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      Bi-allelic variants in the ESAM tight-junction gene cause a neurodevelopmental disorder associated with fetal intracranial hemorrhage.

      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 12 , 12 , 13 , 14 , 15 , 16 , 17 , 17 , 18 , 19 , 20 , 20 , 21 , 22 , 21 , 23 , 24 , 25 , 6 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 1 , 33 , 34 , 35 , 12 , 5 , 30 , 36 , 37
      American journal of human genetics
      Elsevier BV
      ESAM, blood-brain barrier, epilepsy, exome sequencing, global developmental delay, intellectual disability, intracranial hemorrhage, neurodevelopmental disorders, pregnancy loss, retinopathy, tight junctions

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          Abstract

          The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as "tightjunctionopathies."

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          Author and article information

          Journal
          Am J Hum Genet
          American journal of human genetics
          Elsevier BV
          1537-6605
          0002-9297
          Apr 06 2023
          : 110
          : 4
          Affiliations
          [1 ] Department of Molecular Medicine, University of Pavia, Pavia, Italy.
          [2 ] 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.
          [3 ] Molecular Diagnostics and Clinical Genetics Unit, Hospital Universitari Son Espases, Palma, Illes Balears, Spain; Genomics of Health, Institute of Health Research of the Balearic Islands, Palma, Illes Balears, Spain.
          [4 ] Genetics Institute, Rambam Health Care Campus, Haifa, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
          [5 ] AP-HP, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, Paris, France; Université de Paris, INSERM UMR-1141 Neurodiderot, Paris, France.
          [6 ] Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
          [7 ] Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir 35340, Turkey; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35340, Turkey; Department of Medical Biology, School of Medicine, Dokuz Eylul University, Izmir 35340, Turkey.
          [8 ] The Genetic Institute, Emek Medical Center, Afula, Israel.
          [9 ] Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnosis, IRCCS Policlinico San Matteo Foundation, Pavia, Italy.
          [10 ] Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
          [11 ] Department of Molecular Medicine, University of Pavia, Pavia, Italy; Laboratory of Biochemistry-Biotechnology and Advanced Diagnostics, IRCCS Policlinico San Matteo Foundation, Pavia, Italy.
          [12 ] Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
          [13 ] Neuroradiology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
          [14 ] Ophthalmology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
          [15 ] Child Neurology and Psychiatry Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
          [16 ] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait.
          [17 ] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
          [18 ] Tertiary ROP Center, Health Science University Kanuni Sultan Suleyman Training and Research Hospital, Istanbul 34303, Turkey.
          [19 ] Department of Medical Genetics, Basaksehir Cam and Sakura City Hospital, Istanbul 34480, Turkey.
          [20 ] Genomics of Health, Institute of Health Research of the Balearic Islands, Palma, Illes Balears, Spain.
          [21 ] Metabolic Pathologies and Pediatric Neurology Unit, Pediatric Service, Hospital Universitari Son Espases, Palma, Illes Balears, Spain.
          [22 ] Pediatric Radiology Unit, Radiology Service, Hospital Universitari Son Espases, Palma, Illes Balears, Spain.
          [23 ] Neurobiology, Institute of Health Research of the Balearic Islands, Palma, Illes Balears, Spain.
          [24 ] Department of Radiology, Division of Pediatric Radiology, Dana Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel; Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel.
          [25 ] AP-HM, Service de Génétique, Hôpital de la Timone, Marseille, France.
          [26 ] Medical Genetics Service, CHUV, University of Lausanne, Lausanne, Switzerland.
          [27 ] Inonu University, Faculty of Medicine, Turgut Ozal Research Center, Department of Pediatric Neurology, Malatya, Turkey.
          [28 ] Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35340, Turkey; Department of Pediatric Neurology, School of Medicine, Dokuz Eylul University, Izmir 35340, Turkey.
          [29 ] Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir 35340, Turkey; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35340, Turkey.
          [30 ] The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Department of Pediatrics B, Emek Medical Center, Afula, Israel.
          [31 ] Poriya Medical Center and the Azrieli Faculty of Medicine, Bar-Ilan University, Ramat-Gan, Israel.
          [32 ] Department of Molecular Medicine, University of Pavia, Pavia, Italy; Department of Biomedical Engineering, Tufts University, Medford, MA, USA.
          [33 ] Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PY, UK; Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0PY, UK.
          [34 ] Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada; Brain and Mind Research Institute, University of Ottawa, Ottawa ON K1H 8L1, Canada; Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, ON K1H 8L1, Canada.
          [35 ] Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland; University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
          [36 ] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
          [37 ] Department of Molecular Medicine, University of Pavia, Pavia, Italy; Neurogenetics Research Center, IRCCS Mondino Foundation, Pavia, Italy. Electronic address: edoardo.errichiello@unipv.it.
          Article
          S0002-9297(23)00089-7
          10.1016/j.ajhg.2023.03.005
          10119151
          36996813
          cf21f795-53dc-4e25-b643-8a14fde27754
          History

          neurodevelopmental disorders,ESAM,blood-brain barrier,epilepsy,exome sequencing,global developmental delay,intellectual disability,intracranial hemorrhage,pregnancy loss,retinopathy,tight junctions

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