title: Clinical delineation of the PACS1-related syndrome--Report on 19 patients.
abstract: We report on 19 individuals with a recurrent de novo c.607C>T mutation in PACS1. This specific mutation gives rise to a recognizable intellectual disability syndrome. There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual "wavy" profile, flat philtrum, and diastema of the teeth. Intellectual disability, ranging from mild to moderate, was present in all. Hypotonia is common in infancy (8/19). Seizures are frequent (12/19) and respond well to anticonvulsive medication. Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males). Feeding dysfunction is presenting in infancy with failure to thrive (5/19), gastroesophageal reflux (6/19), and gastrostomy tube placement (4/19). There is persistence of oral motor dysfunction. We provide suggestions for clinical work-up and management and hope that the present study will facilitate clinical recognition of further cases.
authors: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors: Janneke H M
authors: JH
authors: Schuurs-Hoeijmakers
authors: Department of Pediatrics, Sanford School of Medicine, University of South Dakota, and Sanford Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota.
authors: Megan L
authors: ML
authors: Landsverk
authors: Wessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.|Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors: Nicola
authors: N
authors: Foulds
authors: Clinical Genetics, Cook Children's Hospital, Fort Worth, Texas.
authors: Mary K
authors: MK
authors: Kukolich
authors: Department of Neurology, Mayo Clinic, Rochester, Minnesota.|Medical Genetics, Mayo Clinic, Rochester, Minnesota.
authors: Ralitza H
authors: RH
authors: Gavrilova
authors: Wessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.|Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors: Stephanie
authors: S
authors: Greville-Heygate
authors: Department of Genetics, Stanford University School of Medicine, Stanford, California.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
authors: Andrea
authors: A
authors: Hanson-Kahn
authors: Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
authors: Jonathan A
authors: JA
authors: Bernstein
authors: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Jennifer
authors: J
authors: Glass
authors: The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.|Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors: David
authors: D
authors: Chitayat
authors: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors: Thomas A
authors: TA
authors: Burrow
authors: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Ammar
authors: A
authors: Husami
authors: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Kathleen
authors: K
authors: Collins
authors: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Katie
authors: K
authors: Wusik
authors: Department of Medical Genetics, University Hospital Antwerp, Antwerp, Belgium.
authors: Nathalie
authors: N
authors: van der Aa
authors: Department of Medical Genetics, University Hospital Antwerp, Antwerp, Belgium.
authors: Frank
authors: F
authors: Kooy
authors: Southwest Thames Regional Genetics Centre, St George's Healthcare NHS Trust, London, United Kingdom.
authors: Kate Tatton
authors: KT
authors: Brown
authors: MVZ Endokrinologikum Hannover, Hannover, Germany.
authors: Dorothea
authors: D
authors: Gadzicki
authors: Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
authors: Usha
authors: U
authors: Kini
authors: NIMgenetics, Madrid, Spain.
authors: Sara
authors: S
authors: Alvarez
authors: School of Medicine, European University of Madrid, Spain.|Neuropediatric Department, "Quiron" University Hospital, Spain.
authors: Alberto
authors: A
authors: Fernández-Jaén
authors: Consultant, Cook Children's Physician Network.
authors: Frank
authors: F
authors: McGehee
authors: Child & family Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.|Division of Pediatric Neurology, Department of Pediatrics, B.C. Children's & Women's Hospital, Vancouver, British Columbia, Canada.
authors: Katherine
authors: K
authors: Selby
authors: Centre for Molecular Medicine and Therapeutics (TIDE-BC), Department of Pediatrics and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Maja
authors: M
authors: Tarailo-Graovac
authors: Child and family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Margot
authors: M
authors: Van Allen
authors: Centre for Molecular Medicine and Therapeutics (TIDE-BC), Department of Pediatrics and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Clara D M
authors: CD
authors: van Karnebeek
authors: Genome Diagnostics, Department of Paediatric Laboratory Medicine, the Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Dimitri J
authors: DJ
authors: Stavropoulos
authors: Genome Diagnostics, Department of Paediatric Laboratory Medicine, the Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Christian R
authors: CR
authors: Marshall
authors: The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Daniele
authors: D
authors: Merico
authors: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors: Anne
authors: A
authors: Gregor
authors: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors: Christiane
authors: C
authors: Zweier
authors: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Robert J
authors: RJ
authors: Hopkin
authors: Department of Paediatrics & Adolescent Medicine, Centre for Genomic Sciences, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong.
authors: Yoyo Wing-Yiu
authors: YW
authors: Chu
authors: Department of Paediatrics & Adolescent Medicine, Centre for Genomic Sciences, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong.
authors: Brian Hon-Yin
authors: BH
authors: Chung
authors: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors: Bert B A
authors: BB
authors: de Vries
authors: Centre for Human Genetics, KU Leuven, Leuven, Belgium.
authors: Koenraad
authors: K
authors: Devriendt
authors: Human Genetics, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors: Matthew E
authors: ME
authors: Hurles
authors: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors: Han G
authors: HG
authors: Brunner
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000927:Anticonvulsants / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D019066:Facies; D005183:Failure to Thrive / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D009123:Muscle Hypotonia / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D017354:Point Mutation; D012640:Seizures / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D012720:Severity of Illness Index; D013577:Syndrome; D033921:Vesicular Transport Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; C491914:PACS1 protein, human; D033921:Vesicular Transport Proteins
keywords: PACS1; case series; clinical features; intellectual disability; mutation hotspot; recurrent mutation; syndrome