title: Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications.
abstract: Point mutations and genomic deletions of the CDKL5 (STK9) gene on chromosome Xp22 have been reported in patients with severe neurodevelopmental abnormalities, including Rett-like disorders. To date, only larger-sized (8-21 Mb) duplications harboring CDKL5 have been described. We report seven females and four males from seven unrelated families with CDKL5 duplications 540-935 kb in size. Three families of different ethnicities had identical 667kb duplications containing only the shorter CDKL5 isoform. Four affected boys, 8-14 years of age, and three affected girls, 6-8 years of age, manifested autistic behavior, developmental delay, language impairment, and hyperactivity. Of note, two boys and one girl had macrocephaly. Two carrier mothers of the affected boys reported a history of problems with learning and mathematics while at school. None of the patients had epilepsy. Similarly to CDKL5 mutations and deletions, the X-inactivation pattern in all six studied females was random. We hypothesize that the increased dosage of CDKL5 might have affected interactions of this kinase with its substrates, leading to perturbation of synaptic plasticity and learning, and resulting in autistic behavior, developmental and speech delay, hyperactivity, and macrocephaly.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Szafranski
authors.affiliation: Departments of Pediatrics and Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Sailaja
authors.initials: S
authors.lastname: Golla
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Weihong
authors.initials: W
authors.lastname: Jin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Fang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Hixson
authors.affiliation: Division of General Academic Pediatrics, Department of Pediatrics, The University of Texas Medical Branch at Galveston, Galveston, TX, USA.
authors.forename: Reuben
authors.initials: R
authors.lastname: Matalon
authors.affiliation: Memorial Children's Hospital Navarre Pediatrics South Bend, South Bend, IN, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kinney
authors.affiliation: Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Bock
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: William
authors.initials: W
authors.lastname: Craigen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Smith
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Sau
authors.initials: S
authors.lastname: Wai Cheung
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bacino
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Paweł
authors.initials: P
authors.lastname: Stankiewicz
mesh_terms: D000293:Adolescent; D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000175:diagnosis / Q000235:genetics; D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D055028:Comparative Genomic Hybridization; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D040582:Inheritance Patterns; D007805:Language Development Disorders / Q000175:diagnosis / Q000235:genetics; D008297:Male; D058627:Megalencephaly / Q000175:diagnosis / Q000235:genetics; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D049951:X Chromosome Inactivation
chemical_list: D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human