Department of pediatrics, Northwest Women's and Children's Hospital, Xi'an, China.
State Key Laboratory of Military Stomatology, Department of Oral Biology, School of Stomatology, Clinic of Oral Rare and Genetic Diseases, National Clinical Research Center for Oral Diseases, The Fourth Military Medical University, Xi'an, China.
J Clin Lab Anal. 2022 Jan;36(1):e24123. doi: 10.1002/jcla.24123. Epub 2021 Nov 17.
Variants in the endosomal solute carrier family 9 member A6 (SLC9A6)/(Na ,K )/H exchanger 6 (NHE6) gene have been linked to epilepsy, speech loss, truncal ataxia, hyperkinesia, and postnatal microcephaly.
In the present study, we evaluated genetic alterations in a 3-year-old Chinese boy displayed features of epilepsy, psychomotor retardation, microcephaly, low body weight, difficulty in feeding, excessive movement, attention loss, ataxia, and cerebellar atrophy and his healthy family using WES method. The identified variant was further confirmed by Sanger sequencing method. Finally, minigene assays were used to verify whether the novel SLC9A6 intronic variant influenced the normal splicing of mRNA.
We identified a novel hemizygous splicing variant [NM_001042537.1: c.1463-1G>A] in SLC9A6 by trio-based exome sequencing. The minigene expression in vitro confirmed the splicing variant altered a consensus splice acceptor site of SLC9A6 intron 11, resulting in skipping over exon 12.
Our finding extends the catalog of pathogenic intronic variants affecting SLC9A6 pre-mRNA splicing and provides a basis for the genetic diagnosis of CS.
内体溶质载体家族 9 成员 A6（SLC9A6）/（Na+，K+）/H 交换器 6（NHE6）基因中的变异与癫痫、言语丧失、躯干共济失调、多动、产后小头畸形有关。
在本研究中，我们使用 WES 方法评估了一名 3 岁中国男孩的遗传改变，该男孩表现出癫痫、精神运动发育迟缓、小头畸形、低体重、喂养困难、过度运动、注意力丧失、共济失调和小脑萎缩，以及他健康的家庭。通过 Sanger 测序方法进一步证实了所识别的变体。最后，使用微基因检测来验证该新的 SLC9A6 内含子变异是否影响 mRNA 的正常剪接。
通过基于三个人的外显子组测序，我们在 SLC9A6 中发现了一个新的杂合剪接变异[NM_001042537.1：c.1463-1G>A]。体外微基因表达证实该剪接变异改变了 SLC9A6 内含子 11 的一个保守剪接受体位点，导致外显子 12 跳过。
我们的发现扩展了影响 SLC9A6 前体 mRNA 剪接的致病性内含子变异目录，并为 CS 的遗传诊断提供了依据。
