Truncating de novo mutations in the Kruppel-type zinc-finger gene ZNF148 in patients with corpus callosum defects, developmental delay, short stature, and dysmorphisms

Autor: Abdallah F. Elias, Helger G. Yntema, Willy M. Nillesen, Stefan H. Lelieveld, Kees E. P. van Roozendaal, Rolph Pfundt, Servi J. C. Stevens, Han G. Brunner, Jaclyn Haven, Alexander P.A. Stegmann, Anthonie J. van Essen, Conny M. A. van Ravenswaaij, Christian Gilissen
Přispěvatelé: Clinical Cognitive Neuropsychiatry Research Program (CCNP), Genetica & Celbiologie, MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA Pat Cytologie (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Klinische Genetica
Rok vydání: 2016
Předmět:
0301 basic medicine
Male
EXPRESSION
Microcephaly
INTELLECTUAL DISABILITY
PROMOTER
Developmental Disabilities
Biology
Bioinformatics
Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12]
DISEASE
Frameshift mutation
03 medical and health sciences
Exon
0302 clinical medicine
medicine
Genetics
Gene family
Humans
Genetics(clinical)
Child
Gene
Molecular Biology
Genetics (clinical)
Exome sequencing
Sequence Deletion
Zinc finger
Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]
De novo mutations
Base Sequence
Research
Infant
Newborn
Whole exome sequencing
Premature termination codon
medicine.disease
Body Dysmorphic Disorders
Human genetics
DNA-Binding Proteins
030104 developmental biology
Molecular Medicine
Female
Agenesis of Corpus Callosum
ZNF148
Corpus callosum development
Neurodevelopmental disorders Radboud Institute for Molecular Life Sciences [Radboudumc 7]
ZBP-89
030217 neurology & neurosurgery
Transcription Factors
Zdroj: Genome Medicine, 8, 131
Genome medicine, 8:131. BMC
Genome Medicine
Genome Medicine, 8, 1, pp. 131
Genome Medicine, 8:131. BioMed Central Ltd
ISSN: 1756-994X
Popis: Contains fulltext : 168247.pdf (Publisher’s version ) (Open Access) BACKGROUND: Kruppel-type zinc finger genes (ZNF) constitute a large yet relatively poorly characterized gene family. ZNF genes encode proteins that recognize specific DNA motifs in gene promotors. They act as transcriptional co-activators or -repressors via interaction with chromatin remodeling proteins and other transcription factors. Only few ZNF genes are currently linked to human disorders and identification of ZNF gene-associated human diseases may help understand their function. Here we provide genetic, statistical, and clinical evidence to support association of ZNF148 with a new intellectual disability (ID) syndrome disorder. METHODS: Routine diagnostic exome sequencing data were obtained from 2172 patients with ID and/or multiple congenital anomalies. RESULTS: In a cohort of 2172 patient-parent trios referred for routine diagnostic whole exome sequencing for ID and/or multiple congenital anomalies (MCA) in the period 2012-2016, four patients were identified who carried de novo heterozygous nonsense or frameshift mutations in the ZNF148 gene. This was the only ZNF gene with recurrent truncating de novo mutations in this cohort. All mutations resulted in premature termination codons in the last exon of ZNF148. The number of the de novo truncating mutations in the ZNF148 gene was significantly enriched (p = 5.42 x 10-3). The newly described ZNF148-associated syndrome is characterized by underdevelopment of the corpus callosum, mild to moderate developmental delay and ID, variable microcephaly or mild macrocephaly, short stature, feeding problems, facial dysmorphisms, and cardiac and renal malformations. CONCLUSIONS: We propose ZNF148 as a gene involved in a newly described ID syndrome with a recurrent phenotype and postulate that the ZNF148 is a hitherto unrecognized but crucial transcription factor in the development of the corpus callosum. Our study illustrates the advantage of whole exome sequencing in a large cohort using a parent-offspring trio approach for identifying novel genes involved in rare human diseases.
Databáze: OpenAIRE
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