2. Academic Validation
  3. A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis

A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis

  • Am J Hum Genet. 2018 May 3;102(5):995-1007. doi: 10.1016/j.ajhg.2018.03.005.
Heather E Olson 1,  Nolwenn Jean-Marçais 2,  Edward Yang 3,  Delphine Heron 4,  Katrina Tatton-Brown 5,  Paul A van der Zwaag 6,  Emilia K Bijlsma 7,  Bryan L Krock 8,  E Backer 9,  Erik-Jan Kamsteeg 10,  Margje Sinnema 11,  Margot R F Reijnders 10,  David Bearden 12,  Amber Begtrup 13,  Aida Telegrafi 13,  Roelineke J Lunsing 14,  Lydie Burglen 15,  Gaetan Lesca 16,  Megan T Cho 13,  Lacey A Smith 1,  Beth R Sheidley 1,  Christelle Moufawad El Achkar 1,  Phillip L Pearl 1,  Annapurna Poduri 1,  Cara M Skraban 17,  Jennifer Tarpinian 17,  Addie I Nesbitt 8,  Dietje E Fransen van de Putte 7,  Claudia A L Ruivenkamp 7,  Patrick Rump 6,  Nicolas Chatron 16,  Isabelle Sabatier 18,  Julitta De Bellescize 19,  Laurent Guibaud 20,  David A Sweetser 21,  Jessica L Waxler 21,  Klaas J Wierenga 22,  DDD Study,  Jean Donadieu 23,  Vinodh Narayanan 24,  Keri M Ramsey 24,  C4RCD Research Group,  Caroline Nava 25,  Jean-Baptiste Rivière 26,  Antonio Vitobello 26,  Frédéric Tran Mau-Them 26,  Christophe Philippe 26,  Ange-Line Bruel 26,  Yannis Duffourd 26,  Laurel Thomas 27,  Stefan H Lelieveld 28,  Janneke Schuurs-Hoeijmakers 29,  Han G Brunner 30,  Boris Keren 25,  Julien Thevenon 31,  Laurence Faivre 31,  Gary Thomas 27,  Christel Thauvin-Robinet 32
Affiliations

Affiliations

  • 1 Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 2 Centre de Génétique Médicale, Centre de Référence "Déficiences Intellectuelles de causes rares," CHU de Dijon Bourgogne, 21079 Dijon, France; Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), CHU de Dijon Bourgogne, 21079 Dijon, France.
  • 3 Department of Radiology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 4 AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, 75013, Paris, France; Centre de Référence "déficiences intellectuelles de causes rares," 75013 Paris, France; Groupe de Recherche Clinique (GRC) "déficience intellectuelle et autisme" UPMC, 75013 Paris, France.
  • 5 St George's University of London, London, UK and South West Thames Regional Genetics Service, St George's Universities NHS Foundation Trust, London SW17 0RE, UK.
  • 6 University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, the Netherlands.
  • 7 Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
  • 8 Department of Pathology and Laboratory Medicine, Division of Genomic Diagnostics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 9 Genomic Diagnostics Laboratory, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, NHS Foundation Trust, Saint Mary's Hospital, Manchester M13 9WL, UK.
  • 10 Department of Human Genetics, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands; Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.
  • 11 Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, Maastricht 6229 ER, the Netherlands.
  • 12 Department of Neurology, Division of Child Neurology, University of Rochester School of Medicine, Rochester, NY 14642, USA.
  • 13 GeneDx program, Gaithersburg, MD 20877, USA.
  • 14 University of Groningen, University Medical Center Groningen, Department of Child Neurology, 9713 GZ Groningen, the Netherlands.
  • 15 Centre de Référence Maladies Rares "Malformations et maladies congénitales du cervelet," Département de Génétique Médicale, APHP, GHUEP, Hôpital Trousseau, 75012 Paris, France; GRC ConCer-LD, Sorbonne Universités, UPMC Univ 06, 75019 Paris, France; INSERM U1141, Université Paris Diderot, 75019 Paris, France.
  • 16 Department of Medical Genetics, Lyon University Hospital, 69677 Lyon, France; CNRS UMR 5292, INSERM U1028, CNRL, 69500 Lyon, France; Université Claude Bernard Lyon 1, GHE, 69100 Lyon, France.
  • 17 Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 18 Department of Pediatric Neurology, Lyon University Hospital, 69677 Lyon, France.
  • 19 Department of clinical epileptology, sleep and functional neurology in children, Lyon University Hospital, 69677 Lyon, France.
  • 20 Université Claude Bernard Lyon I, CHU de Lyon, 69677 Lyon, France; Service de radiologie, Hôpital-Femme-Mère-Enfant, Hospices Civils de Lyon, 69677 Lyon, France.
  • 21 Division of Medical Genetics, Department of Pediatrics and Metabolism, MassGeneral Hospital for Children, Boston, MA 02114, USA.
  • 22 Department of Pediatrics, Oklahoma University Health Sciences Center (OUHSC), Oklahoma City, OK 73104, USA.
  • 23 Service d'hémato-oncologie pédiatrique, Hôpital Trousseau, APHP, 75012 Paris, France.
  • 24 Center for Rare Childhood Disorders, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA.
  • 25 AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, 75013 Paris, France; UPMC, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris 75013, France.
  • 26 Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), CHU de Dijon Bourgogne, 21079 Dijon, France; Inserm UMR1231 GAD, Génétique des Anomalies du Développement, Université de Bourgogne, 21079 Dijon, France.
  • 27 Department of Microbiology and Molecular Genetics and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
  • 28 Department of Human Genetics, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.
  • 29 Department of Human Genetics, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.
  • 30 Department of Human Genetics, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands; Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, Maastricht 6229 ER, the Netherlands.
  • 31 Centre de Génétique Médicale, Centre de Référence "Déficiences Intellectuelles de causes rares," CHU de Dijon Bourgogne, 21079 Dijon, France; Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), CHU de Dijon Bourgogne, 21079 Dijon, France; Inserm UMR1231 GAD, Génétique des Anomalies du Développement, Université de Bourgogne, 21079 Dijon, France.
  • 32 Centre de Génétique Médicale, Centre de Référence "Déficiences Intellectuelles de causes rares," CHU de Dijon Bourgogne, 21079 Dijon, France; Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), CHU de Dijon Bourgogne, 21079 Dijon, France; Inserm UMR1231 GAD, Génétique des Anomalies du Développement, Université de Bourgogne, 21079 Dijon, France. Electronic address: christel.thauvin@chu-dijon.fr.
PMID: 29656858 DOI: 10.1016/j.ajhg.2018.03.005
Abstract

Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome Sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(Furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.

Keywords

PACS-2; PACS2; cerebellar dysgenesis; epilepsy; intellectual disability.

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