Clinical differences between female monozygotic twins with X-linked Alport syndrome with somatic mosaicism

Although female patients with X-linked Alport syndrome (XLAS) have a generally milder prognosis than male counterparts, some female patients show poor prognosis. The clinically observed variation in the severity of female XLAS is thought to be due mainly to X chromosome inactivation (XCI) or modifier gene variants. We describe herein a 4-year-old female patient with persistent hematuria and proteinuria whose monozygotic, twin sister had no apparent abnormality on urinalysis. A kidney biopsy of the patient found the typical pattern of female XLAS. Genetic testing revealed a de novo pathogenic variant of COL4 A5 with somatic mosaicism. However, additional tests revealed that the asymptomatic twin sister had the same COL4 A5 variant with somatic mosaicism, and that the twins had the same ratio of somatic mosaicism and XCI. Moreover, targeted exome sequencing found no other modifier gene variants, suggesting that the severity of female XLAS depends on distinct but unknown factors in addition to the XCI and modifier gene variants. The findings of the present report emphasize the need to identify the hidden factors affecting the severity of Alport syndrome.