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Truncating De Novo Mutations in the Krüppel-Type Zinc-Finger Gene

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Truncating De Novo Mutations in the Krüppel-Type Zinc-Finger Gene University of Groningen Truncating de novo mutations in the Kruppel-type zinc-finger gene ZNF148 in patients with corpus callosum defects, developmental delay, short stature, and dysmorphisms Stevens, Servi J. C.; van Essen, Anthonie J.; van Ravenswaaij, Conny M. A.; Elias, Abdallah F.; Haven, Jaclyn A.; Lelieveld, Stefan H.; Pfundt, Rolph; Nillesen, Willy M.; Yntema, Helger G.; van Roozendaal, Kees Published in: Genome medicine DOI: 10.1186/s13073-016-0386-9 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2016 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Stevens, S. J. C., van Essen, A. J., van Ravenswaaij, C. M. A., Elias, A. F., Haven, J. A., Lelieveld, S. H., Pfundt, R., Nillesen, W. M., Yntema, H. G., van Roozendaal, K., Stegmann, A. P., Gilissen, C., & Brunner, H. G. (2016). Truncating de novo mutations in the Kruppel-type zinc-finger gene ZNF148 in patients with corpus callosum defects, developmental delay, short stature, and dysmorphisms. Genome medicine, 8, [131]. https://doi.org/10.1186/s13073-016-0386-9 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 27-09-2021 Stevens et al. Genome Medicine (2016) 8:131 DOI 10.1186/s13073-016-0386-9 RESEARCH Open Access Truncating de novo mutations in the Krüppel-type zinc-finger gene ZNF148 in patients with corpus callosum defects, developmental delay, short stature, and dysmorphisms Servi J. C. Stevens1*†, Anthonie J. van Essen2†, Conny M. A. van Ravenswaaij2, Abdallah F. Elias3, Jaclyn A. Haven3, Stefan H. Lelieveld4, Rolph Pfundt4, Willy M. Nillesen4, Helger G. Yntema4, Kees van Roozendaal1,4, Alexander P. Stegmann1, Christian Gilissen4 and Han G. Brunner1,4 Abstract Background: Krüppel-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 × 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. Keywords: ZNF148, ZBP-89, Whole exome sequencing, Intellectual disability, Corpus callosum development, De novo mutations, Premature termination codon * Correspondence: [email protected] †Equal contributors 1Department of Clinical Genetics, Maastricht University Medical Center (MUMC+), PO Box 58006202, AZ, Maastricht, The Netherlands Full list of author information is available at the end of the article © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Stevens et al. Genome Medicine (2016) 8:131 Page 2 of 10 Background Statistical analyses The human genome contains over 400 Krüppel-type To assess whether de novo nonsense mutations in the zinc finger (ZNF) genes. For many of these genes a bio- ZNF148 gene occurred significantly more frequently in logical function has not been elucidated thus far [1]. our ID/MCA patient cohort, we made use of the ZNF148- ZNF genes encode DNA-binding proteins, related to the specific loss-of-function (LoF) mutation rates [5], exactly archetypal Drosophila regulatory protein Krüppel, which as we described previously in Lelieveld et al. [6]. The LoF recognizes specific DNA sequence motifs in gene pro- rate was calculated by summing the individual ZNF148 moters. They bind the major groove of the double helix specific de novo mutation rates for nonsense, splice site, by their C2H2 zinc finger domains, each consisting of a and frame-shift variants. Null hypothesis testing of finding chain of two cysteines and two histidines that fold three nonsense or splice site mutations in the ZNF148 around and are stabilized by a single Zn2+ ion. ZNF gene was done using a one-sided exact Poisson test based genes may function as either transcriptional co- on a sample size of 2172 individuals with ID/MCA, repre- activators or repressors. They do so by promoting the senting 4344 alleles. Bonferroni correction for multiple binding of transcription factors to their cognate DNA gene testing was applied by multiplying the obtained recognition site or by recruitment of chromatin remod- p value by 19,280, i.e. the number of genes captured by eling proteins such as histone deacetylases, methyltrans- the exome capture kit. To statistically assess whether de ferases, and demethylases [1, 2]. Most ZNF genes have novo mutations clustered within the ZNF148 gene, been characterized using in vitro binding and reporter random distribution of the mutations over the entire cod- assays for identification of their target genes. By identify- ing region of the gene (2382 bp) was simulated 10,000 ing ZNF genes involved in human disease, their broader times [6]. The mutual distance between these randomly role in ontogeny or physiological processes may be eluci- applied mutations was calculated and statistically com- dated. Despite the extensive size of the gene family, the pared to the actual distances between the observed de number of disease-linked ZNF genes remains relatively novo mutations in our patients, which were present at small. Here we identified truncating de novo mutations c. positions 970, 1581, 1582, and 1792. in the Zinc Finger Protein 148 (ZNF148; also known as ZBP-89 or ZFP148) from a large cohort of patient–par- Results ents trios referred for diagnostic exome sequencing in Clinical reports the period 2012–2016. These de novo mutations lead to Patient 1 is a 6-year-old girl born at 35 + 4 weeks after an syndromic intellectual disability (ID) with corpus callo- uncomplicated pregnancy who presented with respiratory sum anomalies and short stature as shared features, ac- insufficiency and severe feeding problems requiring gav- companied by secondary variable microcephaly or mild age feeding. Birth measurements were normal. Currently, macrocephaly, feeding problems, variable facial features, she has gastrointestinal dysmotility with delayed gastric talipes, and malformations of the heart and kidneys. passage and receives most of her caloric intake through a gastrostomy tube. Biochemical analysis of mitochondrial Methods enzymes showed no abnormalities. Developmental mile- Whole exome sequencing stones were reached late with independent walking and For whole exome sequencing (WES), a parent–off- first words spoken at the age of 3 years. Her first teeth spring trio approach was used as described by us pre- erupted after 3 years. She is hyperactive at times and she viously [3, 4]. Exomes were sequenced using DNA gets upset in crowded environments. WISCIII-III-NL isolated from
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