Identification of COL4A4 variants in Chinese patients with familial hematuria

Yanan Gao; Lamei Yuan; Jinzhong Yuan; Yan Yang; Jiangang Wang; Yong Chen; Hao Zhang; Yinze Ai; Hao Deng

doi:10.3389/fgene.2022.1064491

Identification of COL4A4 variants in Chinese patients with familial hematuria

Front Genet. 2023 Jan 9:13:1064491. doi: 10.3389/fgene.2022.1064491. eCollection 2022.

Authors

Yanan Gao^{1

2}, Lamei Yuan^{1

2

3}, Jinzhong Yuan⁴, Yan Yang⁵, Jiangang Wang¹, Yong Chen⁶, Hao Zhang⁴, Yinze Ai², Hao Deng^{1

2

3}

Affiliations

¹ Health Management Center, The Third Xiangya Hospital, Central South University, Changsha, China.
² Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.
³ Disease Genome Research Center, Central South University, Changsha, China.
⁴ Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China.
⁵ Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China.
⁶ National Health Committee Key Laboratory of Birth Defects for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, China.

Abstract

Background: Benign familial hematuria and Alport syndrome are common causes of familial hematuria among children and young adults, which are attributable to variants in the collagen type IV alpha chain genes, COL4A3, COL4A4, or COL4A5. The study was conducted to identify the underlying genetic causes in patients with familial hematuria. Methods: Two unrelated Han-Chinese pedigrees with familial hematuria were recruited for this study. Whole exome sequencing was combined with in silico analysis to identify potential genetic variants, followed by variant confirmation by Sanger sequencing. Reverse transcription, PCR, and Sanger sequencing were performed to evaluate the effect of the detected splicing variant on mRNA splicing. Results: A novel heterozygous splicing c.595-1G>A variant and a known heterozygous c.1715G>C variant in the collagen type IV alpha 4 chain gene (COL4A4) were identified and confirmed in patients of pedigree 1 and pedigree 2, respectively. Complementary DNA analysis indicated this splicing variant could abolish the canonical splice acceptor site and cause a single nucleotide deletion of exon 10, which was predicted to produce a truncated protein. Conclusions: The two COL4A4 variants, c.595-1G>A variant and c.1715G>C (p.Gly572Ala) variant, were identified as the genetic etiologies of two families with familial hematuria, respectively. Our study broadened the variant spectrum of the COL4A4 gene and explained the possible pathogenesis, which will benefit clinical management and genetic counseling.

Keywords: Alport syndrome; benign familial hematuria; collagen type IV alpha 4 chain gene; splicing variant; whole exome sequencing.

Grants and funding

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81873686 and 81800219), Natural Science Foundation of Hunan Province (Grant Nos. 2020JJ3057 and 2020JJ4830), the Hunan Provincial Innovation Foundation for Postgraduate (Grant No. CX20210378), Province-level College Students’ Innovative Training Plan Program (Grant No. S2022105330781), the Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University (Grant No. YX202109), and Distinguished Professor of the Lotus Scholars Award Program of Hunan Province, China.