title: DYRK1A mutations in two unrelated patients.
abstract: The Dual-specify tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene has been extensively studied for its role in the pathophysiology of intellectual disability (ID) in Down syndrome. The rise of next generation sequencing (NGS) and array-CGH (aCGH) in diagnostic settings for the evaluation of patients with ID allowed the identification of 17 patients carrying heterozygous genetic aberrations involving DYRK1A to date. The rate of DYRK1A mutations in this population reaches >1% in published NGS studies. The current report aims at further defining the phenotype of this encephalopathy with the detailed report of two unrelated patients. Both patients were boys with developmental delay, febrile seizures, facial dysmorphism and brain atrophy on MRI. Patient #1 had autistic behaviors and micropenis and Patient #2 had stereotypies and microcephaly. NGS analyses identified heterozygous de novo variants in DYRK1A: the c.613C >T (p.Arg205*) nonsense mutation in Patient #1 and the c.932C >T (p.Ser311Phe) missense mutation in Patient #2. Together with previously reported cases, patients with DYRK1A mutations share many clinical features and may have a recognizable phenotype that includes, by decreasing order of frequency: developmental delay or ID with behaviors suggesting autism spectrum disorder, microcephaly, epileptic seizures, facial dysmorphism including ear anomalies (large ears, hypoplastic lobes), thin lips, short philtrum and frontal bossing. Delineation of the phenotype/genotype correlation is not feasible at the moment and will be a challenge for the coming years.
authors: Centre de Génétique Humaine, CHU Besançon, France.
authors: Lyse
authors: L
authors: Ruaud
authors: Département de Génétique, APHP, GH Pitié-Salpêtrière, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Paris, France.
authors: Cyril
authors: C
authors: Mignot
authors: Service de Pédiatrie, APHP, Hôpital Louis Mourier, Colombes, France.
authors: Agnès
authors: A
authors: Guët
authors: Centre d'Action Médico-Sociale Précoce, Courbevoie, France.
authors: Christelle
authors: C
authors: Ohl
authors: Département de Génétique, APHP, GH Pitié-Salpêtrière, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Paris, France.
authors: Caroline
authors: C
authors: Nava
authors: Département de Génétique, APHP, GH Pitié-Salpêtrière, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Paris, France.
authors: Delphine
authors: D
authors: Héron
authors: Département de Génétique, APHP, GH Pitié-Salpêtrière, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Paris, France.
authors: Boris
authors: B
authors: Keren
authors: Département de Génétique, APHP, GH Pitié-Salpêtrière, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Paris, France.
authors: Christel
authors: C
authors: Depienne
authors: Institut de pathologie et de Génétique, Gosselies, Belgique.
authors: Valérie
authors: V
authors: Benoit
authors: Institut de pathologie et de Génétique, Gosselies, Belgique.
authors: Isabelle
authors: I
authors: Maystadt
authors: Institut de pathologie et de Génétique, Gosselies, Belgique.
authors: Damien
authors: D
authors: Lederer
authors: Service de Pédiatrie, CHU Besançon, France.
authors: Daniel
authors: D
authors: Amsallem
authors: Centre de Génétique Humaine, CHU Besançon, France. Electronic address: jpiard@chu-besancon.fr.
authors: Juliette
authors: J
authors: Piard
mesh_terms: D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics; D004314:Down Syndrome / Q000175:diagnosis / Q000235:genetics*; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D056426:Genetic Loci; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics; D020125:Mutation, Missense; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2; D055517:snRNP Core Proteins / Q000235:genetics / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D018398:Homeodomain Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012097:Repressor Proteins; D000074165:Zinc Finger E-box Binding Homeobox 2; D055517:snRNP Core Proteins; D000097603:Dyrk Kinases; C497683:FMR1 protein, human; C526417:SNRPN protein, human; C492363:ZEB2 protein, human
keywords: Autism spectrum disorder; DYRK1A mutation; Dysmorphism; Intellectual disability