Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications

Ashish R Deshwar^{1

2}, Cheryl Cytrynbaum^{1

2}, Harsha Murthy², Jessica Zon², David Chitayat¹, Jonathan Volpatti², Ruth Newbury-Ecob³, Sian Ellard⁴, Hana Lango Allen⁵, Emily P Yu⁶, Ramil Noche⁶, Suzi Walker⁷, Stephen W Scherer^{2

7}, Sonal Mahida⁸, Christopher M Elitt^{9

10

11}, Gaël Nicolas¹², Alice Goldenberg¹², Pascale Saugier-Veber¹², Francois Lecoquierre¹², Ivana Dabaj¹³, Hannah Meddaugh¹⁴, Michael Marble^{14

15}, Kim M Keppler-Noreuil¹⁶, Lucy Drayson¹⁷, Kristin W Barañano¹⁸, Anna Chassevent¹⁹, Katie Agre²⁰, Pascaline Létard²¹, Frederic Bilan^{21

22}, Gwenaël Le Guyader^{21

22}, Annie Laquerrière²³, Keri Ramsey²⁴, Lindsay Henderson²⁵, Lauren Brady²⁶, Mark Tarnopolsky²⁶, Matthew Bainbridge²⁷, Jennifer Friedman^{27

28

29}, Yline Capri³⁰, Larissa Athayde³¹, Fernando Kok³¹, Juliana Gurgel-Giannetti³², Luiza L P Ramos³¹, Susan Blaser³³, James J Dowling^{2

34

35}, Rosanna Weksberg^{1

2

35

36}

Affiliations

¹ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
² Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
³ Department of Clinical Genetics, University Hospitals Bristol NHS Foundation Trust, Bristol, BS2 8EG, UK.
⁴ Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, EX2 5DW, UK.
⁵ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0SL, UK.
⁶ Zebrafish Genetics and Disease Models Core Facility, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁷ The Centre for Applied Genomics, Genetics, and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁸ Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
⁹ Fetal-Neonatal Neurology Program, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
¹⁰ F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA.
¹¹ Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
¹² Department of Genetics and Reference Center for Developmental Disorders, Normandy Center for Genomic and Personalized Medicine, UNIROUEN, INSERM U1245 and Rouen University Hospital, Normandie University, F 76000 Rouen, France.
¹³ Department of Neonatology and Pediatric Intensive Care-Pediatric Neurology, Rouen University Hospital, and INSERM U1245, Normandie University, UNIROUEN, 76000 Rouen, France.
¹⁴ Department of Genetics, Children's Hospital of New Orleans, New Orleans, LA 70118, USA.
¹⁵ Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
¹⁶ Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53792, USA.
¹⁷ Pediatric Specialists of Virginia, Fairfax, VA 22031, USA.
¹⁸ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MA 21287, USA.
¹⁹ Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MA 21205, USA.
²⁰ Department of Clinical Genomics, Mayo Clinic, Rochester, NY 55905, USA.
²¹ Department of Clinical Genetics, Service de Génétique, CHU de Poitiers, CS 90577 - 86021 Poitiers Cedex, France.
²² EA3808 NEUVACOD, University of Poitiers, 86073 Poitiers, France.
²³ Department of Pathology, Normandy Centre for Genomic and Personalized Medicine, Normandie Univeristy, UNIROUEN, INSERM U1245 and Rouen University Hospital, F76000 Rouen, France.
²⁴ Translational Genomics Research Institute, Center for Rare Childhood Disorders, Phoenix, AZ 85004, USA.
²⁵ GeneDx, Gaithersburg, MD 20877, USA.
²⁶ Department of Pediatrics, McMaster University, Hamilton, ON L8S 4K1, Canada.
²⁷ Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
²⁸ Department of Neurosciences, University of California San Diego, San Diego, CA 92093, USA.
²⁹ Department of Pediatrics, University of California San Diego, San Diego, CA 92093, USA.
³⁰ Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP) Hôpital Robert Debré, 75019 Paris, France.
³¹ Mendelics Genomic Analysis, Sao Paulo CEP 02511-000, Brazil.
³² Department of Pediatrics, Federal University of Minas Gerais School of Medicine, Belo Horizonte - MG - CEP 31270-901, Brazil.
³³ Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
³⁴ Division of Neurology, The Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
³⁵ Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
³⁶ Institutes of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada.

PMID: 36477332
DOI: 10.1093/brain/awac461

Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications

Ashish R Deshwar et al. Brain. 2023.

. 2023 Jun 1;146(6):2285-2297.

doi: 10.1093/brain/awac461.

Authors

Affiliations

¹ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
² Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
³ Department of Clinical Genetics, University Hospitals Bristol NHS Foundation Trust, Bristol, BS2 8EG, UK.
⁴ Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, EX2 5DW, UK.
⁵ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0SL, UK.
⁶ Zebrafish Genetics and Disease Models Core Facility, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁷ The Centre for Applied Genomics, Genetics, and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁸ Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
⁹ Fetal-Neonatal Neurology Program, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
¹⁰ F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA.
¹¹ Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
¹² Department of Genetics and Reference Center for Developmental Disorders, Normandy Center for Genomic and Personalized Medicine, UNIROUEN, INSERM U1245 and Rouen University Hospital, Normandie University, F 76000 Rouen, France.
¹³ Department of Neonatology and Pediatric Intensive Care-Pediatric Neurology, Rouen University Hospital, and INSERM U1245, Normandie University, UNIROUEN, 76000 Rouen, France.
¹⁴ Department of Genetics, Children's Hospital of New Orleans, New Orleans, LA 70118, USA.
¹⁵ Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
¹⁶ Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53792, USA.
¹⁷ Pediatric Specialists of Virginia, Fairfax, VA 22031, USA.
¹⁸ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MA 21287, USA.
¹⁹ Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MA 21205, USA.
²⁰ Department of Clinical Genomics, Mayo Clinic, Rochester, NY 55905, USA.
²¹ Department of Clinical Genetics, Service de Génétique, CHU de Poitiers, CS 90577 - 86021 Poitiers Cedex, France.
²² EA3808 NEUVACOD, University of Poitiers, 86073 Poitiers, France.
²³ Department of Pathology, Normandy Centre for Genomic and Personalized Medicine, Normandie Univeristy, UNIROUEN, INSERM U1245 and Rouen University Hospital, F76000 Rouen, France.
²⁴ Translational Genomics Research Institute, Center for Rare Childhood Disorders, Phoenix, AZ 85004, USA.
²⁵ GeneDx, Gaithersburg, MD 20877, USA.
²⁶ Department of Pediatrics, McMaster University, Hamilton, ON L8S 4K1, Canada.
²⁷ Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
²⁸ Department of Neurosciences, University of California San Diego, San Diego, CA 92093, USA.
²⁹ Department of Pediatrics, University of California San Diego, San Diego, CA 92093, USA.
³⁰ Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP) Hôpital Robert Debré, 75019 Paris, France.
³¹ Mendelics Genomic Analysis, Sao Paulo CEP 02511-000, Brazil.
³² Department of Pediatrics, Federal University of Minas Gerais School of Medicine, Belo Horizonte - MG - CEP 31270-901, Brazil.
³³ Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
³⁴ Division of Neurology, The Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
³⁵ Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
³⁶ Institutes of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada.

PMID: 36477332
DOI: 10.1093/brain/awac461

Abstract

The blood-brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood-brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype-phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood-brain barrier and impaired neuronal function.

Keywords: CLDN5; blood–brain barrier; brain calcifications.

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Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications

Affiliations

Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases