Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome

Xue Jun Fu, Kandai Nozu, Hiroshi Kaito, Takeshi Ninchoji, Naoya Morisada, Koichi Nakanishi, Norishige Yoshikawa, Hiromi Ohtsubo, Natsuki Matsunoshita, Naohiro Kamiyoshi, Chieko Matsumura, Nobuaki Takagi, Kohei Maekawa, Mariko Taniguchi-Ikeda, Kazumoto Iijima

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

X-linked Alport syndrome (XLAS) is a progressive, hereditary nephropathy. Although men with XLAS usually develop end-stage renal disease before 30 years of age, some men show a milder phenotype and develop end-stage renal disease later in life. However, the molecular mechanisms associated with this milder phenotype have not been fully identified. We genetically diagnosed 186 patients with suspected XLAS between January 2006 and August 2014. Genetic examination involved: (1) extraction and analysis of genomic DNA using PCR and direct sequencing using Sanger's method and (2) next-generation sequencing to detect variant allele frequencies. We identified somatic mosaic variants in the type VI collagen, α5 gene (COL4A5) in four patients. Interestingly, two of these four patients with variant frequencies in kidney biopsies or urinary sediment cells of ≥50% showed hematuria and moderate proteinuria, whereas the other two with variant frequencies of <50% were asymptomatic or only had hematuria. De novo variants can occur even in asymptomatic male cases of XLAS resulting in mosaicism, with important implications for genetic counseling. This is the first study to show a tendency between the variant allele frequency and disease severity in male XLAS patients with somatic mosaic variants in COL4A5. Although this is a very rare status of somatic mosaicism, further analysis is needed to show this correlation in a larger population.

Original languageEnglish
Pages (from-to)387-391
Number of pages5
JournalEuropean Journal of Human Genetics
Volume24
Issue number3
DOIs
Publication statusPublished - 01-03-2016

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Hereditary Nephritis
Mosaicism
Hematuria
Gene Frequency
Chronic Kidney Failure
Collagen Type V
Phenotype
Genetic Counseling
Proteinuria
Kidney
Biopsy
Polymerase Chain Reaction
DNA
Population
Genes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Fu, X. J., Nozu, K., Kaito, H., Ninchoji, T., Morisada, N., Nakanishi, K., ... Iijima, K. (2016). Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome. European Journal of Human Genetics, 24(3), 387-391. https://doi.org/10.1038/ejhg.2015.113
Fu, Xue Jun ; Nozu, Kandai ; Kaito, Hiroshi ; Ninchoji, Takeshi ; Morisada, Naoya ; Nakanishi, Koichi ; Yoshikawa, Norishige ; Ohtsubo, Hiromi ; Matsunoshita, Natsuki ; Kamiyoshi, Naohiro ; Matsumura, Chieko ; Takagi, Nobuaki ; Maekawa, Kohei ; Taniguchi-Ikeda, Mariko ; Iijima, Kazumoto. / Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome. In: European Journal of Human Genetics. 2016 ; Vol. 24, No. 3. pp. 387-391.
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abstract = "X-linked Alport syndrome (XLAS) is a progressive, hereditary nephropathy. Although men with XLAS usually develop end-stage renal disease before 30 years of age, some men show a milder phenotype and develop end-stage renal disease later in life. However, the molecular mechanisms associated with this milder phenotype have not been fully identified. We genetically diagnosed 186 patients with suspected XLAS between January 2006 and August 2014. Genetic examination involved: (1) extraction and analysis of genomic DNA using PCR and direct sequencing using Sanger's method and (2) next-generation sequencing to detect variant allele frequencies. We identified somatic mosaic variants in the type VI collagen, α5 gene (COL4A5) in four patients. Interestingly, two of these four patients with variant frequencies in kidney biopsies or urinary sediment cells of ≥50{\%} showed hematuria and moderate proteinuria, whereas the other two with variant frequencies of <50{\%} were asymptomatic or only had hematuria. De novo variants can occur even in asymptomatic male cases of XLAS resulting in mosaicism, with important implications for genetic counseling. This is the first study to show a tendency between the variant allele frequency and disease severity in male XLAS patients with somatic mosaic variants in COL4A5. Although this is a very rare status of somatic mosaicism, further analysis is needed to show this correlation in a larger population.",
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Fu, XJ, Nozu, K, Kaito, H, Ninchoji, T, Morisada, N, Nakanishi, K, Yoshikawa, N, Ohtsubo, H, Matsunoshita, N, Kamiyoshi, N, Matsumura, C, Takagi, N, Maekawa, K, Taniguchi-Ikeda, M & Iijima, K 2016, 'Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome', European Journal of Human Genetics, vol. 24, no. 3, pp. 387-391. https://doi.org/10.1038/ejhg.2015.113

Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome. / Fu, Xue Jun; Nozu, Kandai; Kaito, Hiroshi; Ninchoji, Takeshi; Morisada, Naoya; Nakanishi, Koichi; Yoshikawa, Norishige; Ohtsubo, Hiromi; Matsunoshita, Natsuki; Kamiyoshi, Naohiro; Matsumura, Chieko; Takagi, Nobuaki; Maekawa, Kohei; Taniguchi-Ikeda, Mariko; Iijima, Kazumoto.

In: European Journal of Human Genetics, Vol. 24, No. 3, 01.03.2016, p. 387-391.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome

AU - Fu, Xue Jun

AU - Nozu, Kandai

AU - Kaito, Hiroshi

AU - Ninchoji, Takeshi

AU - Morisada, Naoya

AU - Nakanishi, Koichi

AU - Yoshikawa, Norishige

AU - Ohtsubo, Hiromi

AU - Matsunoshita, Natsuki

AU - Kamiyoshi, Naohiro

AU - Matsumura, Chieko

AU - Takagi, Nobuaki

AU - Maekawa, Kohei

AU - Taniguchi-Ikeda, Mariko

AU - Iijima, Kazumoto

PY - 2016/3/1

Y1 - 2016/3/1

N2 - X-linked Alport syndrome (XLAS) is a progressive, hereditary nephropathy. Although men with XLAS usually develop end-stage renal disease before 30 years of age, some men show a milder phenotype and develop end-stage renal disease later in life. However, the molecular mechanisms associated with this milder phenotype have not been fully identified. We genetically diagnosed 186 patients with suspected XLAS between January 2006 and August 2014. Genetic examination involved: (1) extraction and analysis of genomic DNA using PCR and direct sequencing using Sanger's method and (2) next-generation sequencing to detect variant allele frequencies. We identified somatic mosaic variants in the type VI collagen, α5 gene (COL4A5) in four patients. Interestingly, two of these four patients with variant frequencies in kidney biopsies or urinary sediment cells of ≥50% showed hematuria and moderate proteinuria, whereas the other two with variant frequencies of <50% were asymptomatic or only had hematuria. De novo variants can occur even in asymptomatic male cases of XLAS resulting in mosaicism, with important implications for genetic counseling. This is the first study to show a tendency between the variant allele frequency and disease severity in male XLAS patients with somatic mosaic variants in COL4A5. Although this is a very rare status of somatic mosaicism, further analysis is needed to show this correlation in a larger population.

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