About half of the human genome is composed of repeated sequences derived from mobile elements, mainly retrotransposons, generally without pathogenic effect. Familial forms of retinoblastoma are caused by germline pathogenic variants in RB1 gene. Here, we describe a family with retinoblastoma affecting a father and his son. No pathogenic variant was identified after DNA analysis of RB1 gene coding sequence and exon-intron junctions. However, RB1 mRNA analysis showed a chimeric transcript with insertion of 114 nucleotides from HPF1 gene inside RB1 gene. This chimeric transcript led to an insertion of 38 amino acids in functional domain of retinoblastoma protein. Subsequent DNA analysis in RB1 intron 17 revealed the presence of a full-length HPF1 retrogene insertion in opposite orientation. Functional assay shows that this insertion has a deleterious impact on retinoblastoma protein function. This is the first report of a full-length retrogene insertion involved in human Mendelian disease leading to a chimeric transcript and a non-functional chimeric protein. Some retrogene insertions may be missed by standard diagnostic genetic testing, so contribution of retrogene insertions to human disease may be underestimated. The increasing use of whole genome sequencing in diagnostic settings will help to get a more comprehensive view of retrogenes.
- genetic predisposition to disease
- genetic phenomena
- genetic variation
- sequence analysis
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JLG and CD contributed equally.
Contributors Conception and design: CD, CH, MGV, LG, FR, HP, FD, LL-LR, DS-L, JLG, AP, SMC, LC, SV and IB. Development of methodology: CD, CH, MGV, FL, JLG, AP, SMC, LC and SV. Acquisition of data: JLG, CD, MB, FL, AP, LC and SV. Analysis and interpretation of data: JLG, CD, FL, AP, SMC, MB, CH, LG, LC and SV. Writing, review and/or revision of the manuscript: JLG, FL and LG. All authors reviewed the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.