title: Case report of novel DYRK1A mutations in 2 individuals with syndromic intellectual disability and a review of the literature.
abstract: BACKGROUND
  Chromosomal deletions encompassing DYRK1A have been associated with intellectual disability for several years. More recently, point mutations in DYRK1A have been shown to be responsible for a recognizable syndrome characterized by microcephaly, developmental delay and intellectual disability (ID) as well as characteristic facial features. Here we present 2 individuals with novel mutations in DYRK1A, and a review of the cases reported to date.
  
  
  METHODS
  Both individuals presented with the well-known characteristic features, as well as rarer anomalies seen in a minority of patients. Patient 1 presented shortly after birth with an enlarged cisterna magna, distal contractures, and distinctive facies that included bitemporal narrowing and deep set eyes. A de novo splice site mutation in DYRK1A [c.951 + 4_951 + 7delAGTA; p.Val222Aspfs*22] was identified by next generation sequencing. Patient 2 presented at 7 months of age with microcephaly and dysmorphic features. She went several years without a diagnosis until a de novo DYRK1A nonsense mutation [c.787C>T; p.(Arg263*)] was identified at age 12. These individuals, and the 52 cases reviewed from the literature, show the characteristic features of the DYRK1A-related syndrome including global developmental delay, ID, microcephaly, feeding difficulties, and the facial gestalt. Other common findings include seizures, vision defects, brain abnormalities and skeletal abnormalities of the hands and feet. Less common features include optic nerve defects, contractures, ataxia, and cardiac anomalies.
  
  
  CONCLUSIONS
  DYRK1A testing should be considered in individuals with the facial features, intellectual disability and post-natal microcephaly. Once diagnosed with DYRK1A-related intellectual disability, a cardiac and ophthalmologic assessment would be recommended as would routine surveillance by a pediatrician for psychomotor development, growth, and feeding.
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, K1H 8L1, Canada. sluco032@uottawa.ca.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Luco
authors.affiliation: Division of Pediatric Neurology, Children's Hospital of Eastern Ontario, Ottawa, K1H 8L1, ON, Canada. dpolh@cheo.on.ca.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pohl
authors.affiliation: Division of Pediatric Neurology, Children's Hospital of Eastern Ontario, Ottawa, K1H 8L1, ON, Canada. esell@cheo.on.ca.
authors.forename: Erick
authors.initials: E
authors.lastname: Sell
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, Ottawa, K1H 8L1, ON, Canada. jwagner@cheo.on.ca.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Wagner
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, K1H 8L1, Canada. ddyment@cheo.on.ca.|Children's Hospital of Eastern Ontario Research Institute, Ottawa, K1H 8L1, ON, Canada. ddyment@cheo.on.ca.
authors.forename: David A
authors.initials: DA
authors.lastname: Dyment
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, K1H 8L1, Canada. hadoud@cheo.on.ca.
authors.forename: Hussein
authors.initials: H
authors.lastname: Daoud
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D002872:Chromosome Deletion; D018389:Codon, Nonsense; D002658:Developmental Disabilities / Q000235:genetics; D005091:Exons; D005260:Female; D015321:Gene Rearrangement; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000235:genetics; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000097603:Dyrk Kinases
chemical_list: D018389:Codon, Nonsense; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases