Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A.
The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures.
Greenwood Genetic Center, Greenwood, SC, USA.
Lucas M
LM
Bronicki
Department of Translational Medicine and Neurogenetics, IGBMC, CNRS UMR 7104, INSERM U964, Strasbourg University, Strasbourg, France.
Claire
C
Redin
Department of Genetics and INSERM U1141, Robert Debré Hospital, Paris, France.
Severine
S
Drunat
Department of Translational Medicine and Neurogenetics, IGBMC, CNRS UMR 7104, INSERM U964, Strasbourg University, Strasbourg, France.|Laboratoire de diagnostic génétique, Faculty of Medicine and CHU Strasbourg, Strasbourg, France.
Amélie
A
Piton
Greenwood Genetic Center, Greenwood, SC, USA.
Michael
M
Lyons
Department of Genetics and INSERM U1141, Robert Debré Hospital, Paris, France.
Sandrine
S
Passemard
Department of Genetics, Robert Debré Hospital, Paris, France.
Clarisse
C
Baumann
Fédération Hospitalo- Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.|Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, Dijon, France.|Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.
Laurence
L
Faivre
Fédération Hospitalo- Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.|Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, Dijon, France.|Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.
Julien
http://orcid.org/0000-0001-9271-3961
J
Thevenon
Fédération Hospitalo- Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France.|Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.|Laboratoire de Génétique Moléculaire, Plateau Technique de Biologie, Centre Hospitalier Universitaire Dijon, Dijon, France.
Jean-Baptiste
JB
Rivière
Medical Genetics- Clinical Genetics Unit, CHU de Nantes, Nantes-Cedex, France.
Bertrand
B
Isidor
Department of Translational Medicine and Neurogenetics, IGBMC, CNRS UMR 7104, INSERM U964, Strasbourg University, Strasbourg, France.
Grace
G
Gan
Service de génétique médicale, CHU de Clermont-Ferrand, Clermont-Ferrand, France.
Christine
C
Francannet
Department of Medical Genetics, Reference Center for Rare Diseases, Developmental Disorders and Multiple Congenital Anomalies, Arnaud de Villeneuve Hospital, Montpellier, France.
Marjolaine
M
Willems
Department of Genetics and Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
Murat
M
Gunel
Greenwood Genetic Center, Greenwood, SC, USA.
Julie R
JR
Jones
Department of Neurosciences, Howard Hughes Medical Institute, Rady Children's Hospital, University of California, San Diego, La Jolla, CA, USA.
Joseph G
JG
Gleeson
Department of Translational Medicine and Neurogenetics, IGBMC, CNRS UMR 7104, INSERM U964, Strasbourg University, Strasbourg, France.|Laboratoire de diagnostic génétique, Faculty of Medicine and CHU Strasbourg, Strasbourg, France.
Jean-Louis
JL
Mandel
Greenwood Genetic Center, Greenwood, SC, USA.
Roger E
RE
Stevenson
Greenwood Genetic Center, Greenwood, SC, USA.
Michael J
MJ
Friez
Departments of Pediatrics and Genetics, Division of Genetics and Metabolism, University of North Carolina, Chapel Hill, NC, USA.
Arthur S
AS
Aylsworth
D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000235:genetics / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D004314:Down Syndrome / Q000235:genetics*; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D000097603:Dyrk Kinases
D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases