Abstract：
Hereditary tyrosinemia type 1 (HT1; OMIM# 276700) is a genetic metabolism disorder caused by disease-causing variants in the fumarylacetoacetate hydrolase (FAH) gene encoding the last enzyme of the tyrosine catabolic pathway. Herein, we describe the clinical features and genetic characteristics of HT1 in a five years and seven months old Chinese patient.
After clinical diagnosis of the proband with HT1, genetic testing was performed by Sanger sequencing of the FAH gene in all family members. Functional analysis of the disease-causing variant was performed by cDNA sequencing to understand the effect of the variant on FAH transcript. To further predict the variant effect, we used Human Splicing Finder (HSF) and PyMol in silico analysis.
We identified a novel previously undescribed intronic variant in the FAH gene (c.914-1G>A). It was detected in a child who was homozygous for the variant and had the clinical presentation of HT1. cDNA sequencing showed that this splice-junction variant affected the transcription of FAH by formation of two different transcripts. Our observations and laboratory experiments were in line with in silico methods.
Our study provides new insight into the HT1 variant spectrum and a better understanding of this disease in the Chinese population. This will be useful for molecular diagnosis in our country in cases where premarital screening, prenatal diagnosis and preimplantation genetic diagnosis are planned.
After clinical diagnosis of the proband with HT1, genetic testing was performed by Sanger sequencing of the FAH gene in all family members. Functional analysis of the disease-causing variant was performed by cDNA sequencing to understand the effect of the variant on FAH transcript. To further predict the variant effect, we used Human Splicing Finder (HSF) and PyMol in silico analysis.
We identified a novel previously undescribed intronic variant in the FAH gene (c.914-1G>A). It was detected in a child who was homozygous for the variant and had the clinical presentation of HT1. cDNA sequencing showed that this splice-junction variant affected the transcription of FAH by formation of two different transcripts. Our observations and laboratory experiments were in line with in silico methods.
Our study provides new insight into the HT1 variant spectrum and a better understanding of this disease in the Chinese population. This will be useful for molecular diagnosis in our country in cases where premarital screening, prenatal diagnosis and preimplantation genetic diagnosis are planned.
摘要：
遗传性酪氨酸血症1型(HT1;OMIM#276700)是由编码酪氨酸分解代谢途径的最后一个酶的富马酸乙酰乙酸水解酶(FAH)基因中的致病变体引起的遗传代谢紊乱。在这里，我们描述了一名5岁零7个月的中国患者中HT1的临床特征和遗传特征。
在用HT1对先证者进行临床诊断后，通过对所有家族成员的FAH基因进行Sanger测序进行基因检测。通过cDNA测序进行致病变体的功能分析以了解变体对FAH转录物的影响。为了进一步预测变异效应，我们使用人类拼接Finder（HSF）和PyMol进行了计算机分析。
我们在FAH基因中鉴定了一种新的先前未描述的内含子变体(c.914-1G>A)。在该变体纯合子且具有HT1临床表现的儿童中检测到。cDNA测序表明，这种剪接接头变体通过形成两种不同的转录本影响FAH的转录。我们的观察和实验室实验与计算机模拟方法一致。
我们的研究为HT1变异谱提供了新的见解，并更好地了解了中国人群中的这种疾病。这将是有用的分子诊断在我国的情况下，婚前筛查，计划进行产前诊断和植入前遗传学诊断。
在用HT1对先证者进行临床诊断后，通过对所有家族成员的FAH基因进行Sanger测序进行基因检测。通过cDNA测序进行致病变体的功能分析以了解变体对FAH转录物的影响。为了进一步预测变异效应，我们使用人类拼接Finder（HSF）和PyMol进行了计算机分析。
我们在FAH基因中鉴定了一种新的先前未描述的内含子变体(c.914-1G>A)。在该变体纯合子且具有HT1临床表现的儿童中检测到。cDNA测序表明，这种剪接接头变体通过形成两种不同的转录本影响FAH的转录。我们的观察和实验室实验与计算机模拟方法一致。
我们的研究为HT1变异谱提供了新的见解，并更好地了解了中国人群中的这种疾病。这将是有用的分子诊断在我国的情况下，婚前筛查，计划进行产前诊断和植入前遗传学诊断。
