PDF(Pubmed)
Abstract：
BACKGROUND: Acid ceramidase (ACDase) deficiency is an ultrarare autosomal recessive lysosomal disorder caused by pathogenic N-acylsphingosine amidohydrolase (ASAH1) variants. It presents with either Farber disease (FD) or spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME).
OBJECTIVE: The study aims to identify a novel splice site variant in a hydrops fetus that causes ASAH1-related disorder, aid genetic counseling, and accurate prenatal diagnosis.
METHODS: We report a case of hydrops fetalis with a novel homozygous mutation in ASAH1 inherited from non-consanguineous parents. We performed copy number variation sequencing (CNV-Seq) and whole exome sequencing (WES) on the fetus and family, respectively. Minigene splicing analyses were conducted to confirm the pathogenic variants.
RESULTS: WES data revealed a splice site variant of the ASAH1 (c.458-2A>T), which was predicted to affect RNA splicing. Minigene splicing analyses found that the c.458-2A>T variant abolished the canonical splicing of intron 6, thereby activating two cryptic splicing products (c.456_458ins56bp and c.458_503del).
CONCLUSIONS: Overall, we identified a novel splice site variant in the mutational spectrum of ASAH1 and its aberrant effect on splicing. These findings highlight the importance of ultrasonic manifestation and family history of fetal hydrops during ASAH1-related disorders and could also aid genetic counseling and accurate prenatal diagnosis. To the best of our knowledge, this is the shortest-lived account of ASAH1-related disorders in utero with severe hydrops fetalis.
OBJECTIVE: The study aims to identify a novel splice site variant in a hydrops fetus that causes ASAH1-related disorder, aid genetic counseling, and accurate prenatal diagnosis.
METHODS: We report a case of hydrops fetalis with a novel homozygous mutation in ASAH1 inherited from non-consanguineous parents. We performed copy number variation sequencing (CNV-Seq) and whole exome sequencing (WES) on the fetus and family, respectively. Minigene splicing analyses were conducted to confirm the pathogenic variants.
RESULTS: WES data revealed a splice site variant of the ASAH1 (c.458-2A>T), which was predicted to affect RNA splicing. Minigene splicing analyses found that the c.458-2A>T variant abolished the canonical splicing of intron 6, thereby activating two cryptic splicing products (c.456_458ins56bp and c.458_503del).
CONCLUSIONS: Overall, we identified a novel splice site variant in the mutational spectrum of ASAH1 and its aberrant effect on splicing. These findings highlight the importance of ultrasonic manifestation and family history of fetal hydrops during ASAH1-related disorders and could also aid genetic counseling and accurate prenatal diagnosis. To the best of our knowledge, this is the shortest-lived account of ASAH1-related disorders in utero with severe hydrops fetalis.
摘要：
背景：酸性神经酰胺酶（ACDase）缺乏症是由致病性N-酰基鞘氨醇酰胺水解酶（ASAH1）变体引起的常染色体隐性溶酶体疾病。它表现为Farber病（FD）或脊髓性肌萎缩伴进行性肌阵挛性癫痫（SMA-PME）。
目的：这项研究的目的是在胎儿积水中发现一种新的剪接位点变异导致ASAH1相关疾病，帮助遗传咨询，和准确的产前诊断。
方法：我们报告一例胎儿水肿，ASAH1有一个新的纯合突变，遗传自非近亲父母。我们对胎儿和家族进行了拷贝数变异测序(CNV-Seq)和全外显子组测序(WES),分别。进行小基因剪接分析以确认致病变体。
结果：WES数据显示ASAH1的剪接位点变体（c.458-2A>T），预测会影响RNA剪接。小基因剪接分析发现c.458-2A>T变体消除了内含子6的经典剪接，从而激活了两个隐蔽剪接产物（c.456_458ins56bp和c.458_503del）。
结论：总体而言，我们在ASAH1的突变谱中发现了一个新的剪接位点变异体及其对剪接的异常影响。这些发现强调了ASAH1相关疾病期间胎儿水肿的超声表现和家族史的重要性，并且还可以帮助遗传咨询和准确的产前诊断。据我们所知,这是子宫内ASAH1相关疾病伴严重胎儿水肿的最短寿命病例.
目的：这项研究的目的是在胎儿积水中发现一种新的剪接位点变异导致ASAH1相关疾病，帮助遗传咨询，和准确的产前诊断。
方法：我们报告一例胎儿水肿，ASAH1有一个新的纯合突变，遗传自非近亲父母。我们对胎儿和家族进行了拷贝数变异测序(CNV-Seq)和全外显子组测序(WES),分别。进行小基因剪接分析以确认致病变体。
结果：WES数据显示ASAH1的剪接位点变体（c.458-2A>T），预测会影响RNA剪接。小基因剪接分析发现c.458-2A>T变体消除了内含子6的经典剪接，从而激活了两个隐蔽剪接产物（c.456_458ins56bp和c.458_503del）。
结论：总体而言，我们在ASAH1的突变谱中发现了一个新的剪接位点变异体及其对剪接的异常影响。这些发现强调了ASAH1相关疾病期间胎儿水肿的超声表现和家族史的重要性，并且还可以帮助遗传咨询和准确的产前诊断。据我们所知,这是子宫内ASAH1相关疾病伴严重胎儿水肿的最短寿命病例.
