Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly.

Autor:	Serey-Gaut M; Centre de génétique humaine, Université de Franche-Comté, Besançon, France. Electronic address: sereymargaux@gmail.com., Cortes M; Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Makrythanasis P; Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland; Department of Genetic Medicine and Development, University of Geneva Medical Faculty, Geneva 1211, Switzerland; Laboratory of Medical Genetics, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Biomedical Research Foundation of the Academy of Athens, Athens, Greece., Suri M; Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK., Taylor AMR; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK., Sullivan JA; Department of Pediatrics, Duke University Medical Center, Durham, NC, USA., Asleh AN; Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Mitra J; Department of Biophysics and Biophysical Chemistry, Biophysics and Biomedical Engineering, JHU Howard Hughes Medical Institute, Baltimore, MD 21205, USA., Dar MA; Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., McNamara A; Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Shashi V; Department of Pediatrics, Duke University Medical Center, Durham, NC, USA., Dugan S; Providence Medical Group Genetic Clinics, Spokane, WA, USA., Song X; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA., Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Cabrol C; Centre de génétique humaine, Université de Franche-Comté, Besançon, France., Iwaszkiewicz J; Molecular Modeling Group, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland., Zoete V; Molecular Modeling Group, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Computer-Aided Molecular Engineering, Department of Oncology, Ludwig Institute for Cancer Research Lausanne Branch, University of Lausanne, Lausanne, Switzerland., Pehlivan D; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; EA481 Integrative and Cognitive Neuroscience Research Unit, University of Franche-Comte, Besancon, France., Akdemir ZC; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; University Texas Health Science Center, Houston, TX 77030, USA., Roeder ER; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA., Littlejohn RO; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA., Dibra HK; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK., Byrd PJ; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK., Stewart GS; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK., Geckinli BB; Department of Medical Genetics, Marmara University School of Medicine, Istanbul 34722, Turkey., Posey J; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA., Westman R; Providence Medical Group Genetic Clinics, Spokane, WA, USA., Jungbluth C; Providence Medical Group Genetic Clinics, Spokane, WA, USA., Eason J; Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK., Sachdev R; Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia., Evans CA; Neuroscience Research Australia (NeuRA) Institute, Sydney, NSW, Australia., Lemire G; Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA., VanNoy GE; Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., O'Donnell-Luria A; Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA., Mau-Them FT; UF6254 Innovation en diagnostic génomique des maladies rares, CHU Dijon Bourgogne, Dijon, France., Juven A; UF6254 Innovation en diagnostic génomique des maladies rares, CHU Dijon Bourgogne, Dijon, France., Piard J; Centre de génétique humaine, Université de Franche-Comté, Besançon, France., Nixon CY; Neuroscience Research Australia (NeuRA) Institute, Sydney, NSW, Australia., Zhu Y; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia., Ha T; Department of Biophysics and Biophysical Chemistry, Biophysics and Biomedical Engineering, JHU Howard Hughes Medical Institute, Baltimore, MD 21205, USA., Buckley MF; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia., Thauvin C; INSERM UMR1231 GAD, Bourgogne Franche-Comté University, Dijon, France; Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Dijon-Burgundy University Hospital, Dijon, France., Essien Umanah GK; Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Van Maldergem L; Centre de génétique humaine, Université de Franche-Comté, Besançon, France; Clinical Investigation Center 1431, National Institute of Health and Medical Research (INSERM), CHU, Besancon, France; EA481 Integrative and Cognitive Neuroscience Research Unit, University of Franche-Comte, Besancon, France., Lupski JR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA., Roscioli T; Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia; Neuroscience Research Australia (NeuRA) Institute, Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia., Dawson VL; Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Dawson TM; Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Antonarakis SE; 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: stylianos.antonarakis@unige.ch.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2023 Mar 02; Vol. 110 (3), pp. 499-515. Date of Electronic Publication: 2023 Jan 31.
DOI:	10.1016/j.ajhg.2023.01.006
Abstrakt:	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). We present clinical, genomic, and functional data from 11 individuals in 9 unrelated families with bi-allelic variants in TTI1. All present with ID, and most with microcephaly, short stature, and a movement disorder. Functional studies performed in HEK293T cell lines and fibroblasts and lymphoblastoid cells derived from 4 unrelated individuals showed impairment of the TTT complex and of mTOR pathway activity which is improved by treatment with Rapamycin. Our data delineate a TTI1-related neurodevelopmental disorder and expand the group of disorders related to the TTT complex. Competing Interests: Declaration of interests S.E.A. is a co-founder and CEO of Medigenome, Swiss Institute of Genomic Medicine, and serves in the Scientific Advisory Board of the “Imagine” Institute in Paris. The Department of Medical and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics Laboratories. J.R.L. has stock ownership in 23andMe; is a paid consultant for Regeneron Genetics Center; and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting, and serves on the Scientific Advisory Board of Baylor Genomics. (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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