ArticleAmerican journal of human genetics2018
A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis.
Erratum issuedOpen access · bronzeAbstract read
In one paragraph
Article in American journal of human genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 34 papers, 1 of them a synthesis that pooled it.
0numbers the graph read from it
0cells of the map it votes in
34citing papers in PubMed, 1 pooled it
5.8field-weighted citation impact, top 4% of its field
What it found
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The trial behind it
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Who cites it
34 citing papers in PubMed, 1 synthesis or guideline pooled it, 77 citations in OpenAlex.
- Pooled it
- Is the Loss of Previously Acquired Skills a Feature of PACS1-, PACS2- and WDR37-Related Syndromes? A Systematized Narrative Review.International journal of molecular sciences · 2026Review
- A cross-vertebrate brain protein interaction map identifies conserved neural and non-neural complexes.Cell reports · 2026Article
- Mitochondria-ER contact sites in neurological disorders.Animal cells and systems · 2026Review
- Article
- AI-Based Facial Phenotyping Supports a Shared Molecular Axis inInternational journal of molecular sciences · 2025Article
- Review
- VerteBrain reveals novel neural and non-neural protein assemblies conserved across vertebrate evolution.bioRxiv : the preprint server for biology · 2025Article
- Article
- Understanding PACS2 syndrome's pathomechanism by studying E209K and E211K mutations.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Review
- Autism Spectrum Disorder and Epilepsy: Pathogenetic Mechanisms and Therapeutic Implications.Journal of clinical medicine · 2025Review
- PACS deficiency disrupts Golgi architecture and causes cytokinesis failures and seizure-like phenotype inOpen biology · 2025Article
- PACS2, PACS1, and VACTERL: A Clinical Overlap.Molecular syndromology · 2025Article
- PACS-1 variant protein is aberrantly localized in Caenorhabditis elegans model of PACS1/PACS2 syndromes.Genetics · 2024Article
- A recurrent missense variant in the E3 ubiquitin ligase substrate recognition subunit FEM1B causes a rare syndromic neurodevelopmental disorder.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- PACS-1 variant protein is aberrantly localized inbioRxiv : the preprint server for biology · 2024Article
- Initial clinical and molecular investigation of 20q13.33 microdeletion with 17q25.3/14q32.31q32.33 microduplication in Chinese pediatric patients.Molecular genetics & genomic medicine · 2024Article
- iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity.Nature communications · 2024Article
- Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy.Nature communications · 2023Article
- Genome-wide kinase-MAM interactome screening reveals the role of CK2A1 in MAM CaProceedings of the National Academy of Sciences of the United States of America · 2023Article
Corrections and comments
- Erratum issued
Authors and funding
58 authors at 20 institutions in 4 countries.
Heather E OlsonEpilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA 02115, USA.
Nolwenn Jean-MarçaisCentre 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.
Edward YangDepartment of Radiology, Boston Children's Hospital, Boston, MA 02115, USA.
Delphine HeronAP-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.
Katrina Tatton-BrownSt 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.
Paul A van der ZwaagUniversity of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, the Netherlands.
Emilia K BijlsmaDepartment of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
Bryan L KrockDepartment 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.
E BackerGenomic Diagnostics Laboratory, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, NHS Foundation Trust, Saint Mary's Hospital, Manchester M13 9WL, UK.
Erik-Jan KamsteegDepartment 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.
Margje SinnemaDepartment of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, Maastricht 6229 ER, the Netherlands.
Margot R F ReijndersDepartment 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.
David BeardenDepartment of Neurology, Division of Child Neurology, University of Rochester School of Medicine, Rochester, NY 14642, USA.
Amber BegtrupGeneDx program, Gaithersburg, MD 20877, USA.
Aida TelegrafiGeneDx program, Gaithersburg, MD 20877, USA.
Roelineke J LunsingUniversity of Groningen, University Medical Center Groningen, Department of Child Neurology, 9713 GZ Groningen, the Netherlands.
Lydie BurglenCentre 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.
Gaetan LescaDepartment 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.
Megan T ChoGeneDx program, Gaithersburg, MD 20877, USA.
Lacey A SmithEpilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA 02115, USA.
Beth R SheidleyEpilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA 02115, USA.
Christelle Moufawad El AchkarEpilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA 02115, USA.
Phillip L PearlEpilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA 02115, USA.
Annapurna PoduriEpilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA 02115, USA.
Cara M SkrabanDivision 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.
Jennifer TarpinianDivision 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.
Addie I NesbittDepartment 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.
Dietje E Fransen van de PutteDepartment of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
Claudia A L RuivenkampDepartment of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
Patrick RumpUniversity of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, the Netherlands.
Nicolas ChatronDepartment 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.
Isabelle SabatierDepartment of Pediatric Neurology, Lyon University Hospital, 69677 Lyon, France.
Julitta De BellescizeDepartment of clinical epileptology, sleep and functional neurology in children, Lyon University Hospital, 69677 Lyon, France.
Laurent GuibaudUniversité Claude Bernard Lyon I, CHU de Lyon, 69677 Lyon, France; Service de radiologie, Hôpital-Femme-Mère-Enfant, Hospices Civils de Lyon, 69677 Lyon, France.
David A SweetserDivision of Medical Genetics, Department of Pediatrics and Metabolism, MassGeneral Hospital for Children, Boston, MA 02114, USA.
Jessica L WaxlerDivision of Medical Genetics, Department of Pediatrics and Metabolism, MassGeneral Hospital for Children, Boston, MA 02114, USA.
Klaas J WierengaDepartment of Pediatrics, Oklahoma University Health Sciences Center (OUHSC), Oklahoma City, OK 73104, USA.
DDD Study
Jean DonadieuService d'hémato-oncologie pédiatrique, Hôpital Trousseau, APHP, 75012 Paris, France.
Vinodh NarayananCenter for Rare Childhood Disorders, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA.
Keri M RamseyCenter for Rare Childhood Disorders, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA.
C4RCD Research Group
Caroline NavaAP-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.
Jean-Baptiste RivièreFédération 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.
Antonio VitobelloFédération 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.
Frédéric Tran Mau-ThemFédération 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.
Christophe PhilippeFédération 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.
Ange-Line BruelFédération 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.
Yannis DuffourdFédération 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.
Laurel ThomasDepartment of Microbiology and Molecular Genetics and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
Stefan H LelieveldDepartment 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.
Janneke Schuurs-HoeijmakersDepartment of Human Genetics, Radboud University Medical Center, Nijmegen 6500 HB, the Netherlands.
Han G BrunnerDepartment 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.
Boris KerenAP-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.
Julien ThevenonCentre 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.
Laurence FaivreCentre 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.
Gary ThomasDepartment of Microbiology and Molecular Genetics and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
Christel Thauvin-RobinetCentre 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.
Inserm · FRBoston Children's Hospital · USRadboud University Nijmegen · NLChildren's Hospital of Philadelphia · USGenex Systems (United States) · USLeiden University Medical Center · NLUniversité Claude Bernard Lyon 1 · FRUniversity Medical Center Groningen · NLCentre National de la Recherche Scientifique · FRHospices Civils de Lyon · FRMassachusetts General Hospital · USSorbonne Université · FRTranslational Genomics Research Institute · USUPMC Hillman Cancer Center · USFédération Hospitalo-Universitaire, Paris Center for Microbiome Medicine · FRMaastricht University · NLOU HealthSt George's, University of London · GBUniversity of Manchester · GBUniversity of Rochester · US
Funding
Mouse Neurodevelopmental Behavior CoreU54HD090255 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI POMEROY, SCOTT LOREN · 2016 to 2020
$5.2MAllosteric regulation of SIRT1 by a PACS-2 and DBC1 regulatory hubR01DK114855 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GRONENBORN, ANGELA M., THOMAS, GARY · 2017 to 2020
$2.4MRegulation of TRAIL Induced Apoptosis in Cancer CellsR01CA151564 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI THOMAS, GARY · 2011 to 2015
$1.6MRegulation of PPAR alpha by PACS-2 in response to nutrient stressR01DK112844 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI THOMAS, GARY · 2017 to 2019
$1.2MNCI NIH HHS R01 CA151564NICHD NIH HHS U54 HD090255NIDDK NIH HHS R01 DK112844NIDDK NIH HHS R01 DK114855
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.
Indexed as
FaciesAge of OnsetCerebellar DiseasesChild, PreschoolEpilepsy, GeneralizedFemaleHeterozygoteHumansInfantInfant, NewbornMaleMutation, MissensePhenotypeVesicular Transport ProteinsPACS2 protein, humanVesicular Transport Proteinscerebellar dysgenesisepilepsyintellectual disabilityPACS-2PACS2
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