Novel variants in POLH and TREM2 genes associated with a complex phenotype of xeroderma pigmentosum variant type and early‐onset dementia

摘要

Background Xeroderma pigmentosum (XP) is a rare, genetically heterogeneous, autosomal recessive disorder caused by defects in the genes involved in repairing DNA damaged by ultraviolet radiation. These defects lead to a propensity to develop skin cancer at early ages as a hallmark, and progressive neurological degeneration can be observed in around 25% of patients. Eight clinically heterogeneous groups have been identified so far (XPA to XPG and XPV). Xeroderma pigmentosum variant type (XPV) is associated with pathogenic variants in POLH on chromosome 6, and no neurological dysfunction has been seen in these cases. However, on the same chromosome, it has been shown that TREM2 is associated with some types of dementia, particularly in patients with a behavioral variant frontotemporal phenotype. Methods Gene mutational analysis was performed by whole‐exome sequencing. Results We report a case of a Caucasian woman with XP that developed behavioral and cognitive impairment at age 37. Whole‐exome sequencing identified novel homozygous variants in POLH c.638CG (p.Ser213*) and TREM2 c.154CT (p.Arg52Cys), classifying the patient as XPV and suggesting that her frontotemporal dementia phenotype could be related to the variant in TREM2. Conclusion This paper describes a rare case of a patient with two novel variants in the same chromosome associated with XPV and early‐onset dementia.