人类基因组中约有一半的部分由移动元件衍生的重复序列组成，主要是反转录转座子，通常没有致病效果。家族性视网膜母细胞瘤是由RB1基因生殖系致病变异所致。在本文中，我们描述了一个父子受到视网膜母细胞瘤影响的家族。通过对RB1基因编码序列和外显子-内含子交界区的DNA分析，未发现致病变异。然而，RB1 mRNA分析显示了一个嵌入了114个核苷酸从HPF1基因到RB1基因内的嵌合转录本。这个嵌合转录本导致视网膜母细胞瘤蛋白功能结构域内嵌入了38个氨基酸。RB1内含子17的后续DNA分析显示了全长HPF1反转录基因以相反方向插入。功能性试验表明，这个插入对视网膜母细胞瘤蛋白功能有不利影响。这是首次报道全长反转录基因插入到人类孟德尔遗传疾病中，产生了嵌合转录本和非功能性嵌合蛋白。一些反转录基因插入可能会被标准诊断遗传学测试遗漏，因此，反转录基因插入对人类疾病的贡献可能被低估。在诊断应用中广泛使用全基因组测序将有助于更全面地了解反转录基因。©作者(或其雇主) 2023年。不得商业复用。见权力和权限。由BMJ出版。

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.© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.