title: The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant.
abstract: The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: David A
authors: DA
authors: Koolen
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Rolph
authors: R
authors: Pfundt
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Katrin
authors: K
authors: Linda
authors: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors: Gea
authors: G
authors: Beunders
authors: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Hermine E
authors: HE
authors: Veenstra-Knol
authors: Department of Laboratories, Seattle Children's Hospital, Seattle, WA, USA.
authors: Jessie H
authors: JH
authors: Conta
authors: Unidade de Genética Médica, Centro de Genética Médica Dr Jacinto Magalhães, Centro Hospitalar do Porto, Porto, Portugal.
authors: Ana Maria
authors: AM
authors: Fortuna
authors: Institut für Humangenetik, University of Luebeck, Luebeck, Germany.
authors: Gabriele
authors: G
authors: Gillessen-Kaesbach
authors: Genetics Department, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.
authors: Sarah
authors: S
authors: Dugan
authors: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors: Sara
authors: S
authors: Halbach
authors: Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Omar A
authors: OA
authors: Abdul-Rahman
authors: St Luke's Pediatric Associates, Duluth, MN, USA.
authors: Heather M
authors: HM
authors: Winesett
authors: Department of Pediatrics and Medicine, Columbia University, New York, NY, USA.
authors: Wendy K
authors: WK
authors: Chung
authors: Counties Manukau District Health Board, South Auckland, New Zealand.
authors: Marguerite
authors: M
authors: Dalton
authors: Epilepsy Center, St Ivan Rilski University Hospital, Sofia, Bulgaria.
authors: Petia S
authors: PS
authors: Dimova
authors: Department of Pediatrics, Medical Genetics University of Catania, Catania, Italy.
authors: Teresa
authors: T
authors: Mattina
authors: Clinical Genetics, Yorkshire Regional Genetics Service, Leeds, UK.
authors: Katrina
authors: K
authors: Prescott
authors: Department of genetics, Yale University School of Medicine, New Haven, CT, USA.
authors: Hui Z
authors: HZ
authors: Zhang
authors: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: Howard M
authors: HM
authors: Saal
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Jayne Y
authors: JY
authors: Hehir-Kwa
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Marjolein H
authors: MH
authors: Willemsen
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Charlotte W
authors: CW
authors: Ockeloen
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Marjolijn C
authors: MC
authors: Jongmans
authors: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors: Nathalie
authors: N
authors: Van der Aa
authors: Pediatrics and Medical Genetics, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy.
authors: Pinella
authors: P
authors: Failla
authors: Pediatrics and Medical Genetics, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy.
authors: Concetta
authors: C
authors: Barone
authors: Pediatrics and Medical Genetics, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy.
authors: Emanuela
authors: E
authors: Avola
authors: Department of Clinical Genetics, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors: Alice S
authors: AS
authors: Brooks
authors: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Sarina G
authors: SG
authors: Kant
authors: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Erica H
authors: EH
authors: Gerkes
authors: Department of Medical Genetics, Cambridge University Addenbrooke's Hospital, Cambridge, UK.
authors: Helen V
authors: HV
authors: Firth
authors: Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
authors: Katrin
authors: K
authors: Õunap
authors: Departments of Neurosciences and Pediatrics, University of California San Diego, and Divisions of Neurology and Genetics, Rady Children's Hospital San Diego, San Diego, CA, USA.
authors: Lynne M
authors: LM
authors: Bird
authors: Departments of Neurosciences and Pediatrics, University of California San Diego, and Divisions of Neurology and Genetics, Rady Children's Hospital San Diego, San Diego, CA, USA.
authors: Diane
authors: D
authors: Masser-Frye
authors: Departments of Neurosciences and Pediatrics, University of California San Diego, and Divisions of Neurology and Genetics, Rady Children's Hospital San Diego, San Diego, CA, USA.
authors: Jennifer R
authors: JR
authors: Friedman
authors: Nacogdoches Pediatrics, Nacogdoches, TX, USA.
authors: Modupe A
authors: MA
authors: Sokunbi
authors: Clinical Genetics, Nottingham City Hospital, Nottingham, UK.
authors: Abhijit
authors: A
authors: Dixit
authors: Northern Genetic Service, Institute of Genetic Medicine, Newcastle upon Tyne, UK.
authors: Miranda
authors: http://orcid.org/0000-0002-8906-7580
authors: M
authors: Splitt
authors: Clinical Genetics, Cook Children's Hospital, Fort Worth, TX, USA.
authors: Mary K
authors: MK
authors: Kukolich
authors: Genetic Health Queensland, Royal Brisbane and Women's Hospital and School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
authors: Julie
authors: J
authors: McGaughran
authors: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
authors: Bradley P
authors: BP
authors: Coe
authors: Department of Physiology and Pharmacology, University of Cantabria, Cantabria, Spain.
authors: Jesús
authors: J
authors: Flórez
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Nael
authors: N
authors: Nadif Kasri
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Han G
authors: HG
authors: Brunner
authors: South Australian Clinical Genetics Service, Women's and Children's Hospital; and Department of Paediatrics, University of Adelaide, Adelaide, South Australia, Australia.
authors: Elizabeth M
authors: EM
authors: Thompson
authors: School of Paediatrics and Reproductive Health and Robinson Research Institute, The University of Adelaide at the Women's and Children's Hospital, North Adelaide, South Australia, Australia.
authors: Jozef
authors: http://orcid.org/0000-0002-7884-6861
authors: J
authors: Gecz
authors: Pediatrics and Medical Genetics, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy.
authors: Corrado
authors: C
authors: Romano
authors: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.|Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
authors: Evan E
authors: EE
authors: Eichler
authors: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Bert B A
authors: BB
authors: de Vries
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics; D000293:Adolescent; D000328:Adult; D002648:Child; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: C574033:NSL1 protein, human; D009687:Nuclear Proteins