 20.

The patient in the study was a 1.5 month-old male who had a family history of suspected Pompe disease. The infant was the fifth birth from a consanguineous marriage. The other births included a miscarriage at 7 weeks, 2 children with hypertrophic cardiomyopathy who died before age 1, and a healthy 9-year-old.

The patient presented with suspected hypertrophic cardiomyopathy, reduced tendon reflexes of the lower limb, elevated levels of liver aminotransferases, and increased activity of creatine kinase. The patient’s levels of GAA were 0.130 μmol/L/h (normal range 1-20), indicating Pompe disease.

“Together, these results strongly suggest that the exonization of the ~3137 b.p. TE sequence using strong acceptor site right downstream of CCCTCT repeats and polyA signal in the 3′ end of the TE with subsequent termination of transcription is the main deleterious consequence of this insertion,” the authors concluded.


Bychkov I, Baydakova G, Filatova A, et al. Complex transposon insertion as a novel cause of Pompe disease. Int J Mol Sci. 2021;22(19):10887. doi:10.3390%2Fijms221910887