Evidence map›Paper›PMID 30526868›Full record

ArticleAmerican journal of human genetics2018

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

Joshi Stephen, Sateesh Maddirevula, Sheela Nampoothiri, John D Burke, Matthew Herzog, Anju Shukla, Katharina Steindl, Ascia Eskin, Siddaramappa J Patil, Pascal Joset and 29 more

Registry-linked trialOpen access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02450851 (Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network), which is not on this map. Cited by 20 papers.

0numbers the graph read from it
0cells of the map it votes in
20citing papers in PubMed
0.7field-weighted citation impact, top 29% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT02450851 recruitingnot on this map

Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network

TypeobservationalSponsorNational Human Genome Research Institute (NHGRI)Ran2015 to 2028Enrolled20,000ConditionsGenetic Disease
3 · Its place in the literature

Who cites it

20 citing papers in PubMed, 29 citations in OpenAlex.

  1. Article
  2. Genetic alterations in SUPT6H are associated with neurodevelopmental disorders.Biochimica et biophysica acta. Molecular basis of disease · 2026
    Article
  3. Spectrum of Congenital Heart Diseases in Iraqi Patients.The Eurasian journal of medicine · 2026
    Article
  4. Article
  5. Article
  6. Article
  7. Article
  8. Article
  9. Loss of the endoplasmic reticulum protein Tmem208 affects cell polarity, development, and viability.Proceedings of the National Academy of Sciences of the United States of America · 2024
    Article
  10. AbioRxiv : the preprint server for biology · 2024
    Article
  11. Article
  12. The role of noncoding genetic variants in cardiomyopathy.Frontiers in cardiovascular medicine · 2023
    Review
  13. Article
  14. Article
  15. Article
  16. The frontiers of sequencing in undiagnosed neurodevelopmental diseases.Current opinion in genetics & development · 2020
    Review
  17. Article
  18. Article
  19. Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

39 authors at 12 institutions in 5 countries.

Joshi StephenSection of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Sateesh MaddirevulaDepartment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Sheela NampoothiriDepartment of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Center, Kerala 682041, India.
John D BurkeSection of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Matthew HerzogDepartment of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
Anju ShuklaDepartment of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India.
Katharina SteindlInstitute 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.
Ascia EskinDepartment of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
Siddaramappa J PatilMazumdar Shaw Medical Center, Narayana Health City, Bangalore 560099, India.
Pascal JosetInstitute 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.
Hane LeeDepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
Lisa J GarrettEmbryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Tadafumi YokoyamaSection of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Nicholas BalandaNIH Undiagnosed Diseases Program, NHGRI and the Common Fund, National Institutes of Health, Bethesda, MD 20892, USA.
Steven P BodineSection of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Nathanial J TolmanNIH Undiagnosed Diseases Program, NHGRI and the Common Fund, National Institutes of Health, Bethesda, MD 20892, USA.
Patricia M ZerfasOffice of Research Services, Division of Veterinary Resources, NIH, Bethesda, MD 20892, USA.
Allison ZhengDepartment of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
Georgia RamantaniNeuropediatrics, University Children's Hospital, Zurich 8032, Switzerland.
Katta M GirishaDepartment of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India.
Cecilia RivasEmbryonic Stem Cell and Transgenic Mouse Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Pujar V SureshDepartment of Pediatric Cardiology, Narayana Institute of Cardiac Sciences, Bangalore 560099, India.
Abdel ElkahlounCancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Hessa S AlsaifDepartment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Salma M WakilDepartment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Laila MahmoudClinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, PO Box 3050, Qatar.
Rehab AliClinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, PO Box 3050, Qatar.
Michaela ProchazkovaFunctional Genomics Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Undiagnosed Diseases Network members
Ashok B KulkarniFunctional Genomics Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Tawfeg Ben-OmranClinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, PO Box 3050, Qatar.
Dilek ColakDepartment of Biostatistics, Epidemiology, and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
H Douglas MorrisMouse Imaging Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 21042, USA.
Anita RauchInstitute 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.
Julian A Martinez-AgostoDepartment of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
Stanley F NelsonDepartment 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.
Fowzan S AlkurayaDepartment 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: falkuraya@kfshrc.edu.sa.
William A GahlSection 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.
May Christine V MalicdanSection 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: malicdanm@mail.nih.gov.
National Institutes of Health · USUniversity of California, Los Angeles · USKing Faisal Specialist Hospital & Research Centre · SANational Human Genome Research Institute · USHamad Medical Corporation · QAUniversity of Zurich · CHManipal Academy of Higher Education · INNarayana Health · INAmrita Institute of Medical Sciences and Research Centre · INCancer Genetics (United States) · USOffice of Research Services · USUniversity Children's Hospital Zurich · CH

Funding

Human Biochemical GeneticsZIAHG000215 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI GAHL, WILLIAM · 2009 to 2025
$72.6M
NHGRI/DIR Embryonic Stem Cell and Transgenic Mouse CoreZICHG200349 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI BURGESS, SHAWN M · 2010 to 2025
$23.8M
UCLA clinical site for the investigation of undiagnosed disordersU01HG007703 · NHGRI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI MARTINEZ-AGOSTO, JULIAN, NELSON, STANLEY F. · 2014 to 2022
$10.1M
NHGRI/DIR Microarray CoreZICHG200365 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI ELKAHLOUN, ABDEL · 2011 to 2025
$9.0M
Clinical Pursuits by the NHGRI Office of the Clinical DirectorZIAHG200402 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI GAHL, WILLIAM · 2019 to 2019
$122k
NHGRI NIH HHS U01 HG007703
6 · The paper itself

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.

Indexed as

Abnormalities, MultipleAdolescentAllelesAnimalsChildChild, PreschoolDevelopmental DisabilitiesFaciesFemaleHeart Defects, CongenitalHumansHypertelorismInfantIntellectual DisabilityMaleMiceNuclear Proteinscongenital heart defectsCRISPR-Cas9facial dysmorphismneurodevelopmental disorderTmem94 knockout mice

Identifiers

PMID30526868
PMCPMC6288279
OpenAlexW2904789592

What OpenQuestion holds

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.