Precision therapy for a medically actionable ATP1A3 variant from a genomic medicine program in an underserved population.
Precision therapy for a medically actionable ATP1A3 variant from a genomic medicine program in an underserved population.
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DOI：
10.1002/mgg3.2272
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发表时间：
2023-12
影响因子：
2
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基因组医学正在彻底改变罕见疾病的诊断，但其实施并没有使代表性不足的人群得到同等程度的受益。在此，我们报告一名 7 岁男孩的病例，该男孩患有肌张力低下、整体发育迟缓、斜视、癫痫发作和先前怀疑的线粒体肌病。该先证者来自代表性不足的少数族裔，他的公共保险拒绝对其进行外显子组测序。获得知情同意后，收集先证者的口腔细胞并进行全外显子组测序。 Baylor Genetics 使用 Illumina Dragen 和 Emedgene 软件来分析数据。根据 ACMG 指南和患者的表型进一步解释了变异。通过社区 Texome 项目下的全外显子组测序 (WES)，发现他位于染色体 19q13 的 ATP1A3 基因中存在杂合的从头致病性变异。回想起来，他的症状符合与 ATP1A3 基因相关的已知医疗状况，即儿童交替性偏瘫 2 (AHC)，这是一种罕见的常染色体显性遗传疾病，发病率为百万分之一。他的单核苷酸变体（c.2401G>A，p.D801N）预计具有破坏性。特定氨基酸变化 p.D801N 以及等位基因变体 p.D801Y 先前已在 ClinVar 中报道过，两者均被认为是致病性的。这种变异的识别改变了该患者的医疗管理，因为他开始服用钙拮抗剂，并且没有报告进一步的偏瘫发作。这个案例说明了在服务不足的人群中实施基因组医学进行精准治疗的价值。针对德克萨斯州服务不足的个体的基因组医学项目已经启动。在先前被排除外显子组的个体中鉴定出 ATP1A3 变异，导致了一种有助于稳定神经系统发作的新治疗方法。
Genomic medicine is revolutionizing the diagnosis of rare diseases, but the implementation has not benefited underrepresented populations to the same degree. Here, we report the case of a 7‐year‐old boy with hypotonia, global developmental delay, strabismus, seizures, and previously suspected mitochondrial myopathy. This proband comes from an underrepresented minority and was denied exome sequencing by his public insurance. After informed consent was obtained, buccal cells from the proband were collected and whole exome sequencing was performed. Illumina Dragen and Emedgene software was used to analyze the data at Baylor Genetics. The variants were further intepreted according to ACMG guidelines and the patient's phenotype. Through whole‐exome sequencing (WES) under the Community Texome project, he was found to have a heterozygous de novo pathogenic variant in the ATP1A3 gene located on chromosome 19q13. In retrospect, his symptomatology matches the known medical conditions associated with the ATP1A3 gene namely Alternating Hemiplegia of Childhood 2 (AHC), a rare autosomal dominant disorder with an incidence of 1 in one million. His single nucleotide variant, (c.2401G>A, p.D801N), is predicted to be damaging. The specific amino acid change p.D801N has been previously reported in ClinVar along with the allelic variant p.D801Y and both are considered pathogenic. The identification of this variant altered medical management for this patient as he was started on a calcium antagonist and has reported no further hemiplegic episodes. This case illustrates the value of implementing genomic medicine for precision therapy in underserved populations. A genomic medicine project for underserved individuals in Texas has been launched. Identification of an ATP1A3 variant in an individual that was previously denied exome led to a new treatment that helped stabilize neurologic episodes.