Noninvasive Genetic Testing for Type IV Collagen Nephropathy Using Oral Mucosa DNA Sampling in Children with Haematuria

Overview

Journal Ren Fail

Publisher Informa Healthcare

Date 2024 Nov 14

PMID 39540369

Authors

Jiaojiao Liu

Dayin Zhou

Xiaowen Wang

Tong Shen

Chunyan Wang

Rufeng Dai

Xinli Han

Lin Huang

Wenli Xu

Jing Chen

Yihui Zhai

Jia Rao

Duan Ma

Qian Shen

Hong Xu

Affiliations

Soon will be listed here.

Abstract

Objective: Hematuria is one of the most common conditions in children, and increase the risk of chronic kidney disease. Persistent hematuria may be the earliest manifestation of type IV collagen-related nephropathy. Early diagnosis is essential for optimized therapy. Due to the invasive nature of kidney biopsy and the high cost of whole exome sequencing, its application in the diagnosis of isolated hematuria is rare. Hence, we performed noninvasive and convenient genetic testing approaches for type IV collagen-related nephropathy.

Methods: We used noninvasive oral mucosa sampling as an alternative method for DNA isolation for genetic testing and designed a panel targeting three type IV collagen nephropathy-related genes in children with hematuria. Children with persistent hematuria unaccompanied by clinically significant proteinuria or renal insufficiency who underwent genetic testing using a hematuria panel were enrolled.

Results: Thirty-seven of 112 (33.0%) patients were found to have a genetic variant in . Pathogenic/likely pathogenic variants were identified in 17 of the 112 patients analyzed (15.2%), which were considered to explain their hematuria manifestations. In addition, variants of unknown significance (VUSs) were found in 17.8% (20/112) of patients. Furthermore, we observed a much greater variant detection rate in patients with a positive family history or more severe hematuria (RBC ≥ 20/HP) or with coexisting microalbuminuria (59.2% vs. 12.7%, < 0.001; 64.0% vs. 24.1%, < 0.001; 66.7% vs. 30.1%, = 0.025).

Conclusions: We present the high prevalence of variants in genes in a multicenter pediatric cohort with hematuria, which requires close monitoring and long-term follow-up.

References

Matthaiou A, Poulli T, Deltas C . Prevalence of clinical, pathological and molecular features of glomerular basement membrane nephropathy caused by or mutations: a systematic review. Clin Kidney J. 2021; 13(6):1025-1036. PMC: 7769542. DOI: 10.1093/ckj/sfz176. View

Zhou L, Xi B, Xu Y, Han Y, Yang Y, Yang J . Clinical, histological and molecular characteristics of Alport syndrome in Chinese children. J Nephrol. 2023; 36(5):1415-1423. DOI: 10.1007/s40620-023-01570-7. View

Savige J, Ariani F, Mari F, Bruttini M, Renieri A, Gross O . Expert consensus guidelines for the genetic diagnosis of Alport syndrome. Pediatr Nephrol. 2018; 34(7):1175-1189. DOI: 10.1007/s00467-018-3985-4. View

Rheault M, McLaughlin H, Mitchell A, Blake L, Devarajan P, Warady B . COL4A gene variants are common in children with hematuria and a family history of kidney disease. Pediatr Nephrol. 2023; 38(11):3625-3633. DOI: 10.1007/s00467-023-05993-z. View

Alge J, Bekheirnia N, Willcockson A, Qin X, Scherer S, Braun M . Variants in genes coding for collagen type IV α-chains are frequent causes of persistent, isolated hematuria during childhood. Pediatr Nephrol. 2022; 38(3):687-695. DOI: 10.1007/s00467-022-05627-w. View

Zhai Y, Xu H, Zhu G, Wei M, Hua B, Shen Q . Efficacy of urine screening at school: experience in Shanghai, China. Pediatr Nephrol. 2007; 22(12):2073-9. DOI: 10.1007/s00467-007-0629-5. View

Rana K, Wang Y, Powell H, Jones C, McCredie D, Buzza M . Persistent familial hematuria in children and the locus for thin basement membrane nephropathy. Pediatr Nephrol. 2005; 20(12):1729-37. DOI: 10.1007/s00467-005-2034-2. View

Zhong X, Ding J, Wang Z, Gao Y, Wu Y, Shen Y . Risk Factors Associated With Abnormal Urinalysis in Children. Front Pediatr. 2021; 9:649068. PMC: 8044805. DOI: 10.3389/fped.2021.649068. View

Savige J . Heterozygous Pathogenic and Variants (Autosomal Dominant Alport Syndrome) Are Common, and Not Typically Associated With End-Stage Kidney Failure, Hearing Loss, or Ocular Abnormalities. Kidney Int Rep. 2022; 7(9):1933-1938. PMC: 9458992. DOI: 10.1016/j.ekir.2022.06.001. View

10.

Savige J, Lipska-Zietkiewicz B, Watson E, Hertz J, Deltas C, Mari F . Guidelines for Genetic Testing and Management of Alport Syndrome. Clin J Am Soc Nephrol. 2021; 17(1):143-154. PMC: 8763160. DOI: 10.2215/CJN.04230321. View

11.

Vivante A, Afek A, Frenkel-Nir Y, Tzur D, Farfel A, Golan E . Persistent asymptomatic isolated microscopic hematuria in Israeli adolescents and young adults and risk for end-stage renal disease. JAMA. 2011; 306(7):729-36. DOI: 10.1001/jama.2011.1141. View

12.

Bockenhauer D, Medlar A, Ashton E, Kleta R, Lench N . Genetic testing in renal disease. Pediatr Nephrol. 2011; 27(6):873-83. DOI: 10.1007/s00467-011-1865-2. View

13.

Moreno J, Yuste C, Gutierrez E, Sevillano A, Rubio-Navarro A, Amaro-Villalobos J . Haematuria as a risk factor for chronic kidney disease progression in glomerular diseases: A review. Pediatr Nephrol. 2015; 31(4):523-33. DOI: 10.1007/s00467-015-3119-1. View

14.

Moriniere V, Dahan K, Hilbert P, Lison M, Lebbah S, Topa A . Improving mutation screening in familial hematuric nephropathies through next generation sequencing. J Am Soc Nephrol. 2014; 25(12):2740-51. PMC: 4243343. DOI: 10.1681/ASN.2013080912. View

15.

Weber S, Strasser K, Rath S, Kittke A, Beicht S, Alberer M . Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy. Pediatr Nephrol. 2016; 31(6):941-55. DOI: 10.1007/s00467-015-3302-4. View

16.

Gross O, Tonshoff B, Weber L, Pape L, Latta K, Fehrenbach H . A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport's syndrome. Kidney Int. 2020; 97(6):1275-1286. DOI: 10.1016/j.kint.2019.12.015. View

17.

Fallerini C, Dosa L, Tita R, Del Prete D, Feriozzi S, Gai G . Unbiased next generation sequencing analysis confirms the existence of autosomal dominant Alport syndrome in a relevant fraction of cases. Clin Genet. 2013; 86(3):252-7. DOI: 10.1111/cge.12258. View

18.

Slajpah M, Gorinsek B, Berginc G, Vizjak A, Ferluga D, Hvala A . Sixteen novel mutations identified in COL4A3, COL4A4, and COL4A5 genes in Slovenian families with Alport syndrome and benign familial hematuria. Kidney Int. 2007; 71(12):1287-95. DOI: 10.1038/sj.ki.5002221. View

19.

Mastrangelo A, Madeira C, Castorina P, Giani M, Montini G . Heterozygous COL4A3/COL4A4 mutations: the hidden part of the iceberg?. Nephrol Dial Transplant. 2022; 37(12):2398-2407. DOI: 10.1093/ndt/gfab334. View

20.

Gibson J, Fieldhouse R, Chan M, Sadeghi-Alavijeh O, Burnett L, Izzi V . Prevalence Estimates of Predicted Pathogenic Variants in a Population Sequencing Database and Their Implications for Alport Syndrome. J Am Soc Nephrol. 2021; 32(9):2273-2290. PMC: 8729840. DOI: 10.1681/ASN.2020071065. View