Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia
Annals of Neurology, vol. 92, pp. 304–321
Abstract
OBJECTIVE: Human genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia is associated with >80 genes, with frequently only few affected individuals described for each gene. Herein, we characterize a large cohort of individuals with biallelic variation in ENTPD1, a gene previously linked to spastic paraplegia 64 (Mendelian Inheritance in Man # 615683). METHODS: Individuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterization were performed. RESULTS: A total of 27 individuals from 17 unrelated families were studied; additional phenotypic information was collected from published cases. Twelve novel pathogenic ENTPD1 variants are described (NM 001776.6): c.398_399delinsAA; p.(Gly133Glu), c.540del; p.(Thr181Leufs*18), c.640del; p.(Gly216Glufs*75), c.185 T > G; p.(Leu62*), c.1531 T > C; p.(*511Glnext*100), c.967C > T; p.(Gln323*), c.414-2_414-1del, and c.146 A > G; p.(Tyr49Cys) including 4 recurrent variants c.1109 T > A; p.(Leu370*), c.574-6_574-3del, c.770_771del; p.(Gly257Glufs*18), and c.1041del; p.(Ile348Phefs*19). Shared disease traits include childhood onset, progressive spastic paraplegia, intellectual disability (ID), dysarthria, and white matter abnormalities. In vitro assays demonstrate that ENTPD1 expression and function are impaired and that c.574-6_574-3del causes exon skipping. Global metabolomics demonstrate ENTPD1 deficiency leads to impaired nucleotide, lipid, and energy metabolism. INTERPRETATION: The ENTPD1 locus trait consists of childhood disease onset, ID, progressive spastic paraparesis, dysarthria, dysmorphisms, and white matter abnormalities, with some individuals showing neurocognitive regression. Investigation of an allelic series of ENTPD1 (1) expands previously described features of ENTPD1-related neurological disease, (2) highlights the importance of genotype-driven deep phenotyping, (3) documents the need for global collaborative efforts to characterize rare autosomal recessive disease traits, and (4) provides insights into disease trait neurobiology. ANN NEUROL 2022;92:304-321.
Authors 64
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Daniel G. Calame corresponding
Baylor College of Medicine · Texas Children's Hospital
Affiliation as printed
Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA
Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics Baylor College of Medicine Houston TX USA
Texas Children's Hospital Houston TX USA
D.G.C. and I.H. contributed equally
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
Texas Children's Hospital, Houston, TX, USA
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Isabella Herman corresponding
Baylor College of Medicine · Texas Children's Hospital
Affiliation as printed
Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA
Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics Baylor College of Medicine Houston TX USA
Texas Children's Hospital Houston TX USA
D.G.C. and I.H. contributed equally
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
Texas Children's Hospital, Houston, TX, USA
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Disorders Queen Square Institute of Neurology, University College London London UK
Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK
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University of Ottawa · Children's Hospital of Eastern Ontario
Affiliation as printed
Children's Hospital of Eastern Ontario Research Institute University of Ottawa Ottawa Ontario Canada
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada
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Universidade Federal do Rio Grande do Sul · Hospital de Clínicas de Porto Alegre
Affiliation as printed
Graduate Program in Genetics and Molecular Biology Federal University of Rio Grande do Sul Porto Alegre Brazil
Medical Genetics Service Porto Alegre Clinical Hospital Porto Alegre Brazil
Graduate Program in Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
Medical Genetics Service, Porto Alegre Clinical Hospital, Porto Alegre, Brazil
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Affiliation as printed
Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
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Affiliation as printed
Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
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Affiliation as printed
Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
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Affiliation as printed
Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
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Unidade Local de Saúde de Coimbra · University of Coimbra
Affiliation as printed
Medical Genetics Unit, Hospital Pediatrico, Centro Hospitalar e Universitario de Coimbra Coimbra Portugal
University Clinic of Genetics, Faculty of Medicine, Universidade de Coimbra Coimbra Portugal
Medical Genetics Unit, Hospital Pediatrico, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal
University Clinic of Genetics, Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal
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Affiliation as printed
Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
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Barrow Neurological Institute · Phoenix Children's Hospital · University of Arizona College of Medicine- Phoenix
Affiliation as printed
Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics University of Arizona College of Medicine–Phoenix Phoenix AZ USA
Pediatric Movement Disorders Program, Division of Pediatric Neurology Barrow Neurological Institute, Phoenix Children's Hospital Phoenix AZ USA
Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA
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University of Ottawa · Children's Hospital of Eastern Ontario
Affiliation as printed
Children's Hospital of Eastern Ontario Research Institute University of Ottawa Ottawa Ontario Canada
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Disorders Queen Square Institute of Neurology, University College London London UK
Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK
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Affiliation as printed
Division of Neuroradiology, Edward B. Singleton Department of Radiology Texas Children's Hospital Houston TX USA
Texas Children's Hospital Houston TX USA
Division of Neuroradiology, Edward B. Singleton Department of Radiology Texas Children's Hospital Houston TX USA
Division of Neuroradiology, Edward B. Singleton Department of Radiology, Texas Children's Hospital, Houston, TX, USA
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Baylor College of Medicine · Texas Children's Hospital
Affiliation as printed
Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA
Texas Children's Hospital Houston TX USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Texas Children's Hospital, Houston, TX, USA
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Baylor College of Medicine · Texas Children's Hospital
Affiliation as printed
Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA
Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics Baylor College of Medicine Houston TX USA
Texas Children's Hospital Houston TX USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
Texas Children's Hospital, Houston, TX, USA
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University of Ottawa · Children's Hospital of Eastern Ontario
Affiliation as printed
Children's Hospital of Eastern Ontario Research Institute University of Ottawa Ottawa Ontario Canada
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada
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Hebrew University of Jerusalem · Hadassah Medical Center
Affiliation as printed
Department of Neurology Hadassah Medical Organization and Faculty of Medicine, Hebrew University Jerusalem Israel
Department of Neurology, Hadassah Medical Organization and Faculty of Medicine, Hebrew University, Jerusalem, Israel
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Hebrew University of Jerusalem · Hadassah Medical Center
Affiliation as printed
Department of Pathology Hadassah Medical Organization and Faculty of Medicine, Hebrew University Jerusalem Israel
Department of Pathology, Hadassah Medical Organization and Faculty of Medicine, Hebrew University, Jerusalem, Israel
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Hebrew University of Jerusalem · Hadassah Medical Center
Affiliation as printed
Hematology and Bone Marrow Transplantation Division Hadassah Medical Center and Hebrew University Jerusalem Israel
Hematology and Bone Marrow Transplantation Division, Hadassah Medical Center and Hebrew University, Jerusalem, Israel
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Hebrew University of Jerusalem · Hadassah Medical Center
Affiliation as printed
Hematology and Bone Marrow Transplantation Division Hadassah Medical Center and Hebrew University Jerusalem Israel
Hematology and Bone Marrow Transplantation Division, Hadassah Medical Center and Hebrew University, Jerusalem, Israel
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Hebrew University of Jerusalem · Hadassah Medical Center
Affiliation as printed
Department of Genetics Hadassah Medical Center and Hebrew University Jerusalem Israel
Department of Genetics, Hadassah Medical Center and Hebrew University, Jerusalem, Israel
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Manon Suerink Aachen Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands Department of Clinical Genetics
Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics Leiden University Medical Center Leiden the Netherlands
Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
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Claudia A. L. Ruivenkamp Aachen Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands Department of Clinical Genetics
Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics Leiden University Medical Center Leiden the Netherlands
Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
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Children's Hospital of Philadelphia
Affiliation as printed
Division of Neurology Children's Hospital of Philadelphia, Abramson Research Center Philadelphia PA USA
Division of Neurology, Children's Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA, USA
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Affiliation as printed
College of Medicine/University of Baghdad Unit of Pediatric Neurology, Children Welfare Teaching Hospital Baghdad Iraq
College of Medicine/University of Baghdad, Unit of Pediatric Neurology, Children Welfare Teaching Hospital, Baghdad, Iraq
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Affiliation as printed
Clinical Genetics Department Human Genetics and Genome Research Institute, Center of Excellence of Human Genetics, National Research Centre Cairo Dokki Egypt
Clinical Genetics Department, Human Genetics and Genome Research Institute, Center of Excellence of Human Genetics, National Research Centre, Cairo, Dokki, Egypt
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Affiliation as printed
Department of Clinical Genetics Erasmus University Medical Center Rotterdam the Netherlands
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands
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Affiliation as printed
Department of Clinical Genetics Erasmus University Medical Center Rotterdam the Netherlands
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands
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Affiliation as printed
Department of Pediatrics Dalhousie University Halifax Nova Scotia Canada
Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada
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University of Ottawa · Children's Hospital of Eastern Ontario
Affiliation as printed
Children's Hospital of Eastern Ontario Research Institute University of Ottawa Ottawa Ontario Canada
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada
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Universidade Federal do Rio Grande do Sul · Hospital de Clínicas de Porto Alegre
Affiliation as printed
Medical Genetics Service Porto Alegre Clinical Hospital Porto Alegre Brazil
Postgraduate Program in Medicine: Medical Sciences Federal University of Rio Grande do Sul Porto Alegre Brazil
Medical Genetics Service, Porto Alegre Clinical Hospital, Porto Alegre, Brazil
Postgraduate Program in Medicine: Medical Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology, University College London London UK
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK
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St George's, University of London
Affiliation as printed
Genetics Section Molecular and Clinical Sciences Institute, St George's University of London London UK
Genetics Section, Molecular and Clinical Sciences Institute, St George's University of London, London, UK
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St George's, University of London
Affiliation as printed
Genetics Section Molecular and Clinical Sciences Institute, St George's University of London London UK
Genetics Section, Molecular and Clinical Sciences Institute, St George's University of London, London, UK
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Affiliation as printed
Pediatric Neurology Children Welfare Teaching Hospital Baghdad Iraq
Pediatric Neurology, Children Welfare Teaching Hospital, Baghdad, Iraq
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Affiliation as printed
School of Health Sciences, Division Biomedicine University of Skövde Skövde Sweden
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Washington University in St. Louis
Affiliation as printed
Department of Genetics Washington University School of Medicine St Louis MO USA
Department of Genetics, Washington University School of Medicine, St Louis, MO, USA
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Mashhad University of Medical Sciences
Affiliation as printed
Medical Genetics Research Center Medical School, Mashhad University of Medical Sciences Mashhad Iran
Pardis Pathobiology and Genetics Laboratory Mashhad Iran
Medical Genetics Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran
Pardis Pathobiology and Genetics Laboratory, Mashhad, Iran
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Mashhad University of Medical Sciences
Affiliation as printed
Pardis Pathobiology and Genetics Laboratory Mashhad Iran
Pardis Pathobiology and Genetics Laboratory, Mashhad, Iran
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Mashhad University of Medical Sciences
Affiliation as printed
Pardis Pathobiology and Genetics Laboratory Mashhad Iran
Pardis Pathobiology and Genetics Laboratory, Mashhad, Iran
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Affiliation as printed
Department of Cell and Molecular Biology & Microbiology Faculty of Biological Science and Technology, University of Isfahan Isfahan Iran
Department of Cell and Molecular Biology & Microbiology Faculty of Biological Science and Technology, University of Isfahan Isfahan Iran
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Affiliation as printed
Department of Human Genetics Graduate School of Public Health, University of Pittsburgh Pittsburgh PA USA
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
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Isfahan University of Medical Sciences
Affiliation as printed
Department of Perinatology Isfahan University of Medical Sciences Isfahan Iran
Department of Perinatology, Isfahan University of Medical Sciences, Isfahan, Iran
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Saudi Aramco Medical Services Organization
Affiliation as printed
Pediatric Services John Hopkins Aramco Health Care Dhahran Saudi Arabia
Pediatric Services, John Hopkins Aramco Health Care, Dhahran, Saudi Arabia
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Affiliation as printed
Centogene GmbH Rostock Germany
Centogene GmbH, Rostock, Germany
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Affiliation as printed
Centogene GmbH Rostock Germany
Centogene GmbH, Rostock, Germany
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Beth Israel Deaconess Medical Center · Harvard University
Affiliation as printed
Center for Inflammation Research, Transplantation, Departments of Medicine and Anesthesia Beth Israel Deaconess Medical Center, Harvard Medical School Boston MA USA
Center for Inflammation Research, Transplantation, Departments of Medicine and Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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Baylor College of Medicine · The University of Texas Health Science Center at Houston
Affiliation as printed
Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA
Human Genetics Center, Department of Epidemiology Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston Houston TX USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA
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Bambino Gesù Children's Hospital
Affiliation as printed
Laboratory of Molecular Medicine, Department of Neuroscience Bambino Gesù Children's Hospital, Scientific Institute for Research and Health Care Rome Italy
Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences Bambino Gesù Children's Hospital, Scientific Institute for Research and Health Care Rome Italy
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Bambino Gesù Children's Hospital
Affiliation as printed
Laboratory of Molecular Medicine, Department of Neuroscience Bambino Gesù Children's Hospital, Scientific Institute for Research and Health Care Rome Italy
Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences Bambino Gesù Children's Hospital, Scientific Institute for Research and Health Care Rome Italy
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Affiliation as printed
Human Genome Sequencing Center Baylor College of Medicine Houston TX USA
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
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Affiliation as printed
Human Genome Sequencing Center Baylor College of Medicine Houston TX USA
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
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Affiliation as printed
Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
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Barrow Neurological Institute · Phoenix Children's Hospital · University of Arizona College of Medicine- Phoenix
Affiliation as printed
Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics University of Arizona College of Medicine–Phoenix Phoenix AZ USA
Pediatric Movement Disorders Program, Division of Pediatric Neurology Barrow Neurological Institute, Phoenix Children's Hospital Phoenix AZ USA
Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA
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University of Ottawa · Children's Hospital of Eastern Ontario · Newborn Screening Ontario
Affiliation as printed
Children's Hospital of Eastern Ontario Research Institute University of Ottawa Ottawa Ontario Canada
Newborn Screening Ontario Ottawa Ontario Canada
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada
Newborn Screening Ontario, Ottawa, Ontario, Canada
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Universidade Federal do Rio Grande do Sul · Hospital de Clínicas de Porto Alegre
Affiliation as printed
Department of Internal Medicine Federal University of Rio Grande do Sul Porto Alegre Brazil
Medical Genetics Service Porto Alegre Clinical Hospital Porto Alegre Brazil
Neurology Service Porto Alegre Clinical Hospital Porto Alegre Brazil
Department of Internal Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
Medical Genetics Service, Porto Alegre Clinical Hospital, Porto Alegre, Brazil
Neurology Service, Porto Alegre Clinical Hospital, Porto Alegre, Brazil
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Disorders Queen Square Institute of Neurology, University College London London UK
Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK
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Children's Hospital of Philadelphia · University of Pennsylvania
Affiliation as printed
Department of Neurology, Perelman School of Medicine University of Pennsylvania Philadelphia PA USA
Division of Neurology Children's Hospital of Philadelphia, Abramson Research Center Philadelphia PA USA
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Division of Neurology, Children's Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA, USA
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Affiliation as printed
Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
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Baylor College of Medicine · Texas Children's Hospital
Affiliation as printed
Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA
Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics Baylor College of Medicine Houston TX USA
Texas Children's Hospital Houston TX USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
Texas Children's Hospital, Houston, TX, USA
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Baylor College of Medicine · Kuwait University
Affiliation as printed
Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA
Department of Pediatrics Faculty of Medicine, Kuwait University Safat Kuwait
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait
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James R. Lupski corresponding
Baylor College of Medicine · Texas Children's Hospital
Affiliation as printed
Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA
Department of Pediatrics Baylor College of Medicine Houston TX USA
Human Genome Sequencing Center Baylor College of Medicine Houston TX USA
Texas Children's Hospital Houston TX USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
Texas Children's Hospital, Houston, TX, USA
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