河南省新生儿希特林蛋白缺乏症筛查、临床特征及基因变异分析

Newborn screening,clinical features and genetic analysis for Citrin deficiency in Henan province

目的分析河南省新生儿希特林蛋白缺乏症的患病率、临床特征、基因变异情况及预后。方法回顾性分析2013年1月至2021年12月在郑州大学第三附属医院应用串联质谱法完成的986565例河南省新生儿的筛查结果。采用二代测序法对希特林蛋白缺乏症筛查阳性的患儿进行SLC25A13基因的变异分析及亲代验证。综合希特林蛋白缺乏症患儿的临床、生化和基因变异特征,指导饮食治疗,随访生长发育情况。采用配对设计t检验比较患儿治疗前后外周血的氨基酸水平。结果本研究在986565例新生儿中共确诊9例希特林蛋白缺乏症。9例患儿均有血瓜氨酸特异性的升高,基因测序共检出6种变异,其中c.852_855delTATG、c.615+5G>A、c.550C>T、IVS16ins3kb为已知变异,c.1111_1112delAT、c.837T>A为新发现的变异。c.852_855delTATG变异的检出率最高,占61.6%(11/18),IVS16ins3kb次之,占16.7%(3/18)。9例患儿经治疗后均症状缓解,血氨基酸谱及生化指标明显改善,逐渐降至正常水平。截至2022年6月,所有患儿均预后良好。结论河南省新生儿串联质谱法筛查希特林蛋白缺乏症的患病率为1/109618,人群SLC25A13基因致病性变异的携带率为1/166。c.852_855delTATG可能是河南省希特林蛋白缺乏症患者的热点变异。新发现的变异丰富了SLC25A13基因的变异谱,为该病的早期诊断、治疗、预后和遗传咨询提供了依据。

Objective To explore the prevalence,clinical features,genetic characteristics and prognosis of Citrin deficiency in Henan province of China.Methods A total of 986565 neonates screened by tandem mass spectrometry at the Third Affiliated Hospital of Zhengzhou University from January 2013 to December 2021 were retrospectively analyzed.Analysis of SLC25A13 gene variants and parental verification were carried out for neonates suspected for Citrin deficiency by next-generation sequencing.The clinical,biochemical and genetic characteristics of Citrin deficiency patients were integrated to guide the diet treatment and follow up the growth and development.Paired-t test was used to compare the amino acid levels in the peripheral blood samples before and after the treatment.Results Nine cases of Citrin deficiency were diagnosed among the 986565 neonates.Specific elevation of citrulline was observed in all of the 9 cases.Six variants were detected by genetic sequencing,among which c.852_855delTATG,c.615+5G>A,c.550C>T and IVS16ins3kb were known pathogenic variants,whilst c.1111_1112delAT and c.837T>A were unreported previously.The detection rate for c.852_855delTATG was the highest(61.6%,11/18),followed by IVS16ins3kb(16.7%,3/18).The clinical symptoms of all patients were relieved after the treatment,and the blood amino acid profile and biochemical parameters were significantly improved by gradually falling within the normal range.By June 2022,all patients had shown a good prognosis.Conclusion The prevalence of Citrin deficiency among neonates from Henan Province by tandem mass spectrometry is 1/109618,and the carrier rate for the pathogenic variants of the SLC25A13 gene was 1/166.The c.852_855delTATG may be a hot spot variant among the patients.Discovery of the novel variants has enriched the mutational spectrum of the SLC25A13 gene.Above results have provided a basis for the early diagnosis,treatment,prognosis and genetic counseling for the affected families.