We describe a male patient with a novel TTI2 variant, which has not been previously associated with a human phenotype. His features include intellectual disability, primary microcephaly, delayed psychomotor development, speech delay, short stature, dysmorphic facial features, esotropia, kyphoscoliosis, and behavior abnormalities (Figure). Next generation sequencing revealed autosomal recessive TTI2 variant with uncertain significance, denoted as c.21_22insAAGCGCTCTG (p.Glu8Lysfs × 12). TTI2 encodes a regulator of DNA damage response and helps maintain steady levels of the PIKK family of protein kinases. No disease-causing variants in other genes potentially linked to his clinical presentation were identified. We report a novel loss-of-function homozygous variant in TTI2 that leads to syndromic intellectual disability and primary microcephaly.
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| http://dx.doi.org/10.1155/2022/2766957 | DOI Listing |
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Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly.
Am J Hum Genet
March 2023
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland; Department of Genetic Medicine and Development, University of Geneva Medical Faculty, Geneva 1211, Switzerland; Medigenome, Swiss Institute of Genomic Medicine, 1207 Geneva, Switzerland. Electronic address:
Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKKs), including mTOR, ATM, and ATR, by regulating the assembly of mTOR complex 1 (mTORC1). The TTT complex is essential for the expression, maturation, and stability of ATM and ATR in response to DNA damage. TELO2- and TTI2-related bi-allelic autosomal-recessive (AR) encephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal microcephaly, and a movement disorder (in the case of variants within TELO2).
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August 2022
Division of Women and Child Health, The Aga Khan University, Karachi, Pakistan.
We describe a male patient with a novel TTI2 variant, which has not been previously associated with a human phenotype. His features include intellectual disability, primary microcephaly, delayed psychomotor development, speech delay, short stature, dysmorphic facial features, esotropia, kyphoscoliosis, and behavior abnormalities (Figure). Next generation sequencing revealed autosomal recessive TTI2 variant with uncertain significance, denoted as c.
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Département de Biochimie et Génétique du CHU d'Angers, Centre Hospitalier Universitaire d'Angers, Angers, France.
TTI2 (MIM 614126) has been described as responsible for autosomal recessive intellectual disability (ID; MRT39, MIM:615541) in only two inbred families. Here, we give an account of two individuals from two unrelated outbred families harbouring compound heterozygous TTI2 pathogenic variants. Together with severe ID, progressive microcephaly, scoliosis and sleeping disorder are the most striking features in the two individuals concerned.
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