The phenotypic spectrum of PCDH12 associated disorders – Five new cases and review of the literature.

October 30, 2021

Fazeli W1, Bamborschke D S2, Moawia A2, Bakhtiari S3, Tafakhori A4, Giersdorf M5, Hahn A6, Weik A7, Kolzter K8, Shafiee S9, Jin SC10, Körber F11, Lee-Kirsch MA12, Darvish H13, Cirak S2, Kruer MC3, Koy A5

Abstract

PCDH12 is a member of the non-clustered protocadherin family of calcium-dependent cell adhesion proteins, which are involved in the regulation of brain development and endothelial adhesion. To date, only 15 families have been reported with PCDH12 associated disease. The main features previously associated with PCDH12 deficiency are developmental delay, movement disorder, epilepsy, microcephaly, visual impairment, midbrain malformations, and intracranial calcifications. Here, we report novel clinical features such as onset of epilepsy after infancy, episodes of transient developmental regression, and dysplasia of the medulla oblongata associated with three different novel truncating PCDH12 mutations in five cases (three children, two adults) from three unrelated families. Interestingly, our data suggests a clinical overlap with interferonopathies, and we show an elevated interferon score in two pediatric patients. This case series expands the genetic and phenotypic spectrum of PCDH12 associated diseases and highlights the broad clinical variability.

Keywords: Brain malformation; Epilepsy; Interferonopathy; Intracranial calcification; Movement disorder; PCDH12.

  1. Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Institute for Molecular and Behavioral Neuroscience, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Department of Neuropediatrics, University Hospital Bonn, Bonn, Germany. Electronic address: walid.fazeli@ukbonn.de.
  2. Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  3. Pediatric Movement Disorders Program, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, USA; Departments of Child Health, Cellular & Molecular Medicine, and Neurology and Program in Genetics, University of Arizona College of Medicine Phoenix, Phoenix, AZ, USA.
  4. Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
  5. Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  6. Department of Child Neurology, Justus-Liebig-University Giessen, Giessen, Germany.
  7. CeGAT GmbH and Praxis für Humangenetik Tübingen, Tübingen, Germany..
  8. Children’s Hospital Amsterdamer Straße, Kliniken der Stadt Köln, Cologne, Germany.
  9. Neurological Surgery Department, Mazandaran University of Medical Sciences, Sari, Iran.
  10. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
  11. Department of Radiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  12. Department of Pediatrics, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
  13. Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.