Abstract
X-linked Alport syndrome (XLAS) is a progressive hereditary kidney disease caused by mutations in the COL4A5 gene encoding the type IV collagen α5 chain. To date, 11 cases having somatic mosaic variants in COL4A5 have been reported; however, all of them involved single-nucleotide variations (SNVs). Here, we report a female XLAS patient with somatic mosaicism identified by copy number variation (CNV) in COL4A5. The case was a 35-year-old female, the mother of the proband, whose only clinical symptom was hematuria. The proband, who was the son of this patient, was diagnosed with XLAS by gene testing, which showed a large hemizygous deletion from exon 3–51 in COL4A5 detected by next-generation sequencing and then confirmed by multiplex ligation-dependent probe amplification (MLPA). Then, MLPA analysis revealed that the female patient had the same deletion with only a 20% copy number reduction compared with a normal female control; she was thus diagnosed with XLAS with somatic mosaicism. CNVs in COL4A5 are relatively rare and, to the best of our knowledge, somatic mosaic variants with CNVs have never been reported. This case clearly featured a germline variant because the patient’s son exhibited XLAS. This is thus the first case report on an XLAS patient having CNV in COL4A5 with somatic mosaicism. The obtained findings were very important for the genetic counseling of this family.
Similar content being viewed by others
References
Bekheirnia MR, Reed B, Gregory MC, McFann K, Shamshirsaz AA, Masoumi A, et al. Genotype-phenotype correlation in X-linked Alport syndrome. J Am Soc Nephrol. 2010;21(5):876–83. https://doi.org/10.1681/ASN.2009070784.
Gross O, Netzer KO, Lambrecht R, Seibold S, Weber M. Meta-analysis of genotype-phenotype correlation in X-linked Alport syndrome: impact on clinical counselling. Nephrol Dial Transplant. 2002;17(7):1218–27.
Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, et al. X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males. J Am Soc Nephrol. 2000;11(4):649–57.
Nozu K, Nakanishi K, Abe Y, Udagawa T, Okada S, Okamoto T, et al. A review of clinical characteristics and genetic backgrounds in Alport syndrome. Clin Exp Nephrol. 2019;23(2):158–68. https://doi.org/10.1007/s10157-018-1629-4.
Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, et al. X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a "European Community Alport syndrome concerted action" study. J Am Soc Nephrol. 2003;14(10):2603–10.
Yamamura T, Nozu K, Fu XJ, Nozu Y, Ye MJ, Shono A, et al. Natural history and genotype-phenotype correlation in female X-linked Alport syndrome. Kidney Int Rep. 2017;2(5):850–5. https://doi.org/10.1016/j.ekir.2017.04.011.
Beicht S, Strobl-Wildemann G, Rath S, Wachter O, Alberer M, Kaminsky E, et al. Next generation sequencing as a useful tool in the diagnostics of mosaicism in Alport syndrome. Gene. 2013;526(2):474–7. https://doi.org/10.1016/j.gene.2013.05.045.
Bu L, Chen J, Nelson AC, Katz A, Kashtan CE, Kim Y, et al. Somatic mosaicism in a male patient with X-linked Alport syndrome. Kidney Int Rep. 2019;4(7):1031–5. https://doi.org/10.1016/j.ekir.2019.03.005.
Fu XJ, Nozu K, Kaito H, Ninchoji T, Morisada N, Nakanishi K, et al. Somatic mosaicism and variant frequency detected by next-generation sequencing in X-linked Alport syndrome. Eur J Hum Genet. 2016;24(3):387–91. https://doi.org/10.1038/ejhg.2015.113.
Krol RP, Nozu K, Nakanishi K, Iijima K, Takeshima Y, Fu XJ, et al. Somatic mosaicism for a mutation of the COL4A5 gene is a cause of mild phenotype male Alport syndrome. Nephrol Dial Transplant. 2008;23(8):2525–30. https://doi.org/10.1093/ndt/gfn005.
Plant KE, Boye E, Green PM, Vetrie D, Flinter FA. Somatic mosaicism associated with a mild Alport syndrome phenotype. J Med Genet. 2000;37(3):238–9. https://doi.org/10.1136/jmg.37.3.238.
Yokota K, Nozu K, Minamikawa S, Yamamura T, Nakanishi K, Kaneda H, et al. Female X-linked Alport syndrome with somatic mosaicism. Clin Exp Nephrol. 2017;21(5):877–83. https://doi.org/10.1007/s10157-016-1352-y.
Nozu K, Krol RP, Nakanishi K, Yoshikawa N, Nozu Y, Ohtsuka Y, et al. Detection by multiplex ligation-dependent probe amplification of large deletion mutations in the COL4A5 gene in female patients with Alport syndrome. Pediatr Nephrol. 2009;24(9):1773–4. https://doi.org/10.1007/s00467-009-1122-0.
Nagano C, Nozu K, Morisada N, Yazawa M, Ichikawa D, Numasawa K, et al. Detection of copy number variations by pair analysis using next-generation sequencing data in inherited kidney diseases. Clin Exp Nephrol. 2018;22(4):881–8. https://doi.org/10.1007/s10157-018-1534-x.
Yamamura T, Nozu K, Minamikawa S, Horinouchi T, Sakakibara N, Nagano C, et al. Comparison between conventional and comprehensive sequencing approaches for genetic diagnosis of Alport syndrome. Mol Genet Genomic Med. 2019;7(9):e883. https://doi.org/10.1002/mgg3.883.
Spinner NB, Conlin LK. Mosaicism and clinical genetics. Am J Med Genet C Semin Med Genet. 2014;166C(4):397–405. https://doi.org/10.1002/ajmg.c.31421.
Zhang Y, Ding J, Zhang H, Yao Y, Xiao H, Wang S, et al. Effect of heterozygous pathogenic COL4A3 or COL4A4 variants on patients with X-linked Alport syndrome. Mol Genet Genomic Med. 2019;7(5):e647. https://doi.org/10.1002/mgg3.647.
Fallerini C, Baldassarri M, Trevisson E, Morbidoni V, La Manna A, Lazzarin R, et al. Alport syndrome: impact of digenic inheritance in patients management. Clin Genet. 2017;92(1):34–44. https://doi.org/10.1111/cge.12919.
Mencarelli MA, Heidet L, Storey H, van Geel M, Knebelmann B, Fallerini C, et al. Evidence of digenic inheritance in Alport syndrome. J Med Genet. 2015;52(3):163–74. https://doi.org/10.1136/jmedgenet-2014-102822.
Nakanishi K, Yoshikawa N. Alport syndrome. Nihon Jinzo Gakkai Shi. 2015;57(4):736–42.
Acknowledgments
We thank Edanz (www.edanzediting.co.jp) for editing the English text of a draft of this manuscript.
Funding
This study was supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (subject ID: 17H04189 to Kazumoto Iijima and 19K08726 to Kandai Nozu), and by the Japan Agency for Medical Research and Development (AMED) (Grant Number JP19ek0109231h0003 to Kandai Nozu and Kazumoto Iijima).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Kazumoto Iijima has received grant support from Daiichi Sankyo Co., Ltd., as well as consulting fees from Takeda Pharmaceutical Company and Kyowa Hakko Kirin Co., Ltd. Kandai Nozu has received lecture fees from Novartis Pharmaceuticals Corporation. Kazumoto Iijima and Kandai Nozu have filed a patent application regarding the development of antisense nucleotides for exon-skipping therapy in Alport syndrome.
Ethical approval
All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research committee at Kobe University and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all of the participants included in the study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Aoto, Y., Kise, T., Nakanishi, K. et al. A case with somatic and germline mosaicism in COL4A5 detected by multiplex ligation-dependent probe amplification in X-linked Alport syndrome. CEN Case Rep 9, 431–436 (2020). https://doi.org/10.1007/s13730-020-00503-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13730-020-00503-8