小脑畸形(LIS)是一种皮质畸形,以光滑或接近光滑的脑表面和缺乏回旋和沟发育为特征,这是由胚胎发育过程中神经元迁移不足引起的。神经元迁移涉及许多基因产物,其中有PAFAH1B1基因的产物,与这种疾病相关。LIS是一种罕见的疾病,人口频率低,并伴有非特异性临床症状,如早期癫痫,发育迟缓或脑瘫样运动问题。鉴于高通量测序技术一直在改善诊断,我们选择了这种技术来解决这个病人。
我们介绍了一个7岁男性患者的病例,他患有一种未确诊的罕见疾病,具有非特异性临床症状,可能与间脑畸形相容。该患者参加了一项研究,包括对其整个基因组进行测序。在生物信息学管道之后分析序列数据。对获得的变体进行注释,然后进行不同的过滤器以进行优先级排序。还分析了线粒体基因组。在已知的PAFAH1B1基因中发现了一个新的候选移码插入,解释索引病例表型。通过硅片工具进行的评估报告说,它会导致无意义介导的机制,并且具有很高的置信度得分。插入会导致阅读框架发生变化,并产生一个过早的终止密码子,严重影响蛋白质功能,可能是一个等位基因的沉默。健康的母亲没有携带突变,未受影响的父亲无法进行分析。
通过这项工作,我们在LIS1/PAFAH1B1基因中发现了一个新的从头突变,作为一个具有非特异性临床症状的小男孩的罕见疾病的可能原因。所发现的突变与所研究的表型相关,因为在这种情况下已经描述了基因产物中的功能丧失。由于PAFAH1B1基因中没有其他变异,种群频率低,并且由于家族史,提出了一种从头疾病机制。
Lissencephaly (LIS) is a cortical malformation, characterized by smooth or nearly smooth cerebral surface and a shortage of gyral and sulcal development, which is caused by deficient neuronal migration during embryogenesis. Neuronal migration involves many gene products, among which is the product of the
PAFAH1B1 gene, associated with this disease. LIS is a rare disease, characterized by low population frequency, and with non-specific clinical symptoms such as early epilepsy, developmental delay or cerebral palsy-like motor problems. Given that high-throughput sequencing techniques have been improving diagnosis, we have chosen this technique for addressing this patient.
We present the case of a seven years old male patient with an undiagnosed rare disease, with non-specific clinical symptoms possibly compatible with lissencephaly. The patient was enrolled in a study that included the sequencing of his whole genome. Sequence data was analyzed following a bioinformatic pipeline. The variants obtained were annotated and then subjected to different filters for prioritization. Also mitochondrial genome was analyzed. A novel candidate frameshift insertion in known
PAFAH1B1 gene was found, explaining the index case phenotype. The assessment through in silico tools reported that it causes nonsense mediated mechanisms and that it is damaging with high confidence scores. The insertion causes a change in the reading frame, and produces a premature stop codon, severely affecting the protein function and probably the silencing of one allele. The healthy mother did not carry the mutation, and the unaffected father was not available for analysis.
Through this work we found a novel de novo mutation in LIS1/
PAFAH1B1 gene, as a likely cause of a rare disease in a young boy with non-specific clinical symptoms. The mutation found correlates with the phenotype studied since the loss of function in the gene product has already been described in this condition. Since there are no other variants in the
PAFAH1B1 gene with low population frequency and due to family history, a de novo disease mechanism is proposed.