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Female X-linked Alport syndrome with somatic mosaicism

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X-linked Alport syndrome (XLAS) is a progressive, hereditary nephropathy. Although males with XLAS usually develop end-stage renal disease before 30 years of age, some men show a milder phenotype and possess somatic mosaic variants of the type IV collagen α5 gene (COL4A5), with severity depending on variant frequencies. In females, somatic mosaic variants are rarely reported in XLAS, and it is not clear what determines severity.


Two females with somatic mosaic mutations in COL4A5 with variant frequencies of 17.9 and 22.1% were detected using the next-generation sequencing. One patient only had hematuria. The other, however, had moderate proteinuria, which is a severe phenotype for a female XLAS patient of her age. The molecular mechanisms for the severe phenotype were investigated by examining variant frequencies in urinary sediment cells and X chromosome inactivation patterns, and by looking for modifier variants in podocyte-related genes using the next-generation sequencing.


The severe phenotype patient had a variant frequency of 36.6% in urinary sediment cells, which is not markedly high, nor did she show skewed X chromosome inactivation. However, she did have the heterozygous variant in COL4A3, which can affect severity.


Factors determining severity in female XLAS patients remain unclear. One studied patient with the somatic variant in COL4A5 showed a severe phenotype without skewed X chromosome inactivation, which might be derived from digenic variants in COL4A3 and COL4A5. Further studies are required to determine molecular mechanisms behind female XLAS resulting in the severe phenotype.

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This study was supported by a Grant from the Ministry of Health, Labor and Welfare of Japan for Research on Rare Intractable Diseases in Kidney and Urinary Tract (H24-nanchitou (nan)-ippan-041 to Kazumoto Iijima) in the “Research on Measures for Intractable Diseases” Project; a Grant-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Subject ID: 25893131 to Kandai Nozu and 26293203 to Kazumoto Iijima).

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Correspondence to Kandai Nozu.

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Kandai Nozu received lecture fees from Novartis Pharma K.K. and Taisho Pharm. Co. Kazumoto Iijima has received grants from Daiichi Sankyo Co., Ltd., Japan Blood Product Organization, Miyarisan Pharmaceutical Co., Ltd., AbbVie LLC, CSL Behring, JCR Pharmaceuticals Co., Ltd., Teijin Pharma Ltd., Novo Nordisk Pharma Ltd., AIR WATER MEDICAL Inc., Astellas Pharma Inc., Takeda Pharmaceutical Company Ltd. and Taisho Toyama Pharmaceutical Co., Ltd. and lecture fees from Meiji Seika Pharma Co., Ltd., Novartis Pharma K.K., Zenyaku Kogyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Co., Ltd., Springer Japan, Asahi Kasei Pharma Corp, Boehringer Ingelheim, Medical Review Co., Ltd., NIKKEI RADIO BROADCASTING CORPORATION, Japan Blood Product Organization and CSL Behring and manuscript fees from Chugai Pharmaceutical Co., Ltd., and consulting fees from Zenyaku Kogyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Takeda Pharmaceutical Company Ltd., Ono Pharmaceutical Co., Ltd. and Kyowa Hakko Kirin Co. Ltd.

Ethical consideration and informed consent

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Review Board of Kobe University School of Medicine (IRB approval number 301) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

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Yokota, K., Nozu, K., Minamikawa, S. et al. Female X-linked Alport syndrome with somatic mosaicism. Clin Exp Nephrol 21, 877–883 (2017).

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