IVD基因复合杂合变异导致异戊酸血症一例

Isovaleric acidemia caused by compound heterozygous variants of IVD gene in a case

目的分析一个异戊酸血症家系患儿的临床特征、生化特征以及分子致病机制。方法综合分析患儿的临床表型及血清氨基酸和尿有机酸谱,并应用靶向捕获高通量测序及Sanger测序进行突变位点分析和家系验证。结果患儿生后10天出现体重不增、食纳差,并伴有嗜睡,精神差,有"汗脚"体味。生化检查提示高氨血症,血清氨基酸谱显示异戊酰肉碱C5明显升高(3.044,参考值0.04~0.4μmol/L),尿有机酸分析显示异戊酰甘氨酸明显升高(669.53,参考值0~0.5),临床初步诊断为异戊酸血症;基因检测结果显示患儿IVD基因上携带父源的c.149G>A(p.R50H)杂合变异和母源的c.1123G>A(p.G375S)杂合变异,患儿哥哥携带c.1123G>A(p.G375S)杂合变异,符合常染色体隐性遗传规律。其中c.149G>A(p.R50H)为已报道的致病性变异,c.1123G>A(p.G375S)变异未见既往研究报道。结论从遗传学角度明确了患儿的发病原因,为其临床诊断和治疗提供分子依据,并为该家系的再生育提供产前遗传咨询。

Objective To analyze the clinical features,biochemical characteristics and molecular pathogenesis of a girl with isovaleric acidemia.Methods Clinical features,blood spot amino acid profiles and urinary organic acid profiles of the patient were comprehensively analyzed.Targeted capture,next generation sequencing and Sanger sequencing were carried out to detect potential variant of the IVD gene.Results The patient presented with weight growth failure,poor feeding,lethargy,and a"sweaty feet"odor at 10 days after birth.Biochemical test suggested hyperammonemia.Blood spot amino acid profiles displayed a dramatic increase in isovalerylcarnitine(C5:3.044,reference range 0.04-0.4μmol/L),organic acid analysis of urine revealed a high level of isovaleric glycine(669.53,reference range 0-0.5).The child was ultimately diagnosed with isovaleric acidemia,and was found to harbor a paternally derived heterozygous variant c.149G>A(p.R50H)and a maternally derived heterozygous variant c.1123G>A(p.G375S)of the IVD gene.Her elder brother was a heterozygous carrier of c.1123G>A(p.G375S)variant.The c.149G>A(p.R50H)was a known pathogenic variant,while the c.1123G>A(p.G375S)variant was previously unreported.Conclusion The pathogenesis of the patient was delineated from the perspective of genetics,which has provided a basis for clinical diagnosis and treatment,as well as genetic counseling.