title: Female X-linked Alport syndrome with somatic mosaicism.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 6500017, Japan.
authors: Kana
authors: K
authors: Yokota
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 6500017, Japan. nozu@med.kobe-u.ac.jp.
authors: Kandai
authors: K
authors: Nozu
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 6500017, Japan.
authors: Shogo
authors: S
authors: Minamikawa
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 6500017, Japan.
authors: Tomohiko
authors: T
authors: Yamamura
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 6500017, Japan.
authors: Keita
authors: K
authors: Nakanishi
authors: Department of Pediatrics, Komatsu Municipal Hospital, Komatsu, Ishikawa, Japan.
authors: Hisashi
authors: H
authors: Kaneda
authors: Department of Nephrology, Tokyo Metropolitan Children's Medical Center, Fuchu, Tokyo, Japan.
authors: Riku
authors: R
authors: Hamada
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 6500017, Japan.
authors: Yoshimi
authors: Y
authors: Nozu
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 6500017, Japan.
authors: Akemi
authors: A
authors: Shono
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 6500017, Japan.
authors: Takeshi
authors: T
authors: Ninchoji
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 6500017, Japan.
authors: Naoya
authors: N
authors: Morisada
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 6500017, Japan.
authors: Shingo
authors: S
authors: Ishimori
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 6500017, Japan.
authors: Junya
authors: J
authors: Fujimura
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 6500017, Japan.
authors: Tomoko
authors: T
authors: Horinouchi
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 6500017, Japan.
authors: Hiroshi
authors: H
authors: Kaito
authors: Department of Pediatrics, Wakayama Medical University, Wakayama, Japan.
authors: Koichi
authors: K
authors: Nakanishi
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 6500017, Japan.
authors: Ichiro
authors: I
authors: Morioka
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 6500017, Japan.
authors: Mariko
authors: M
authors: Taniguchi-Ikeda
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 6500017, Japan.
authors: Kazumoto
authors: K
authors: Iijima
mesh_terms: D000328:Adult; D002648:Child; D041321:Chromosomes, Human, X; D024141:Collagen Type IV / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D060045:Genes, Modifier; D020022:Genetic Predisposition to Disease; D006417:Hematuria / Q000235:genetics; D040941:Heredity; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009030:Mosaicism; D009154:Mutation; D059645:Mutation Rate; D009394:Nephritis, Hereditary / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011507:Proteinuria / Q000235:genetics; D012720:Severity of Illness Index; D049951:X Chromosome Inactivation
chemical_list: C478159:COL4A5 protein, human; D024141:Collagen Type IV
keywords: Female; Modifier gene; Next-generation sequencing; Somatic mosaic variants; X chromosome inactivation