title: DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies.
abstract: Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from -2 SD to -5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broad-based gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, CA, USA.|UCLA Clinical Genomics Center, Los Angeles, CA, USA.
authors.forename: Jianling
authors.initials: J
authors.lastname: Ji
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, CA, USA.|UCLA Clinical Genomics Center, Los Angeles, CA, USA.
authors.forename: Hane
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Medical Genetics, Cumming School of Medicine, University of Calgary, and Alberta Children's Hospital Research Institute for Child and Maternal Health, Calgary, AB, Canada.
authors.forename: Bob
authors.initials: B
authors.lastname: Argiropoulos
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, CA, USA.|UCLA Clinical Genomics Center, Los Angeles, CA, USA.|Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
authors.forename: Naghmeh
authors.initials: N
authors.lastname: Dorrani
authors.affiliation: Kaiser Permanente, Fresno, CA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Mann
authors.affiliation: UCLA Clinical Genomics Center, Los Angeles, CA, USA.|Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, CA, USA.|Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
authors.forename: Julian A
authors.initials: JA
authors.lastname: Martinez-Agosto
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Gomez-Ospina
authors.affiliation: Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Gallant
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Bernstein
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Louanne
authors.initials: L
authors.lastname: Hudgins
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Slattery
authors.affiliation: CHU Nantes, Service de Génétique Médicale, and Inserm UMR957, Faculté de Médecine, Nantes, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.affiliation: CHU Nantes, Service de Génétique Médicale, and Inserm UMR957, Faculté de Médecine, Nantes, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Le Caignec
authors.affiliation: CHU Nantes, Service de Génétique Médicale, and Inserm UMR957, Faculté de Médecine, Nantes, France.
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.affiliation: Institute of Mother and Child, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Obersztyn
authors.affiliation: Institute of Mother and Child, Warsaw, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Wiśniowiecka-Kowalnik
authors.affiliation: UCLA Clinical Genomics Center, Los Angeles, CA, USA.|Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Fox
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, CA, USA.|UCLA Clinical Genomics Center, Los Angeles, CA, USA.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Deignan
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, CA, USA.|UCLA Clinical Genomics Center, Los Angeles, CA, USA.|Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, CA, USA.|Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Vilain
authors.affiliation: Seattle Children's Research Institute, Seattle, WA, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Hendricks
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Horton Harr
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Noon
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Jessi R
authors.initials: JR
authors.lastname: Jackson
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Alisha
authors.initials: A
authors.lastname: Wilkens
authors.affiliation: Seattle Children's Research Institute, Seattle, WA, USA.
authors.forename: Ghayda
authors.initials: G
authors.lastname: Mirzaa
authors.affiliation: Department of Radiology, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
authors.forename: Noriko
authors.initials: N
authors.lastname: Salamon
authors.affiliation: Department of Physiology, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.|The Institute for Stem Cell Biology and Regenerative Medicine (inStem), National Centre for Biological Sciences-Tata Institute of Fundamental Research, Bangalore, Karnataka, India.
authors.forename: Jeff
authors.initials: J
authors.lastname: Abramson
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Elaine H
authors.initials: EH
authors.lastname: Zackai
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Krantz
authors.affiliation: Department of Medical Genetics, Cumming School of Medicine, University of Calgary, and Alberta Children's Hospital Research Institute for Child and Maternal Health, Calgary, AB, Canada.
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, CA, USA.|UCLA Clinical Genomics Center, Los Angeles, CA, USA.|Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, CA, USA.|Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, CA, USA.|UCLA Clinical Genomics Center, Los Angeles, CA, USA.|Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, CA, USA.|Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Grody
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, CA, USA.|UCLA Clinical Genomics Center, Los Angeles, CA, USA.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Quintero-Rivera
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000503:physiopathology; D002872:Chromosome Deletion; D004314:Down Syndrome / Q000235:genetics* / Q000473:pathology; D019066:Facies; D005260:Female; D057895:Haploinsufficiency; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D000097603:Dyrk Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases