title: PIAS4 is associated with macro/microcephaly in the novel interstitial 19p13.3 microdeletion/microduplication syndrome.
abstract: Array comparative genomic hybridization (aCGH) is a powerful genetic tool that has enabled the identification of novel imbalances in individuals with intellectual disability (ID), autistic disorders and congenital malformations. Here we report a 'genotype first' approach using aCGH on 13 unrelated patients with 19p13.3 submicroscopic rearrangement (11 deletions and 2 duplications) and review cases in the literature and in public databases. Shared phenotypic features suggest that these patients represent an interstitial microdeletion/microduplication syndrome at 19p13.3. Common features consist of abnormal head circumference in most patients (macrocephaly with the deletions and microcephaly with the duplications), ID with developmental delay (DD), hypotonia, speech delay and common dysmorphic features. The phenotype is associated with at least a ~0.113 Mb critical region harboring three strong candidate genes probably associated with DD, ID, speech delay and other dysmorphic features: MAP2K2, ZBTB7A and PIAS4, an E3 ubiquitin ligase involved in the ubiquitin signaling pathways, which we hypothesize for the first time to be associated with head size in humans.
authors: Section of Functional and Structural Genomics Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.|CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.
authors: Julián
authors: J
authors: Nevado
authors: Signature Genomic Laboratories, PerkinElmer Inc., Spokane, WA, USA.
authors: Jill A
authors: http://orcid.org/0000-0001-5664-7987
authors: JA
authors: Rosenfeld
authors: Section of Functional and Structural Genomics Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
authors: Rocío
authors: R
authors: Mena
authors: Section of Functional and Structural Genomics Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.|CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.
authors: María
authors: M
authors: Palomares-Bralo
authors: Section of Functional and Structural Genomics Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.|CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.
authors: Elena
authors: E
authors: Vallespín
authors: Section of Functional and Structural Genomics Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.|CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.
authors: María
authors: M
authors: Ángeles Mori
authors: Section of Functional and Structural Genomics Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
authors: Jair A
authors: JA
authors: Tenorio
authors: AI DuPont Hospital for Children, Wilmington, DE, USA.
authors: Karen W
authors: KW
authors: Gripp
authors: AI DuPont Hospital for Children, Wilmington, DE, USA.
authors: Elizabeth
authors: E
authors: Denenberg
authors: Hospital Vall D'Hebron, Barcelona, Spain.
authors: Miguel
authors: M
authors: Del Campo
authors: Hospital Vall D'Hebron, Barcelona, Spain.
authors: Alberto
authors: A
authors: Plaja
authors: Section of Functional and Structural Genomics Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
authors: Rubén
authors: R
authors: Martín-Arenas
authors: Section of Clinical Genetics, INGEMM-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
authors: Fernando
authors: F
authors: Santos-Simarro
authors: Q-Genomics Laboratory, Barcelona, Spain.
authors: Lluis
authors: L
authors: Armengol
authors: University of Louisville, Kentucky, USA.
authors: Gordon
authors: G
authors: Gowans
authors: CGC-Genetics, Madrid, Spain.
authors: María
authors: M
authors: Orera
authors: CGC-Genetics, Madrid, Spain.
authors: M Carmen
authors: MC
authors: Sanchez-Hombre
authors: CGC-Genetics, Madrid, Spain.
authors: Esther
authors: E
authors: Corbacho-Fernández
authors: Hospital Quirón de Madrid, Madrid, Spain.
authors: Alberto
authors: A
authors: Fernández-Jaén
authors: Wake Forest University, Winston-Salem, NC, USA.
authors: Chad
authors: C
authors: Haldeman-Englert
authors: Medical Genetics Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA.
authors: Sulagna
authors: S
authors: Saitta
authors: The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: Holly
authors: H
authors: Dubbs
authors: Hospital Saint Vincent de Paul, Lille, France.
authors: Duban B
authors: DB
authors: Bénédicte
authors: Ameripath Northeast, Shelton, CT, USA.
authors: Xia
authors: X
authors: Li
authors: Henry Ford Health System, Sterling Heights, Michigan, USA.
authors: Lani
authors: L
authors: Devaney
authors: Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
authors: Mary Beth
authors: MB
authors: Dinulos
authors: Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
authors: Stephanie
authors: S
authors: Vallee
authors: Section of Functional and Structural Genomics Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
authors: M Carmen
authors: MC
authors: Crespo
authors: Section Cytogenetics, INGEMM-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
authors: Blanca
authors: B
authors: Fernández
authors: Section of Functional and Structural Genomics Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
authors: Victoria E
authors: VE
authors: Fernández-Montaño
authors: Section of Functional and Structural Genomics Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
authors: Inmaculada
authors: I
authors: Rueda-Arenas
authors: CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.|Section Cytogenetics, INGEMM-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
authors: María Luisa
authors: ML
authors: de Torres
authors: Kaiser Permanente, San Francisco, CA, USA.
authors: Jay W
authors: JW
authors: Ellison
authors: Center for Health and Biological Sciences, Pontifícia Universidade Católica do Paraná (PUC-PR), Curitiba, Brazil.
authors: Salmo
authors: S
authors: Raskin
authors: Genetic Unit Hospital General de México, México, México.|School of Medicine. Universidad Autónoma de México, México, México.
authors: Carlos A
authors: CA
authors: Venegas-Vega
authors: Genetic Unit Hospital General de México, México, México.
authors: Fernando
authors: F
authors: Fernández-Ramírez
authors: CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.|Section Cytogenetics, INGEMM-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
authors: Alicia
authors: A
authors: Delicado
authors: CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.|Section of Clinical Genetics, INGEMM-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
authors: Sixto
authors: S
authors: García-Miñaúr
authors: CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.|Section of Clinical Genetics, INGEMM-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
authors: Pablo
authors: P
authors: Lapunzina
mesh_terms: D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D058674:Chromosome Duplication; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D048370:MAP Kinase Kinase 2 / Q000235:genetics; D008297:Male; D058627:Megalencephaly / Q000235:genetics* / Q000473:pathology; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics*; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D014157:Transcription Factors; C485514:ZBTB7A protein, human; C482128:MAP2K2 protein, human; D048370:MAP Kinase Kinase 2