ACADVL基因复合杂合变异致极长链酰基辅酶A脱氢酶缺乏症一家系分析

doi:10.12280/gjszjk.20260273

摘要/Abstract

摘要：

报告1例ACADVL基因复合杂合变异致极长链酰基辅酶A脱氢酶缺乏症患儿。患儿因血串联质谱分析显示多种长链酰基肉碱水平升高，提示可能存在长链或极长链脂肪酸氧化代谢障碍，行家系全外显子组测序，对可疑致病变异进行Sanger测序，发现患儿ACADVL基因存在c.623-3C>G和c.1366C>T(p.Arg456Cys)复合杂合变异，分别遗传自表型正常的母亲和父亲。根据美国医学遗传学与基因组学学会指南，c.623-3C>G评级为临床意义未明变异（PM2_Supporting+PM3+PP3+PP4）；c.1366C>T（p.Arg456Cys）评级为可能致病性变异（PM1+PM2_Supporting+PM3_Strong+PP1+PP3）。为进一步明确病因，通过minigene实验证实c.623-3C>G突变可能通过外显子跳跃机制影响可变剪接，据此将该变异评级升级为可能致病性变异（PS3+PM2_Supporting+PM3+PP3+PP4）。基于上述检查，明确了ACADVL基因复合杂合变异为该家系患儿的致病原因，丰富了ACADVL基因的变异谱与表型谱。同时证实minigene技术可有效验证剪接区变异的致病性，为临床意义未明变异的精准解读提供了可靠依据。

关键词: 极长链酰基辅酶A脱氢酶缺乏症, 肌疾病, 酰基CoA脱氢酶, 长链, ACADVL基因, 全外显子组测序, RNA剪接位点

Abstract:

We report a child with the very long chain acyl-CoA dehydrogenase deficiency (VLCADD) caused by compound heterozygous variants in the ACADVL gene. The tandem mass spectrometry detection of the patient's blood showed the increased levels of multiple long-chain acylcarnitines, suggesting a potential disorder of long-chain or very long-chain fatty acid oxidation. Trio whole exome sequencing was performed, and candidate pathogenic variants were verified by Sanger sequencing. The child was found to carry the compound heterozygous variants in the ACADVL gene: c.623-3C>G and c.1366C>T(p.Arg456Cys), which were inherited from her mother and father with normal phenotypes. According to the American College of Medical Genetics and Genomics guidelines, the c.623-3C>G variant was initially classified as a variant of uncertain significance (PM2_Supporting+PM3+PP3+PP4), while the c.1366C>T(p.Arg456Cys) variant was classified as likely pathogenic (PM1+PM2_Supporting+PM3_Strong+PP1+PP3). To further clarify the etiology, minigene assays confirmed that the c.623-3C>G variant may affect alternative splicing through an exon-skipping mechanism, based on which this variant was upgraded to a likely pathogenic variant (PS3+PM2_Supporting+PM3+PP3+PP4). This study confirms that the compound heterozygous variants in the ACADVL gene are the causative factors for the proband in this pedigree, thereby expanding the variant and phenotypic spectrum of the ACADVL gene. It also demonstrates that the minigene assay can effectively validate the pathogenicity of splice site variants, providing a reliable basis for the precise interpretation of the variants with uncertain significance.

Key words: Very long chain acyl-CoA dehydrogenase deficiency, Muscular diseases, Acyl-CoA dehydrogenase, long-chain, ACADVL gene, Whole exome sequencing, RNA splice sites

杨蕊琼, 周秉博, 张钏, 潘海瑞, 王玉佩, 康启超, 惠玲. ACADVL基因复合杂合变异致极长链酰基辅酶A脱氢酶缺乏症一家系分析[J]. 国际生殖健康/计划生育杂志, 2026, 45(5): 380-385.

YANG Rui-qiong, ZHOU Bing-bo, ZHANG Chuan, PAN Hai-rui, WANG Yu-pei, KANG Qi-chao, HUI Ling. Analysis of A Family with Very Long Chain Acyl-CoA Dehydrogenase Deficiency Caused by Compound Heterozygous Variants in the ACADVL Gene[J]. Journal of International Reproductive Health/Family Planning, 2026, 45(5): 380-385.

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参考文献 21

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项目名称	检测值（μmol/L）	参考范围（μmol/L）	升高/ 降低
己二酰肉碱（C6DC）	0.44	0.03~0.29	升高
癸酰肉碱（C10）	0.21	0.02~0.19	升高
十二碳酰肉碱（C12）	0.42	0.02~0.22	升高
十四碳酰肉碱（C14）	2.31	0.05~0.39	升高
十四碳烯酰肉碱（C14:1）	6.39	0.02~0.29	升高
3-羟基-十四碳酰肉碱（C14OH）	0.04	0.00~0.03	升高
十四碳二烯酰肉碱（C14:2）	1.09	0.01~0.07	升高
3-羟基-十六碳酰肉碱（C16OH）	0.06	0.01~0.05	升高
十六碳烯酰肉碱（C16:1）	1.94	0.02~0.39	升高
3-羟基-十六碳烯酰肉碱（C16:1-OH）	0.19	0.01~0.13	升高
十八碳酰肉碱（C18）	2.47	0.21~1.68	升高
十八碳烯酰肉碱（C18:1）	3.71	0.39~2.75	升高
3-羟基-十八碳烯酰肉碱（C18:1-OH）	0.07	0.01~0.06	升高
十八碳二烯酰肉碱（C18:2）	1.13	0.07~0.66	升高
十四碳烯酰肉碱/十六碳酰肉碱（C14:1/C16）	1.69	0.01~0.21	升高
3-羟基-十六碳酰肉碱/十六碳酰肉碱（C16OH/C16）	0.05	0.00~0.03	升高
十四碳烯酰肉碱/十二碳烯酰肉碱（C14:1/C12:1）	71.00	0.75~5.00	升高
十六碳酰肉碱/丙酰肉碱（C16/C3)	5.74	0.40~5.61	升高

项目名称	检测值（μmol/L）	参考范围（μmol/L）	升高/ 降低
己二酰肉碱（C6DC）	0.44	0.03~0.29	升高
癸酰肉碱（C10）	0.21	0.02~0.19	升高
十二碳酰肉碱（C12）	0.42	0.02~0.22	升高
十四碳酰肉碱（C14）	2.31	0.05~0.39	升高
十四碳烯酰肉碱（C14:1）	6.39	0.02~0.29	升高
3-羟基-十四碳酰肉碱（C14OH）	0.04	0.00~0.03	升高
十四碳二烯酰肉碱（C14:2）	1.09	0.01~0.07	升高
3-羟基-十六碳酰肉碱（C16OH）	0.06	0.01~0.05	升高
十六碳烯酰肉碱（C16:1）	1.94	0.02~0.39	升高
3-羟基-十六碳烯酰肉碱（C16:1-OH）	0.19	0.01~0.13	升高
十八碳酰肉碱（C18）	2.47	0.21~1.68	升高
十八碳烯酰肉碱（C18:1）	3.71	0.39~2.75	升高
3-羟基-十八碳烯酰肉碱（C18:1-OH）	0.07	0.01~0.06	升高
十八碳二烯酰肉碱（C18:2）	1.13	0.07~0.66	升高
十四碳烯酰肉碱/十六碳酰肉碱（C14:1/C16）	1.69	0.01~0.21	升高
3-羟基-十六碳酰肉碱/十六碳酰肉碱（C16OH/C16）	0.05	0.00~0.03	升高
十四碳烯酰肉碱/十二碳烯酰肉碱（C14:1/C12:1）	71.00	0.75~5.00	升高
十六碳酰肉碱/丙酰肉碱（C16/C3)	5.74	0.40~5.61	升高