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

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.

SUBMITTER: Wang R

PROVIDER: S-EPMC6830114 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Wang Rongrong R Han Shirui S Liu Hongyan H Khan Amjad A Xiaerbati Habulieti H Yu Xue X Huang Jia J Zhang Xue X

Frontiers in genetics 20191029

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 <i>TTI2</i> using whole-exome sequencing (WES) in a Chinese family with a recessive inheritance pattern of syndromic intellectual disability. The patients displayed intel ...[more]

PMID: 31737043

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Project description:INTRODUCTION:Recent evidence has emerged linking mutations in CDK13 to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with CDK13 mutations. METHODS:Patients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause. RESULTS:Our cohort comprised 16 individuals aged 4-16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898-1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain. CONCLUSIONS:These patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the CDK13 gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.

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

Publications

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

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