Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.
Mol Genet Genomic Med. 2024 Jan;12(1):e2317. doi: 10.1002/mgg3.2317. Epub 2023 Nov 14.
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).
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.
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.
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).
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.
酸性鞘磷脂酶（ACDase）缺乏症是一种极罕见的常染色体隐性溶酶体疾病，由致病性鞘氨醇酰基水解酶（ASAH1）变异引起。它表现为法伯病（FD）或伴有进行性肌阵挛癫痫的脊髓性肌萎缩症（SMA-PME）。
本研究旨在鉴定导致 ASAH1 相关疾病的水肿胎儿中的新型剪接位点变异，以辅助遗传咨询和准确的产前诊断。
我们报告了一例由非近亲父母遗传的 ASAH1 中新型纯合突变引起的水肿胎儿病例。我们分别对胎儿和家庭进行了拷贝数变异测序（CNV-Seq）和全外显子组测序（WES）。进行了小基因拼接分析以确认致病性变异。
WES 数据显示 ASAH1 的剪接位点变异（c.458-2A>T），预测会影响 RNA 剪接。小基因拼接分析发现，c.458-2A>T 变异消除了内含子 6 的经典剪接，从而激活了两个隐性剪接产物（c.456_458ins56bp 和 c.458_503del）。
总体而言，我们在 ASAH1 的突变谱中发现了一种新型剪接位点变异及其对剪接的异常影响。这些发现强调了在 ASAH1 相关疾病期间超声表现和胎儿水肿的家族史的重要性，并且可以辅助遗传咨询和准确的产前诊断。据我们所知，这是关于伴有严重胎儿水肿的 ASAH1 相关疾病的最短存活期病例。
