Novel Compound Heterozygous Mutations in TTI2 Cause Syndromic Intellectual Disability in a Chinese Family

Rongrong Wang; Shirui Han; Hongyan Liu; Amjad Khan; Habulieti Xiaerbati; Xue Yu; Jia Huang; Xue Zhang

doi:10.3389/fgene.2019.01060

Novel Compound Heterozygous Mutations in TTI2 Cause Syndromic Intellectual Disability in a Chinese Family

Front Genet. 2019 Oct 29:10:1060. doi: 10.3389/fgene.2019.01060. eCollection 2019.

Authors

Rongrong Wang¹, Shirui Han^{1

2}, Hongyan Liu³, Amjad Khan^{1

2}, Habulieti Xiaerbati¹, Xue Yu^{1

4}, Jia Huang^{1

2}, Xue Zhang¹

Affiliations

¹ McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
² The Research Center for Medical Genomics, Key Laboratory of Medical Cell Biology, College of Basic Medical Science, China Medical University, Shenyang, China.
³ Medical Genetics Institute, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China.
⁴ Department of Pediatrics, the First Affiliated Hospital of Guangxi Medical University, Guangxi, China.

Abstract

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.

Keywords: TTI2; intellectual disability; pathogenic mutations; triple T complex; whole-exome sequencing.