Table_1_Novel Compound Heterozygous Mutations in TTI2 Cause Syndromic Intellectual Disability in a Chinese Family.docx

Telomere maintenance 2 (TELO2)–interacting protein 2 (TTI2) interacts with TTI1 and TELO2 to form the Triple T complex, which is required for various cellular processes, including the double-strand DNA break response, nonsense-mediated mRNA decay, and telomerase assembly. Herein, we identified compound heterozygous mutations in TTI2 using whole-exome sequencing (WES) in a Chinese family with a recessive inheritance pattern of syndromic intellectual disability. The patients displayed intellectual disability, aggressive and self-injurious behaviors, facial dysmorphic features, microcephaly, and skeletal anomalies. In addition, one patient showed cerebral white matter abnormality. Maternal novel indel mutation resulted in a premature termination codon and nonsense-mediated mRNA decay. Paternal reported c.1100C > T mutation changed the highly conserved proline to leucine that located in the DUF2454 domain. Immunoblotting experiments showed significantly decreased TTI2, TTI1, and TELO2 in the patients’ lymphocytes. These results indicated that TTI2 loss-of-function mutations might cause an autosomal-recessive syndromic intellectual disability by affecting the Triple T complex. Our report expands the genetic causes of syndromic intellectual disability in the Chinese population.

端粒维护2（TELO2）-相互作用蛋白2（TTI2）与TTI1和TELO2相互作用，形成三重T复合体，该复合体对于多种细胞过程至关重要，包括双链DNA断裂反应、非编码介导的mRNA降解和端粒酶组装。在本研究中，我们利用全外显子测序（WES）在一位具有隐性遗传综合征性智力障碍的中国家族中鉴定了TTI2的复合杂合突变。患者表现出智力障碍、攻击性和自我伤害行为、面部畸形、小头畸形和骨骼异常。此外，一名患者显示出大脑白质异常。母系新发现的插入缺失突变导致终止密码子提前终止和编码介导的mRNA降解。父系报道的c.1100C > T突变将高度保守的脯氨酸转变为亮氨酸，该亮氨酸位于DUF2454结构域。免疫印迹实验显示患者淋巴细胞中的TTI2、TTI1和TELO2显著减少。这些结果表明，TTI2功能丧失突变可能导致常染色体隐性综合征性智力障碍，通过影响三重T复合体。我们的报告扩展了在中国人群中综合征性智力障碍的遗传原因。