Department of Medical Genetics, Centro Hospitalar Universitário de São João, Porto, Portugal.
Department of Neuropediatrics, Centro Hospitalar Universitário de São João, Porto, Portugal.
Neuropediatrics. 2023 Apr;54(2):120-125. doi: 10.1055/s-0042-1760366. Epub 2023 Jan 18.
Biallelic pathogenic variants in gene cause hypomyelinating leukodystrophy type 3, a severe neurodegenerative disorder with early onset characterized by microcephaly, axial hypotonia, epilepsy, spasticity, and developmental delay.
Clinical exome sequence was performed on patient's DNA and Sanger sequencing was used to confirm the candidate variant. To better characterize the effect of the genetic variant, functional analysis based on Sanger sequencing of the proband's complementary DNA (cDNA) was performed.
We report a case of 2-year-old girl with microcephaly, significant global developmental delay, refractory epilepsy, flaccid paralysis, hypomyelination, leukodystrophy, and cerebral atrophy on brain magnetic resonance imaging (MRI). Clinical exome sequencing revealed a novel splice site variant c.603 + 1G > A in homozygosity in the gene. Studies on patient's cDNA showed that the variant disrupts the canonical donor splice site of intron 5, with the recognition of a cryptic splice site within exon 5, leading to the skipping of the last 24 nucleotides of this exon together with the flanking intron. This alteration is predicted to cause an in-frame deletion of eight amino acids (p.Val194_Gln201del) belonging to the tRNA-biding domain of the protein.
To the best of our knowledge, this is the first report of a splice site variant in the gene causing hypomyelinating leukodystrophy. The description of this patient not only expands the mutational spectrum of but also provides deeper insights on genotype-phenotype correlation by comparing the clinical features of our patient with previously reported affected individuals.
基因中的双等位致病性变异导致 3 型脑白质营养不良，这是一种严重的神经退行性疾病，发病早，表现为小头畸形、轴性张力减退、癫痫、痉挛和发育迟缓。
对患者的 DNA 进行临床外显子组测序，并使用 Sanger 测序来确认候选变异。为了更好地描述遗传变异的影响，对先证者 cDNA 进行了基于 Sanger 测序的功能分析。
我们报告了一例 2 岁女孩，表现为小头畸形、严重的全面发育迟缓、难治性癫痫、弛缓性瘫痪、髓鞘生成不良、白质营养不良和脑磁共振成像（MRI）上的脑萎缩。临床外显子组测序显示，该基因在纯合子中存在一个新的剪接位点变异 c.603 + 1G > A。对患者 cDNA 的研究表明，该变异破坏了内含子 5 的典型供体位点，识别出内含子 5 内的隐蔽剪接位点，导致该外显子的最后 24 个核苷酸与侧翼内含子一起跳过。这种改变预计会导致该蛋白的 tRNA 结合域内的 8 个氨基酸（p.Val194_Gln201del）缺失。
据我们所知，这是第一个报道基因中的剪接位点变异导致髓鞘生成不良的病例。该患者的描述不仅扩展了 的突变谱，还通过比较我们患者的临床特征与先前报道的受累个体，提供了对基因型-表型相关性的更深入了解。
