11例原发性肾性糖尿患儿SLC5A2基因变异分析

doi:10.12372/jcp.2022.22e0998

摘要/Abstract

摘要：

目的总结原发性肾性糖尿（PRG）患儿的临床特点，分析SLC5A2基因变异情况。方法回顾性分析2013—2021年诊断PRG患儿的临床资料及基因检测结果。结果 11例PRG患儿，男5例、女6例，男/女比例为1:1.2；诊断中位数年龄为29个月（1天~13岁）；5例有糖尿家族史，均无糖尿病家族史；2例为轻度糖尿，9例为重度糖尿，所有患儿监测血糖、糖化血红蛋白、胰岛素、C肽、肾功能、肾脏超声均正常。患儿随访期间临床均无糖尿病“三多一少”症状或全身乏力表现，生长发育正常，无严重并发症。SLC5A2基因检测结果未发现纯合变异，杂合变异比例36%（4/11例），复合杂合变异64%（7/11例）；共发现14种变异，其中有10种错义变异、1种缺失变异、3种剪接变异，其中5种变异文献已报道，p.S161F、p.A169T、p.P275L、p.A312P、p.A365T、p.Y410C、p.F471L、c.1889_1891del、c.1665+5G>C 9种变异为新发变异，软件及功能预测均可能致病。4例杂合变异患儿中，2例为轻度糖尿，2例为重度糖尿；7例复合杂合变异患儿均表现为重度糖尿。结论 SLC5A2基因检测有助于PRG的诊断，其临床表型与基因型有一定的相关性，杂合变异可表现为轻度或重度糖尿，复合杂合变异多表现为重度糖尿，PRG多为良性过程，不影响儿童的生长发育。

关键词: 肾性糖尿, 基因变异, 基因型, 表型

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

万灵, 陈朝英, 涂娟, 李华荣. 11例原发性肾性糖尿患儿SLC5A2基因变异分析[J]. 临床儿科杂志, 2022, 40(12): 912-918.

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.

图/表 4

表1

表2

ACMG指南进行变异蛋白的致病性预测"

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

表2

图1

图2

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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