title: The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy.
abstract: BACKGROUND
  DYRK1A plays different functions during development, with an important role in controlling brain growth through neuronal proliferation and neurogenesis. It is expressed in a gene dosage dependent manner since dyrk1a haploinsufficiency induces a reduced brain size in mice, and DYRK1A overexpression is the candidate gene for intellectual disability (ID) and microcephaly in Down syndrome. We have identified a 69 kb deletion including the 5' region of the DYRK1A gene in a patient with growth retardation, primary microcephaly, facial dysmorphism, seizures, ataxic gait, absent speech and ID. Because four patients previously reported with intragenic DYRK1A rearrangements or 21q22 microdeletions including only DYRK1A presented with overlapping phenotypes, we hypothesised that DYRK1A mutations could be responsible for syndromic ID with severe microcephaly and epilepsy.
  
  
  METHODS
  The DYRK1A gene was studied by direct sequencing and quantitative PCR in a cohort of 105 patients with ID and at least two symptoms from the Angelman syndrome spectrum (microcephaly < -2.5 SD, ataxic gait, seizures and speech delay).
  
  
  RESULTS
  We identified a de novo frameshift mutation (c.290_291delCT; p.Ser97Cysfs*98) in a patient with growth retardation, primary severe microcephaly, delayed language, ID, and seizures.
  
  
  CONCLUSIONS
  The identification of a truncating mutation in a patient with ID, severe microcephaly, epilepsy, and growth retardation, combined with its dual function in regulating the neural proliferation/neuronal differentiation, adds DYRK1A to the list of genes responsible for such a phenotype. ID, microcephaly, epilepsy, and language delay are the more specific features associated with DYRK1A abnormalities. DYRK1A studies should be discussed in patients presenting such a phenotype.
authors.affiliation: Equipe émergente GAD EA 4271 (Génétique des Anomalies du développement), IFR Santé STIC, Université de Bourgogne, Dijon, France.
authors.forename: Jean-Benoît
authors.initials: JB
authors.lastname: Courcet
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.forename: Perrine
authors.initials: P
authors.lastname: Malzac
authors.forename: Alice
authors.initials: A
authors.lastname: Masurel-Paulet
authors.forename: Estelle
authors.initials: E
authors.lastname: Lopez
authors.forename: Patrick
authors.initials: P
authors.lastname: Callier
authors.forename: Laetitia
authors.initials: L
authors.lastname: Lambert
authors.forename: Martine
authors.initials: M
authors.lastname: Lemesle
authors.forename: Julien
authors.initials: J
authors.lastname: Thevenon
authors.forename: Nadège
authors.initials: N
authors.lastname: Gigot
authors.forename: Laurence
authors.initials: L
authors.lastname: Duplomb
authors.forename: Clémence
authors.initials: C
authors.lastname: Ragon
authors.forename: Nathalie
authors.initials: N
authors.lastname: Marle
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Mosca-Boidron
authors.forename: Frédéric
authors.initials: F
authors.lastname: Huet
authors.forename: Christophe
authors.initials: C
authors.lastname: Philippe
authors.forename: Anne
authors.initials: A
authors.lastname: Moncla
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004569:Electroencephalography; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics*; D019066:Facies; D005260:Female; D023061:Gene Order; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D013577:Syndrome; D000097603:Dyrk Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases