Mei Lianni, Hu Chunchun, Jin Guangbo, Ge Chuanhui, Zhu Yiting, Li Dongyun, Peng Wenzhu, Li Huiping, Xu Xiu, Jiang Yan, Xu Guoliang, Xu Qiong
Department of Child Health Care, Children's Hospital of Fudan University, Shanghai, China.
Institutes of Biomedical Sciences, Shanghai Xuhui Central Hospital, Medical College of Fudan University, Chinese Academy of Medical Sciences (RU069), Shanghai, China.
Hum Genomics. 2025 Apr 21;19(1):42. doi: 10.1186/s40246-025-00748-3.
Neurodevelopmental disorders (NDDs) pose significant challenges due to their impact on cognitive, social and motor abilities, often rooted in genetic factors such as copy number variations (CNVs) and single nucleotide variantions (SNVs). Molecular genetic testing, advanced due to sequencing technologies, is instrumental in diagnosing NDDs, with twins offering unique perspectives in detecting novel de novo CNVs and SNVs. The study enrolled 32 pairs of twins that underwent molecular genetic testing and comprehensive clinical data collection. Additionally, we analyzed the potential deleterious effects of a novel de novo TET methylcytosine dioxygenase 3 (TET3) variant (c.4927G > A) using western blotting, immunofluorescence assay and enzymatic activity assay. Analyzing simultaneously, the overall detection yield of molecular genetic testing was 17.2% (11/64). Children with disease-related genetic variants had lower total developmental quotients (DQ) than children without disease-related genetic variants. One pair of monozygotic twins carried a novel de novo TET3 variant. Immunostaining assay revealed that while the wildtype TET3 protein was evenly distributed in the nucleus, the variant was concentrated around the nucleus. Anenzymatic assay using corresponding TET2 mutants suggested that the variant has a significantly reduced activity. Taken together, our study elaborated molecular genetic testing results of 32 pairs of twins and found that children with lower developmental levels are prone to possessing identifiable genetic variants. We reported the clinical phenotype of a pair of monozygotic twins carrying a novel de novo TET3 variant and confirmed the detrimental effects of this variant in vitro.
神经发育障碍（NDDs）因其对认知、社交和运动能力的影响而带来重大挑战，这些障碍通常源于基因因素，如拷贝数变异（CNVs）和单核苷酸变异（SNVs）。由于测序技术的发展，分子遗传学检测在NDDs的诊断中发挥着重要作用，双胞胎为检测新的新生CNVs和SNVs提供了独特的视角。该研究招募了32对双胞胎，他们接受了分子遗传学检测并收集了全面的临床数据。此外，我们使用蛋白质免疫印迹法、免疫荧光测定法和酶活性测定法分析了一种新的新生四氢叶酸甲基胞嘧啶双加氧酶3（TET3）变体（c.4927G＞A）的潜在有害影响。同时分析发现，分子遗传学检测的总体检出率为17.2%（11/64）。患有疾病相关基因变异的儿童的总发育商数（DQ）低于没有疾病相关基因变异的儿童。一对同卵双胞胎携带一种新的新生TET3变体。免疫染色分析显示，野生型TET3蛋白均匀分布在细胞核中，而该变体则集中在细胞核周围。使用相应的TET2突变体进行的酶活性测定表明，该变体的活性显著降低。综上所述，我们的研究阐述了32对双胞胎的分子遗传学检测结果，发现发育水平较低的儿童更容易拥有可识别的基因变异。我们报告了一对携带新的新生TET3变体的同卵双胞胎的临床表型，并在体外证实了该变体的有害影响。
