2. Academic Validation
  3. Bi-allelic TMEM94 Truncating Variants Are Associated with Neurodevelopmental Delay, Congenital Heart Defects, and Distinct Facial Dysmorphism

Bi-allelic TMEM94 Truncating Variants Are Associated with Neurodevelopmental Delay, Congenital Heart Defects, and Distinct Facial Dysmorphism

  • Am J Hum Genet. 2018 Dec 6;103(6):948-967. doi: 10.1016/j.ajhg.2018.11.001.
Joshi Stephen 1,  Sateesh Maddirevula 2,  Sheela Nampoothiri 3,  John D Burke 1,  Matthew Herzog 4,  Anju Shukla 5,  Katharina Steindl 6,  Ascia Eskin 4,  Siddaramappa J Patil 7,  Pascal Joset 6,  Hane Lee 8,  Lisa J Garrett 9,  Tadafumi Yokoyama 1,  Nicholas Balanda 10,  Steven P Bodine 1,  Nathanial J Tolman 10,  Patricia M Zerfas 11,  Allison Zheng 4,  Georgia Ramantani 12,  Katta M Girisha 5,  Cecilia Rivas 9,  Pujar V Suresh 13,  Abdel Elkahloun 14,  Hessa S Alsaif 2,  Salma M Wakil 2,  Laila Mahmoud 15,  Rehab Ali 15,  Michaela Prochazkova 16,  Undiagnosed Diseases Network members,  Ashok B Kulkarni 16,  Tawfeg Ben-Omran 15,  Dilek Colak 17,  H Douglas Morris 18,  Anita Rauch 6,  Julian A Martinez-Agosto 4,  Stanley F Nelson 19,  Fowzan S Alkuraya 20,  William A Gahl 21,  May Christine V Malicdan 22
Affiliations

Affiliations

  • 1 Section of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 2 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • 3 Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Center, Kerala 682041, India.
  • 4 Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
  • 5 Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India.
  • 6 Institute of Medical Genetics, University of Zurich, Schlieren-Zurich 8952, Switzerland and radiz - "Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich," Zurich 8032, Switzerland.
  • 7 Mazumdar Shaw Medical Center, Narayana Health City, Bangalore 560099, India.
  • 8 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
  • 9 Embryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 10 NIH Undiagnosed Diseases Program, NHGRI and the Common Fund, National Institutes of Health, Bethesda, MD 20892, USA.
  • 11 Office of Research Services, Division of Veterinary Resources, NIH, Bethesda, MD 20892, USA.
  • 12 Neuropediatrics, University Children's Hospital, Zurich 8032, Switzerland.
  • 13 Department of Pediatric Cardiology, Narayana Institute of Cardiac Sciences, Bangalore 560099, India.
  • 14 Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 15 Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, PO Box 3050, Qatar.
  • 16 Functional Genomics Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
  • 17 Department of Biostatistics, Epidemiology, and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • 18 Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 21042, USA.
  • 19 Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
  • 20 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Human Genome Program, King Abdulaziz City of Science and Technology, Riyadh 11442, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia. Electronic address: [email protected].
  • 21 Section of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA; NIH Undiagnosed Diseases Program, NHGRI and the Common Fund, National Institutes of Health, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 22 Section of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA; NIH Undiagnosed Diseases Program, NHGRI and the Common Fund, National Institutes of Health, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: [email protected].
PMID: 30526868 DOI: 10.1016/j.ajhg.2018.11.001
Abstract

Neurodevelopmental disorders (NDD) are genetically and phenotypically heterogeneous conditions due to defects in genes involved in development and function of the nervous system. Individuals with NDD, in addition to their primary neurodevelopmental phenotype, may also have accompanying syndromic features that can be very helpful diagnostically especially those with recognizable facial appearance. In this study, we describe ten similarly affected individuals from six unrelated families of different ethnic origins having bi-allelic truncating variants in TMEM94, which encodes for an uncharacterized transmembrane nuclear protein that is highly conserved across mammals. The affected individuals manifested with global developmental delay/intellectual disability, and dysmorphic facial features including triangular face, deep set eyes, broad nasal root and tip and anteverted nostrils, thick arched eye brows, hypertrichosis, pointed chin, and hypertelorism. Birthweight in the upper normal range was observed in most, and all but one had congenital heart defects (CHD). Gene expression analysis in available cells from affected individuals showed reduced expression of TMEM94. Global transcriptome profiling using microarray and RNA sequencing revealed several dysregulated genes essential for cell growth, proliferation and survival that are predicted to have an impact on cardiotoxicity hematological system and neurodevelopment. Loss of Tmem94 in mouse model generated by CRISPR/Cas9 was embryonic lethal and led to craniofacial and cardiac abnormalities and abnormal neuronal migration pattern, suggesting that this gene is important in craniofacial, cardiovascular, and nervous system development. Our study suggests the genetic etiology of a recognizable dysmorphic syndrome with NDD and CHD and highlights the role of TMEM94 in early development.

Keywords

CRISPR-Cas9; Tmem94 knockout mice; congenital heart defects; facial dysmorphism; neurodevelopmental disorder.

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