11例原发性肾性糖尿患儿SLC5A2基因变异分析

doi:10.12372/jcp.2022.22e0998

Abstract

Abstract:

Objective To summarize the clinical characteristics of children with primary renal glucosuria (PRG), and analyze the variation of SLC5A2 gene. Methods The clinical data and genetic test results of children diagnosed with PRG from 2013 to 2021 were retrospectively analyzed. Results There were 11 children (5 boys and 6 girls) with PRG, with a male/female ratio of 1:1.2. The median age at diagnosis was 29 months (1 day to 13 years). Five patients had a family history of glucosuria and none had a family history of diabetes. Two patients had mild and 9 patients had severe glucosuria. The blood glucose, glycated hemoglobin, insulin, C-peptide, renal function and renal ultrasound results were normal in all children. During the follow-up period, there were no symptoms of diabetes or systemic fatigue, and the children had normal growth and development without serious complications. No homozygous variation was found in SLC5A2 gene, the proportion of heterozygous variation was 36% (4/11), and the proportion of compound heterozygous variation was 64% (7/11). A total of 14 variants were found, including 10 missense variants, 1 deletion variant and 3 splicing variants. Among them, 5 variants have been reported in the literature, and 9 variants, p.S161F, p.A169T, p.P275L, p.A312P, p.A365T, p.Y410C, p.F471L, c. 1889_1891del, and c. 1665+5G> C, are new variants, which are predicted to be pathogenic by software and function. Among the 4 children with heterozygous variation, 2 had mild and 2 had severe glucosuria. Seven children with compound heterozygous variation showed severe diabetes. Conclusions SLC5A2 gene detection is helpful for the diagnosis of PRG. The clinical phenotype of PRG is correlated with its genotype. Heterozygous variation may show mild or severe glucosuria, while compound heterozygous variation mostly shows severe glucosuria. The clinical manifestation of children with PRG is mostly benign and does not affect the growth and development of children.

Key words: renal glucosuria, variation, genotype, phenotype

WAN Ling, CHEN Chaoying, TU Juan, LI Huarong. Analysis of SLC5A2 gene variation in 11 children with primary renal glucosuria[J].Journal of Clinical Pediatrics, 2022, 40(12): 912-918.

Figures/Tables 4

核苷酸改变	ACMG证据等级	ACMG
c.655G>A	PS4_Supporting：常染色体显性疾病，极罕见变异，在1个具有相同表型的无亲缘关系患者中观察到该变异。 PM2-supporting: 千人数据库、EXAC数据库中正常对照人群中未发现的变异。 PP3: 多种统计方法预测出该变异会对基因或基因产物造成有害的影响（REVEL:0.77）	VUS
c.1889_1891del	PM2-supporting: 千人数据库、EXAC数据库中正常对照人群中未发现的变异。 PM4_Supporting：非重复区框内插入/缺失或终止密码子丧失导致的蛋白质长度变化。	VUS
c.1540C>T	PS4_Moderate：常染色体显性疾病，极罕见变异，在最少3个具有相同表型的无亲缘关系患者中观察到该变异。 PM2-supporting: 千人数据库、EXAC数据库中低频变异。	VUS
IVS1-16C>A	PS4_Supporting：常染色体显性疾病，极罕见变异，在1个具有相同表型的无亲缘关系患者中观察到该变异。 PM2-supporting: 千人数据库、EXAC数据库中低频变异。	VUS
c.1229A>G	PM2-supporting: 千人数据库、EXAC数据库中正常对照人群中未发现的变异。 PP3: 多种统计方法预测出该变异会对基因或基因产物造成有害的影响（REVEL:0.83）	VUS
c.1665+5G>C	PM2-supporting: 千人数据库、EXAC数据库中低频变异。 PP3: 多种统计方法预测出该变异会对基因或基因产物造成有害的影响（Ada Score=1; RF Score=0.962）。	VUS
c.482C>T	PP3: 多种统计方法预测出该变异会对基因或基因产物造成有害的影响(REVEL=0.923)。	VUS
c.1449+1G>C	PM2-supporting: 千人数据库、EXAC数据库中正常对照人群中未发现的变异。 PP3: 多种统计方法预测出该变异会对基因或基因产物造成有害的影响（Ada Score=1; RF Score=0.932）。	VUS
c.505G>A	PM2-supporting: 千人数据库、EXAC数据库中低频变异。	VUS
c.736C>T	PM2-supporting: 千人数据库、EXAC数据库中低频变异。	VUS
c.1093G>A	PM2-supporting: 千人数据库、EXAC数据库中低频变异。 PP3: 多种统计方法预测出该变异会对基因或基因产物造成有害的影响(REVEL=0.889)。	VUS
c.824C>T	PM2-supporting: 千人数据库、EXAC数据库中正常对照人群中未发现的变异。 PP3: 多种统计方法预测出该变异会对基因或基因产物造成有害的影响(REVEL=0.815)。	VUS
c.1413C>	PM2-supporting: 千人数据库、EXAC数据库中低频变异。	VUS
c.934G>C	PM2-supporting: 千人数据库、EXAC数据库中低频变异。 PP3: 多种统计方法预测出该变异会对基因或基因产物造成有害的影响(REVEL=0.847)。	VUS

References 27

[1]	Sada K, Hidaka S, Imaishi N, et al. Clinical and genetic analysis in a family with familial renal glucosuria: Identification of an N101K mutation in the sodium-glucose cotransporter 2 encoded by a solute carrier family 5 member 2 gene[J]. J Diabetes Investig. 2020, 11(3):573-577.
[2]	望赛, 刘雪梅, 赵向忠, 等. 中国家族性肾性糖尿SGLT2基因变异分析及肾葡萄糖阈值的测定[J]. 中华肾脏病杂志, 2018, 34(11): 816-821. doi: 10.3760/cma.j.issn.1001-7097.2018.11.003
[3]	付红波, 李楠, 裴育, 等. 钠-葡萄糖共转运蛋白2基因变异致原发性肾性糖尿一例并文献复习[J]. 中华糖尿病杂志, 2018, 10(2): 150-153.
[4]	余自华, 陈丽珠. 肾性糖尿的诊疗现状[J]. 中华实用儿科临床杂志, 2018, 33(17): 1286-1289.
[5]	Santer R, Calado J. Familial renal glucosuria and SGLT2: from a mendelian trait to a therapeutic target[J]. Clin J Am Soc Nephrol, 2010, 5(1): 133-141. doi: 10.2215/CJN.04010609
[6]	Perry RJ, Shulman GI. Sodium-glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks[J]. J Biol Chem, 2020, 295(42): 14379-14390. doi: 10.1074/jbc.REV120.008387
[7]	Djeddi D, Cauliez A, Oulebsir A, et al. Persistently high urine glucose levels caused by familial renal glycosuria[J]. Arch Pediatr, 2020, 27(7): 386-387. doi: 10.1016/j.arcped.2020.07.002 pmid: 32807621
[8]	Yu L, Wu M, Hou P, et al. SLC5A2 mutations, including two novel mutations, responsible for renal glucosuria in Chinese families[J]. BMC Nephrol, 2020, 21(1): 69. doi: 10.1186/s12882-020-01725-9
[9]	Zhao X, Cui L, Lang Y, et al. A recurrent deletion in the SLC5A2 gene including the intron 7 branch site responsible for familial renal glucosuria[J]. Sci Rep, 2016, 6: 33920. doi: 10.1038/srep33920
[10]	Santer R, Kinner M, Lassen CL, et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria[J]. J Am Soc Nephrol, 2003, 14(11): 2873-2882. pmid: 14569097
[11]	Dorum S, Erdoğan H, Köksoy AY, et al. Clinical features of pediatric renal glucosuria cases due to SLC5A2 gene variants[J]. Pediatr Int, 2022, 64(1): e14948..
[12]	Wang S, Wang Y, Wang J, et al. Six exonic variants in the SLC5A2 gene cause exon skipping in a minigene assay[J]. Front Genet, 2020, 11: 585064. doi: 10.3389/fgene.2020.585064
[13]	Santer R, Calado J. Familial renal glucosuria and SGLT2: from a mendelian trait to a therapeutic target[J]. Clin J Am Soc Nephrol, 2010, 5(1): 133-141. doi: 10.2215/CJN.04010609
[14]	王晓慧, 赵向忠, 李春梅, 等. 中国家族性肾性糖尿SGLT2基因变异分析及表型和基因型相关性研究[J]. 中华肾脏病杂志, 2016, 32(1): 1-8. doi: 10.3760/cma.j.issn.1001-7097.2016.01.001
[15]	Wang S, Zhao X, Zhang R, et al. Identification of ten novel SLC5A2 mutations and determination of the renal threshold for glucose excretion in Chinese patients with familial renal glucosuria[J]. Clin Chim Acta, 2019, 490: 102-106. doi: S0009-8981(18)30654-5 pmid: 30593819
[16]	Calado J, Loeffler J, Sakallioglu O, et al. Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting[J]. Kidney Int, 2006, 69(5): 852-855. pmid: 16518345
[17]	Xiong HY, Alipanahi B, Lee LJ, et al. RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease[J]. Science, 2015, 347(6218): 1254806. doi: 10.1126/science.1254806
[18]	Lee H, Han KH, Park HW, et al. Familial renal glucosuria: a clinicogenetic study of 23 additional cases[J]. Pediatr Nephrol. 2012, 27(7): 1091-1095. doi: 10.1007/s00467-012-2109-9 pmid: 22314875
[19]	Wang X, Yu M, Wang T, et al. Genetic analysis and literature review of Chinese patients with familial renal glucosuria: Identification of a novel SLC5A2 mutation[J]. Clin Chim Acta, 2017, 469: 105-110. doi: 10.1016/j.cca.2017.03.027
[20]	Gu X, Chen M, Xu Y, et al. Acquired renal glucosuria in an undifferentiated connective tissue disease patient with a SLC5A2 heterozygous mutation: A case report[J]. Medicine (Baltimore), 2018, 97(50): e13664. doi: 10.1097/MD.0000000000013664
[21]	Li S, Yang Y, Huang L, et al. A novel compound heterozygous mutation in SLC5A2 contributes to familial renal glucosuria in a Chinese family, and a review of the relevant literature[J]. Mol Med Rep. 2019, 19(5): 4364-4376.
[22]	Yu L, Lv JC, Zhou XJ, et al. Abnormal expression and dysfunction of novel SGLT2 mutations identified in familial renal glucosuria patients[J]. Hum Genet, 2011, 129(3): 335-344. doi: 10.1007/s00439-010-0927-z
[23]	Calado J, Sznajer Y, Metzger D, et al. Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion[J]. Nephrol Dial Transplant, 2008, 23(12): 3874-3879. doi: 10.1093/ndt/gfn386
[24]	Santer R, Kinner M, Lassen CL, et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria[J]. J Am Soc Nephrol, 2003, 14(11): 2873-2882. pmid: 14569097
[25]	Lee H, Han KH, Park HW, et al. Familial renal glucosuria: a clinicogenetic study of 23 additional cases[J]. Pediatr Nephrol, 2012, 27(7): 1091-1095. doi: 10.1007/s00467-012-2109-9 pmid: 22314875
[26]	Toka HR, Yang J, Zera CA, et al. Pregnancy-associated polyuria in familial renal glycosuria[J]. Am J Kidney Dis, 2013, 62(6): 1160-1164. doi: 10.1053/j.ajkd.2013.05.018 pmid: 23871407
[27]	Leslie BR, Gerwin LE, Taylor SI. Sodium-glucose cotransporter-2 inhibitors: lack of a complete history delays diagnosis[J]. Ann Intern Med, 2019, 171(6): 421-426. doi: 10.7326/M19-1463 pmid: 31525753

病例编号	性别	发病年龄	家族史	起病表现	尿糖	核苷酸改变	氨基酸改变	Het/ Hom	父源/ 母源	是否报道	SIFT	Polyphen2	Mutation Taster
1	男	6岁	无	无	+++~++++	c.655G>A	p.A219T	Het	ND	Y	D	PD	D
2	男	13岁	无	无	+~++	c.1889_1891del	p.631del	Het	父源	N	NA	NA	NA
3	女	2岁5月	父尿糖+	外耳手术住院发现	+++~++++	c.1540C>T IVS1-16C>A	p.P514S 剪接变异	Het	母源父源	Y	T	PD	D
3	女	2岁5月	父尿糖+	外耳手术住院发现	+++~++++	c.1540C>T IVS1-16C>A	p.P514S 剪接变异	Het	母源父源	N	NA	NA	NA
4	男	2岁11月	父尿糖+	尿液黏稠	+++~++++	c.1229A>G c.1665+5G>C	p.Y410C 剪接变异	Het	父源母源	N	D	PD	D
4	男	2岁11月	父尿糖+	尿液黏稠	+++~++++	c.1229A>G c.1665+5G>C	p.Y410C 剪接变异	Het	父源母源	N	NA	NA	NA
5	女	1岁6月	父尿糖+	尿频	+++~++++	c.482C>T c.1449+1G>C	p.S161F 剪接变异	Het	父源母源	N	D	PD	D
5	女	1岁6月	父尿糖+	尿频	+++~++++	c.482C>T c.1449+1G>C	p.S161F 剪接变异	Het	父源母源	Y	NA	NA	NA
6	男	4岁	无	无	++++	c.505G>A IVS1-16C>A	p.A169T 剪接变异	Het	ND	N	T	PD	D
6	男	4岁	无	无	++++	c.505G>A IVS1-16C>A	p.A169T 剪接变异	Het	ND	Y	NA	NA	NA
7	女	2岁2月	无	尿色浑浊	++++	c.736C>T c.1093G>A	p.P246S p.A365T	Het	父源母源	Y	T	PD	D
7	女	2岁2月	无	尿色浑浊	++++	c.736C>T c.1093G>A	p.P246S p.A365T	Het	父源母源	N	D	PD	D
8	女	2岁	无	尿急	+++~++++	c.1449+1G>C	剪接变异	Het	母源	Y	NA	NA	NA
9	女	1岁7月	父尿糖+	无	+++~++++	c.824C>T c.1540C>T	p.P275L p.P514S	Het	父源母源	N	D	PD	D
9	女	1岁7月	父尿糖+	无	+++~++++	c.824C>T c.1540C>T	p.P275L p.P514S	Het	父源母源	Y	T	PD	D
10	女	1天	母尿糖+	黄疸住院发现	++++	c.1413C>G c.934G>C	p.F471L p.A312P	Het	父源母源	N	D	PD	D
10	女	1天	母尿糖+	黄疸住院发现	++++	c.1413C>G c.934G>C	p.F471L p.A312P	Het	父源母源	N	D	PD	D
11	男	7岁9月	无	无	+~++	c.505G>A	p.A169T	Het	母源	N	T	PD	D

Analysis of SLC5A2 gene variation in 11 children with primary renal glucosuria

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