John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA.
Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA.
Mol Genet Genomic Med. 2022 Apr;10(4):e1892. doi: 10.1002/mgg3.1892. Epub 2022 Mar 5.
Neurodegenerative disorders and leukodystrophies are progressive neurologic conditions that can occur following the disruption of intricately coordinated patterns of gene expression. Exome sequencing has been adopted as an effective diagnostic tool for determining the underlying genetic etiology of Mendelian neurologic disorders, however genome sequencing offer advantages in its ability to identify and characterize copy number, structural, and sequence variants in noncoding regions. Genome sequencing from peripheral leukocytes was performed on two patients with progressive neurologic disease of unknown etiology following negative genetic investigations including exome sequencing. RNA sequencing from peripheral blood was performed to determine gene expression patterns in one of the patients. Potential causative variants were matched to the patients' clinical presentation. The first proband was found to be heterozygous for a likely pathogenic missense variant in PLA2G6 (c.386T>C; p.Leu129Pro) and have an additional deep intronic variant in PLA2G6 (c.2035-926G>A). RNA sequencing indicated this latter variant created a splice acceptor site leading to the incorporation of a pseudo-exon introducing a premature termination codon. The second proband was heterozygous for a 261 kb deletion upstream of LMNB1 that included an enhancer region. Previous reports of copy number variants spanning this region of cis-acting regulatory elements corroborated its pathogenicity. When combined with clinical presentations, these findings led to a definitive diagnosis of autosomal recessive infantile neuroaxonal dystrophy and autosomal dominant adult-onset demyelinating leukodystrophy, respectively. In patients with progressive neurologic disease of unknown etiology, genome sequencing with the addition of RNA analysis where appropriate should be considered for the identification of causative noncoding pathogenic variants.
神经退行性疾病和脑白质营养不良是进行性神经疾病，可能在错综复杂的基因表达模式被破坏后发生。外显子组测序已被采用为确定孟德尔神经疾病潜在遗传病因的有效诊断工具，然而基因组测序在识别和表征非编码区域的拷贝数、结构和序列变异方面具有优势。对两名病因不明的进行性神经疾病患者进行了外周白细胞基因组测序，这些患者在进行外显子组测序等阴性遗传研究后仍未确定病因。对其中一名患者进行了外周血 RNA 测序，以确定基因表达模式。将潜在的致病变异与患者的临床表现相匹配。第一个先证者被发现 PLA2G6 中存在可能致病的错义变异杂合子(c.386T>C;p.Leu129Pro)，并且在 PLA2G6 中还有一个额外的深内含子变异(c.2035-926G>A)。RNA 测序表明，后者变异创造了一个剪接受体位点，导致引入一个提前终止密码子的假外显子的掺入。第二个先证者为 LMNB1 上游 261kb 的缺失杂合子，该缺失包括一个增强子区域。以前报道的跨越该顺式作用调节元件区域的拷贝数变异证实了其致病性。将这些发现与临床表现相结合，分别导致常染色体隐性婴儿型神经轴索营养不良和常染色体显性成人发病脱髓鞘性脑白质营养不良的明确诊断。对于病因不明的进行性神经疾病患者，应考虑进行基因组测序并酌情进行 RNA 分析，以识别致病的非编码致病性变异。
