Onset mechanism of a female patient with Dent disease 2

Background Approximately 15% of patients with Dent disease have pathogenic variants in theOCRLgene on Xq25-26, a condition that is referred to as Dent disease 2 (Dent-2). Dent-2 patients sometimes show mild extrarenal features of Lowe syndrome, such as mild mental retardation, suggesting that Dent-2 represents a mild form of Lowe syndrome. To date, eight female patients with Lowe syndrome have been reported, but no female Dent-2 patients have been reported. Methods In this study, we performed genetic testing of the first female Dent-2 patient to detect the presence of anOCRLvariant. Aberrant splicing was demonstrated by in vivo, in vitro, and in silico assays, and skewed X-chromosome inactivation (XCI) in our patient and asymptomatic mothers of three Lowe patients with the heterozygousOCRLvariant was evaluated by HUMARA assays using genomic DNA and RNA expression analysis. Results Our patient had anOCRLheterozygous intronic variant of c.1603-3G > C in intron 15 that led to a 169-bp insertion in exon 16, yielding the truncating mutation r.1602_1603ins (169) (p.Val535Glyfs*6) in exon 16. HUMARA assays of leukocytes obtained from this patient demonstrated incompletely skewed XCI (not extremely skewed). On the other hand, the asymptomatic mothers of 3 Lowe patients demonstrated random XCI. These results may lead to our patient's Dent-2 phenotype. Conclusions This is the first report of a female patient clinically and genetically diagnosed with Dent-2 caused by anOCRLheterozygous splicing site variant and skewed XCI. Skewed XCI may be one of the factors associated with phenotypic diversity in female patients with Lowe syndrome and Dent-2.