title: A de novo non-sense mutation in ZBTB18 in a patient with features of the 1q43q44 microdeletion syndrome.
abstract: The phenotype of patients with a chromosome 1q43q44 microdeletion (OMIM; 612337) is characterized by intellectual disability with no or very limited speech, microcephaly, growth retardation, a recognizable facial phenotype, seizures, and agenesis of the corpus callosum. Comparison of patients with different microdeletions has previously identified ZBTB18 (ZNF238) as a candidate gene for the 1q43q44 microdeletion syndrome. Mutations in this gene have not yet been described. We performed exome sequencing in a patient with features of the 1q43q44 microdeletion syndrome that included short stature, microcephaly, global developmental delay, pronounced speech delay, and dysmorphic facial features. A single de novo non-sense mutation was detected, which was located in ZBTB18. This finding is consistent with an important role for haploinsufficiency of ZBTB18 in the phenotype of chromosome 1q43q44 microdeletions. The corpus callosum is abnormal in mice with a brain-specific knock-out of ZBTB18. Similarly, most (but not all) patients with the 1q43q44 microdeletion syndrome have agenesis or hypoplasia of the corpus callosum. In contrast, the patient with a ZBTB18 point mutation reported here had a structurally normal corpus callosum on brain MRI. Incomplete penetrance or haploinsufficiency of other genes from the critical region may explain the absence of corpus callosum agenesis in this patient with a ZBTB18 point mutation. The findings in this patient with a mutation in ZBTB18 will contribute to our understanding of the 1q43q44 microdeletion syndrome.
authors.affiliation: Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Sonja A
authors.initials: SA
authors.lastname: de Munnik
authors.affiliation: Department of Clinical Genetics, Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Sixto
authors.initials: S
authors.lastname: García-Miñaúr
authors.affiliation: Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Bregje W
authors.initials: BW
authors.lastname: van Bon
authors.affiliation: Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.affiliation: Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Schoots
authors.affiliation: Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Lies H
authors.initials: LH
authors.lastname: Hoefsloot
authors.affiliation: Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Nine V A M
authors.initials: NV
authors.lastname: Knoers
authors.affiliation: Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Ernie M H F
authors.initials: EM
authors.lastname: Bongers
authors.affiliation: Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics / Q000473:pathology; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000235:genetics / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D012097:Repressor Proteins / Q000235:genetics*; D013577:Syndrome
chemical_list: D018389:Codon, Nonsense; D012097:Repressor Proteins; C115048:ZBTB18 protein, human