Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia.

Autor: Calame DG; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Hospital, Houston, TX, USA., Herman I; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Hospital, Houston, TX, USA., Maroofian R; Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK., Marshall AE; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada., Donis KC; 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., Fatih JM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Mitani T; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Du H; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Grochowski CM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Sousa SB; 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., Gijavanekar C; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Bakhtiari S; Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA.; Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA., Ito YA; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada., Rocca C; Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK., Hunter JV; Texas Children's Hospital, Houston, TX, USA.; Division of Neuroradiology, Edward B. Singleton Department of Radiology, Texas Children's Hospital, Houston, TX, USA., Sutton VR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Hospital, Houston, TX, USA., Emrick LT; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Hospital, Houston, TX, USA., Boycott KM; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada., Lossos A; Department of Neurology, Hadassah Medical Organization and Faculty of Medicine, Hebrew University, Jerusalem, Israel., Fellig Y; Department of Pathology, Hadassah Medical Organization and Faculty of Medicine, Hebrew University, Jerusalem, Israel., Prus E; Hematology and Bone Marrow Transplantation Division, Hadassah Medical Center and Hebrew University, Jerusalem, Israel., Kalish Y; Hematology and Bone Marrow Transplantation Division, Hadassah Medical Center and Hebrew University, Jerusalem, Israel., Meiner V; Department of Genetics, Hadassah Medical Center and Hebrew University, Jerusalem, Israel., Suerink M; Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands., Ruivenkamp C; Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands., Muirhead K; Division of Neurology, Children's Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA, USA., Saadi NW; College of Medicine/University of Baghdad, Unit of Pediatric Neurology, Children Welfare Teaching Hospital, Baghdad, Iraq., Zaki MS; Clinical Genetics Department, Human Genetics and Genome Research Institute, Center of Excellence of Human Genetics, National Research Centre, Cairo, Dokki, Egypt., Bouman A; Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands., Barakat TS; Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands., Skidmore DL; Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada., Osmond M; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada., Silva TO; 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., Murphy D; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK., Karimiani EG; Genetics Section, Molecular and Clinical Sciences Institute, St George's University of London, London, UK., Jamshidi Y; Genetics Section, Molecular and Clinical Sciences Institute, St George's University of London, London, UK., Jaddoa AG; Pediatric Neurology, Children Welfare Teaching Hospital, Baghdad, Iraq., Tajsharghi H; School of Health Sciences, Division Biomedicine, University of Skövde, Skövde, Sweden., Jin SC; Department of Genetics, Washington University School of Medicine, St Louis, MO, USA., Abbaszadegan MR; Medical Genetics Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran.; Pardis Pathobiology and Genetics Laboratory, Mashhad, Iran., Ebrahimzadeh-Vesal R; Pardis Pathobiology and Genetics Laboratory, Mashhad, Iran., Hosseini S; Pardis Pathobiology and Genetics Laboratory, Mashhad, Iran., Alavi S; Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran., Bahreini A; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA., Zarean E; Department of Perinatology, Isfahan University of Medical Sciences, Isfahan, Iran., Salehi MM; Department of Pediatrics, Isfahan University of Medical Sciences, Isfahan, Iran., Al-Sannaa NA; Pediatric Services, John Hopkins Aramco Health Care, Dhahran, Saudi Arabia., Zifarelli G; Centogene GmbH, Rostock, Germany., Bauer P; Centogene GmbH, Rostock, Germany., Robson SC; Center for Inflammation Research, Transplantation, Departments of Medicine and Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA., Coban-Akdemir Z; 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., Travaglini L; Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, Scientific Institute for Research and Health Care, Rome, Italy.; Laboratory of Molecular Medicine, Department of Neuroscience, Bambino Gesù Children's Hospital, Scientific Institute for Research and Health Care, Rome, Italy., Nicita F; Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, Scientific Institute for Research and Health Care, Rome, Italy.; Laboratory of Molecular Medicine, Department of Neuroscience, Bambino Gesù Children's Hospital, Scientific Institute for Research and Health Care, Rome, Italy., Jhangiani SN; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA., Gibbs RA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA., Posey JE; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Kruer MC; Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA.; Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA., Kernohan KD; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.; Newborn Screening Ontario, Ottawa, Ontario, Canada., Morales Saute JA; Medical Genetics Service, Porto Alegre Clinical Hospital, Porto Alegre, Brazil.; Department of Internal Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.; Neurology Service, Porto Alegre Clinical Hospital, Porto Alegre, Brazil., Houlden H; Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK., Vanderver A; 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., Elsea SH; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Pehlivan D; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Hospital, Houston, TX, USA., Marafi D; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait., Lupski JR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Hospital, Houston, TX, USA.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Jazyk: angličtina
Zdroj: Annals of neurology [Ann Neurol] 2022 Aug; Vol. 92 (2), pp. 304-321. Date of Electronic Publication: 2022 May 28.
DOI: 10.1002/ana.26381
Abstrakt: 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.
(© 2022 American Neurological Association.)
Databáze: MEDLINE
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