Unidad de Bioinformática, Institut Pasteur de Montevideo, Montevideo, Uruguay.
Departamento de Informática y Ciencias de la computación, Facultad de Ingeniería, Universidad Católica del Uruguay, Montevideo, Uruguay.
Mol Genet Genomic Med. 2021 May;9(5):e1622. doi: 10.1002/mgg3.1622. Epub 2021 Mar 22.
The etiology of many genetic diseases is challenging. This is especially true for developmental disorders of the central nervous system, since several genes can be involved. Many of such pathologies are considered rare diseases, since they affect less than 1 in 2000 people. Due to their low frequency, they present several difficulties for patients, from the delay in the diagnosis to the lack of treatments. Next-generation sequencing techniques have improved the search for diagnosis in several pathologies. Many studies have shown that the use of whole-exome/genome sequencing in rare Mendelian diseases has a diagnostic yield between 30% and 50% depending on the disease.
Here, we present the case of an undiagnosed 6-year-old boy with severe encephalopathy of unclear cause, whose etiological diagnosis was achieved by whole-genome sequencing.
We found a novel variant that has not been previously reported in patients nor it has been described in GnomAD. Segregation analysis supports a de novo mutation, since it is not present in healthy parents. The change is predicted to be harmful to protein function, since it falls in the first quarter of the protein producing an altered reading frame and generating a premature stop codon. Additionally, the variant is classified as pathogenic according to ACMG criteria (PVS1, PM2, and PP3). Furthermore, there are several reported frameshift mutations in nearby codons as well as nonsense mutations that are predicted as pathogenic in other studies.
We found a novel de novo frameshift mutation in the PURA gene (MIM number 600473), c.151_161del, with sufficient evidence of its pathogenicity.
许多遗传性疾病的病因难以确定。中枢神经系统发育障碍尤其如此，因为可能涉及多个基因。此类许多病理疾病被认为是罕见病，因为它们影响不到每 2000 人中的 1 人。由于其发病率低，患者会面临许多困难，从诊断延迟到缺乏治疗方法。新一代测序技术已提高了多种疾病的诊断搜索能力。许多研究表明，在罕见的孟德尔疾病中使用全外显子/基因组测序的诊断率在 30%到 50%之间，具体取决于疾病。
在这里，我们介绍了一例病因不明的 6 岁严重脑病患儿的病例，其病因诊断通过全基因组测序实现。
我们发现了一种以前从未在患者中报道过、也未在 GnomAD 中描述过的新型变异。连锁分析支持新生突变，因为它不存在于健康父母中。该变化预计会对蛋白质功能造成危害，因为它发生在产生改变的阅读框并产生过早终止密码子的蛋白质的前四分之一。此外，根据 ACMG 标准（PVS1、PM2 和 PP3），该变体被归类为致病性。此外，在附近密码子中也有报道过几个移码突变，以及在其他研究中预测为致病性的无义突变。
我们在 PURA 基因（MIM 编号 600473）中发现了一种新型的新生移码突变，c.151_161del，其致病性有充分证据。
