HSD17B10和ACAT1基因变异所致异亮氨酸代谢障碍性疾病3例患儿的临床分析与遗传学诊断

Clinical analysis and genetic diagnosis of three children with Isoleucine metabolic disorders due to variants of HSD17B10 and ACAT1 genes

目的探讨3例HSD17B10和ACAT1基因变异所致异亮氨酸代谢障碍性疾病患儿的临床、生化及基因特点。方法选取2014年至2021年于上海市儿童医院就诊的2例17β羟基类固醇脱氢酶10(HSD17B10)缺乏症和1例β酮硫解酶缺乏症(BKD)患儿为研究对象。收集患儿的临床资料,对其进行血酰基肉碱、尿有机酸及基因检测,对候选变异进行生物信息学分析。结果3例患儿的主要临床症状包括癫痫、发育落后、肌张力减退和酸中毒等。血酰基肉碱谱中甲基巴豆酰基肉碱(C5:1)、3-羟基异戊酰基肉碱(C5-OH)、3-羟基丁酰肉碱(C4OH)均有不同程度的升高,尿有机酸检测甲基巴豆酰甘氨酸和2-甲基-3-羟基丁酸均显著增高。患儿1检出HSD17B10基因c.347G>A(p.R116Q)杂合变异,患儿2检出HSD17B10基因c.274G>A(p.A92T)杂合变异,患儿3检出ACAT1基因c.547G>A(p.G183R)和c.331G>C(p.A111P)复合杂合变异,其中c.274G>A(p.A92T)与c.331G>C(p.A111P)既往均未见报道。根据美国医学遗传学与基因组学学会(ACMG)相关指南,二者被分别判定为临床意义未明(PP3_Strong+PM2_supporting)和疑似致病性变异(PM3+PM2_Supporting+PP3_Moderate+PP4)。结论HSD17B10缺乏症与BKD均可能导致异亮氨酸代谢障碍,临床难以鉴别,而基因检测可明确诊断。上述发现的HSD17B10基因c.274G>A(p.A92T)与ACAT1基因c.331G>C(p.A111P)变异丰富了该2种疾病的变异谱。

Objective To explore the clinical,biochemical and genetic characteristics of three children with Isoleucine metabolic disorders due to variants of HSD17B10 and ACAT1 genes.Methods Two children with 17βhydroxysteroid dehydrogenase 10(HSD17B10)deficiency and a child withβ-ketothiolase deficiency(BKD)diagnosed at Shanghai Children′s Hospital between 2014 and 2021 were selected as the study subjects.Clinical data of the children were collected.The children were subjected to blood acylcarnitine,urinary organic acid and genetic testing,and candidate variants were analyzed with bioinformatic tools.Results The main symptoms of the three children had included epilepsy,developmental delay,hypotonia and acidosis.Their blood acylcarnitine methylcrotonyl carnitine(C5:1),3-hydroxyisovalerylcarnitine(C5-OH)and 3-hydroxybutylcarnitine(C4OH)were increased to various extents,and urine organic acids including methyl crotonylglycine and 2-methyl-3-hydroxybutyric acid were significantly increased.Child 1 and child 2 were respectively found to harbor a c.347G>A(p.R116Q)variant and a c.274G>A(p.A92T)variant of the HSD17B10 gene,and child 3 was found to harbor compound heterozygous variants of the ACAT1 gene,namely c.547G>A(p.G183R)and a c.331G>C(p.A111P).Among these,the c.274G>A(p.A92T)and c.331G>C(p.A111P)variants were unreported previously.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),they were respectively classified as variant of unknown significance(PP3_Strong+PM2_supporting)and likely pathogenic(PM3+PM2_Supporting+PP3_Moderate+PP4).Conclusion Both the HSD17B10 deficiency and BKD can lead to Isoleucine metabolism disorders,which may be difficult to distinguish clinically.Genetic testing can further confirm the diagnosis.Discoveries of the HSD17B10:c.274G>A(p.A92T)variant and the ACAT1:c.331G>C(p.A111P)variant have enriched the mutational spectrum of the two diseases.