A Novel Nonsense Variant of the AGXT Identified in a Chinese Family
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Xu et al. BMC Nephrology (2021) 22:83 https://doi.org/10.1186/s12882-021-02276-3 CASE REPORT Open Access A novel nonsense variant of the AGXT identified in a Chinese family: special variant research in the Chinese reference genome Chang Bao Xu1†, Xu Dong Zhou1†, Hong En Xu1,2,3, Yong Li Zhao1, Xing Hua Zhao1, Dan Hua Liu1, Yong An Tian4, Xin Xin Hu1,3, Jing Yuan Guan1,3, Jian Cheng Guo1,2,3,5, Wen Xue Tang1,2,3,5 and Xia Xue2,3* Abstract Background: Primary hyperoxaluria(PH)is a rare autosomal recessive genetic disease that contains three subtypes (PH1, PH2 and PH3). Approximately 80% of PH patients has been reported as subtype PH1, this subtype of PH has been related to a higher risk of renal failure at any age. Several genetic studies indicate that the variants in gene AGXT are responsible for the occurrence of PH1. However, the population heterogeneity of the variants in AGXT makes the genetic diagnosis of PH1 more challenging as it is hard to locate each specific variant. It is valuable to have a complete spectrum of AGXT variants from different population for early diagnosis and clinical treatments of PH1. Case presentation: In this study, We performed high-throughput sequencing and genetic analysis of a 6-year-old male PH1 patient from a Chinese family. Two variants (c.346G > A: p.Gly116Arg; c.864G > A: p.Trp288X) of the gene AGXT were identified. We found a nonsense variant (c.864G > A: p.Trp288X) that comes from the proband’smotherand has never been reported previously. The other missense variant (c.346G > A: p.Gly116Arg) was inherited from his father and has been found previously in a domain of aminotransferase, which plays an important role in the function of AGT protein. Furthermore, we searched 110 pathogenic variants of AGXT that have been reported worldwide in healthy local Chinese population, none of these pathogenic variants was detected in the local genomes. Conclusions: Our research provides an important diagnosis basis for PH1 on the genetic level by updating the genotype of PH1 and also develops a better understanding of the variants in AGXT by broadening the variation database of AGXT according to the Chinese reference genome. Keywords: Primary hyperoxaluria type1, AGXT, Local genome reference, Whole-exome sequencing, case report * Correspondence: [email protected] †Chang Bao Xu and Xu Dong Zhou are joint first authors. 2Academy of Medical Sciences, ZhengZhou University, Zhengzhou, China 3Precision Medicine Center of ZhengZhou University, Zhengzhou, China Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Xu et al. BMC Nephrology (2021) 22:83 Page 2 of 8 Background Case presentation Primary hyperoxaluria type1(PH1, OMIM:259900) is a Clinical data of a young PH1 patient rare glyoxylate metabolism disorder caused by the func- The patient is a 6-year-old Chinese boy (ethnic Han), tional deficiency of alanine glyoxylate aminotransferase who was admitted to the hospital due to dysuria and (AGT). AGT is a liver-specific enzyme and its deficiency intermittent abdominal pain for the last ten days. A can damage the glyoxylate metabolism in peroxisomes stone was passed spontaneously by the patient seven of hepatocytes by causing oxalate-overproduction [1]. days before sent to the urological clinic. The boy was Compare with PH2 and PH3, PH1 has a higher inci- born in Henan Province of China (Central China, Han) dence and risk of leading to renal failure [2, 3]. Clinic- and was the second child of non-consanguineous par- ally, PH1 has been reported as a highly heterogeneous ents. The family denied the presence of PH in the family disorder with various clinical performances that range history. The physical examination of the patient was in from asymptomatic to renal failure [1]. Thus, it is difficult normal range. The boy has moderate nutrition, normal to confirm PH1 at the early stage, as several have not been intelligence, a height of 130 cm, a weight of 24 kg, a conclusively linked to symptomatic or asymptomatic con- blood pressure of 105/77 mmHg. A computerized tom- ditions. PH1 could be fatal, especially for young children, ography (CT) scan showed the hydronephrosis in his about half of the PH1 patients with early onset will have right kidney, and stones occurred in his left kidney, right end-stage renal disease (ESRD) before adulthood [1, 4, 5]. ureter and bladder (Fig. 1). The crystals passed by the Therefore, it is vital to find an accurate approach to con- patient spontaneously were identified as mostly (> 95%) firm PH1 at the early stage in order to provide timely and composed of calcium oxalate monohydrate according to appropriate treatments. PH1 has significant genetic het- the infrared spectroscopy test (Supplementary Fig. 1). erogeneity and phenotypic diversity [6], and gene AGXT From the examination of his renal and liver function, we has been identified as the key gene associated with the on- found the serum creatinine concentration was as low as set of PH1 [2, 7, 8]. A complete pathogenic variant 2.07 mmol/1.73m2/24 h, the concentration of urinary ox- spectrum of AGXT from different populations would pro- alate was 2.44 mmol/1.73m2/24 h (Table 1). vide a valuable resource for diagnosing PH1 at the genetic Due to the high concentration of urinary oxalate and level by exposing potential genetic markers for the PH1 the composition of the stone from the patient, we highly subtype of this diease. suspected that the subject might suffer PH because of a AGXT (OMIM:604285), maps to chromosome 2q37.1, genetic variant inherited from this family. In order to is about 10 kb with 11 exons that encode the AGT pro- identify the type of PH for the patient and appropriately tein [9]. The variants in gene AGXT could be found in conduct further treatment, the Whole Exome Sequen- more than 99% of PH1 patients [7, 10]. To date, at least cing (WES) was performed on the patient (described 190 different pathogenic variants have been reported in below). gene AGXT, over 55% of these variants are missense that Based on the four follow-up visits of the patient, the could result in aberrant gene products [7–10]. Compare function of his liver and kidney were back to normal and with missense variants in AGXT, fewer nonsense vari- all clinical examinations were within the normal range ants have been described worldwide, and the impacts of after the first treatment. Four 2–3 mm new kidney nonsense variants on the AGT protein functioning are stones were found in the second examination and passed uncertain [11]. Benefiting from the rapid development of with the aid of physical auxiliary vibration, no obvious Next Generation Sequencing (NGS) technology, more stone residue was found afterward. The patient was AGXT variants have been recently identified in the under a conservative treatment that consisted in a pre- Chinese population [12–14]. scription of oral pyridoxine and drinking plenty of fluids In the present report, a six year old boy with con- (2 ~ 3 L/m2 water per day). During this period, the urin- firmed PH1was treated conservatively for five months. ary oxalate level decrease but the citrate level increased Two variant points in gene AGXT were identified in his (Fig. 2). family by Whole Exon Sequencing (WES), including a novel nonsense variant from his mother and a missense WES identifies two variants in the gene AGXT variant from his father [6, 15, 16]. To update PH1 geno- WES was conducted on the patient to identify the spe- types in Chinese population and elucidate the AGXT cific type of PH that the subject has. We obtained the variants spectrum in the local population, we built a original data size of 15.74G with 93.2% of bases having local reference genome by collecting genomes from 300 Phred quality score of > = 30 (Q30). The mapping rate of healthy Chinese Han people. By searching110 pathogenic sequencing reads to the reference genome was over variants of AGXT in the local reference genomes, we 99.9%, and the average sequencing depth was 100X with aim to provide more reliable genetic markers for PH1 97% of captured regions that have a minimum depth of early diagnosis and treatment in Chinese population. 20X. Variant characterization and filtering found two Xu et al. BMC Nephrology (2021) 22:83 Page 3 of 8 Fig. 1 Radiographic findings in patient, the arrows indicate stones. a: KUB film, R indicates the right side of the body and the two red arrows indicate the stone detected in the kidney (arrow 1) and the bladder (arrow 2); b, c, d (CT axial image): b: the average CT value of arrow 3 is 1395.28HU; c: arrow 4 indicates hydronephrosis in the right kidney; d: the average CT values of arrows 5 and 6 are 1501.58HU and 1283.38HU respectively variants in the AGXT gene in the proband (supplemen- frequency (0.00001878) in the healthy population database tary Table 2).