A new neurodevelopmental-congenital heart disease syndrome caused by variants in a novel disease gene, TELO2. J. You1,2, N. Sobreira1, D. Gable1,2, J. Jurgens1,2, D. Valle2,4,5, M. Armanios2,6, J. Hoover Fong3,5 1) Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; 2) McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; 3) McKusick-Nathans Institute of Genetic Medicine, Greenberg Center for Skeletal Dysplasias, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; 4) Center for Inherited Disease Research, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA; 5) Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; 6) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

   TELO2, together with TTI1 and TTI2 forms an evolutionarily conserved complex, the TTT complex, which is thought to function as a chaperone. The TTT complex plays a critical role in maturing and stabilizing phosphoinositide-3-kinase-related protein kinases (PIKKs), which are important signal transducers, involved in genome stability, response to nutritional supply, nonsense mediated decay, gene expression and suppression of tumorigenesis. LangouŽt et al. (2013) have shown that a missense mutation in TTI2 causes a phenotype characterized by developmental delay and facial dysmorphisms. Here we report a family with three affected siblings (one set of dizygotic twins and a younger brother) with overlapping clinical features including global development delay, short stature, hearing loss, cardiac anomalies and photophobia with decreased visual acuity though structurally normal eyes. Using whole exome sequencing of the siblings and their parents, we identified compound heterozygous variants in TELO2 (p. C367F; p. D720V) segregating with the phenotype. No other candidate genes were identified for the autosomal recessive inheritance model, including homozygous and compound heterozygous. There was no sensitivity to irradiation or mitomycin C in fibroblasts of affected subjects, and the lymphocyte telomere length was normal. We next investigated the effect of these missense mutations on TELO2 protein stability. Immunoblot for TELO2 from the patients showed reduced levels at 30-40% of controls. TTI1 and TTI2 levels were also similarly reduced at 40-50%. This effect was seen in both fibroblasts and lymphoblastoid cells. Despite the reduction of the TTT proteins, the levels of PIKK proteins including ATM, ATR, DNA-PK, mTOR were unchanged. To our knowledge, this is the first report linking TELO2 mutations to a Mendelian disorder. Our findings support that TELO2 missense mutations result in loss of function and disturb TELO2 protein and TTT complex integrity. In light of the associated clinical phenotype, our findings indicate TELO2 functions are relevant to neurodevelopmental and cardiac disease genetics.

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