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For Peer Review 20 Research Priority Program Radiz (Rare Disease Initiative Zurich), Fondazione Bambino Gesù (Vite 21 22 Coraggiose) and Fondazione Umberto Veronesi

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For Peer Review 20 Research Priority Program Radiz (Rare Disease Initiative Zurich), Fondazione Bambino Gesù (Vite 21 22 Coraggiose) and Fondazione Umberto Veronesi Human Mutation Clinical and functional characterization of two novel ZBTB20 mutations causing Primrose syndrome Journal: Human Mutation Manuscript ForID Draft Peer Review Wiley - Manuscript type: Brief Report Date Submitted by the Author: n/a Complete List of Authors: Stellacci, Emilia; Istituto Superiore di Sanità, Oncologia e Medicina Molecolare Steindl, Katharina; Institute of Medical Genetics, University of Zurich Joset, Pascal; Institute of Medical Genetics, University of Zurich Mercurio, Laura; Istituto Superiore di Sanità, Oncologia e Medicina Molecolare Anselmi, Massimiliano; Università di Roma 'Tor Vergata', Dipartimento di Scienze e Tecnologie Chimiche Cecchetti, Serena; Istituto Superiore di Sanità, Servizio grandi strumentazioni e core facilities Gogoll, Laura; Institute of Medical Genetics, University of Zurich Zweier, Markus; Institute of Medical Genetics, University of Zurich Hackenberg, Annette; University Children's Hospital Zürich, Division of Pediatric Neurology Bocchinfuso, Gianfranco; Università di Roma 'Tor Vergata', Dipartimento di Scienze e Tecnologie Chimiche Stella, Lorenzo; Universita' "Tor Vergata", Dipartimento di Scienze e Tecnologie Chimiche Tartaglia, Marco; Bambino Gesù Children’s Hospital, IRCCS, Division of Genetic Disorders and Rare Diseases Rauch, Anita; University of Zurich, Institute of Medical Genetics Primrose syndrome, <i>ZBTB20</i>, 3q13.31 microdeletion syndrome, Key Words: mutation spectrum, functional analyses John Wiley & Sons, Inc. Page 1 of 22 Human Mutation Stellacci, Steindl, et al. Pag. 1 1 2 3 Clinical and functional characterization of two novel ZBTB20 mutations causing Primrose 4 5 syndrome 6 7 8 9 Emilia Stellacci1*, Katharina Steindl2*, Pascal Joset2, Laura Mercurio1, Massimiliano Anselmi3, 10 11 Serena Cecchetti4, Laura Gogoll2, Markus Zweier2, Annette Hackenberg5, Gianfranco 12 13 3 3 6§ 2,7,8,9§ 14 Bocchinfuso , Lorenzo Stella , Marco Tartaglia , Anita Rauch 15 16 17 1 18 Dipartimento di Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy; 19 2 Institute of Medical Genetics,For University Peer of Zurich, Review Schlieren-Zurich, Switzerland; 20 21 3 Dipartimento di Scienze e Tecnologie Chimiche, Universita` di Roma ‘‘Tor Vergata’’ Rome, 22 23 Italy; 24 4 Servizio grandi strumentazioni e core facilities, Istituto Superiore di Sanità, Rome, Italy; 25 26 5 Division of Paediatric Neurology, University Children’s Hospital Zurich, Zürich, Switzerland; 27 6 28 Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy; 29 7 radiz—Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases 30 31 University of Zurich, Zurich, Switzerland 32 8 Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland 33 34 9 Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland 35 36 37 *These authors equally contributed to this work. 38 39 §These authors jointly coordinated this work. 40 41 42 43 *Corresponding authors: 44 45 Emilia Stellacci, 46 Department of Oncology and Molecular Medicine, 47 48 Istituto Superiore di Sanità, 49 Viale Regina Elena, 299, Rome 00161, Italy. 50 Phone: +390649903197; e-mail: [email protected] 51 52 Katharina Steindl, 53 Institute of Medical Genetics, 54 University of Zurich, 55 Wagistrasse 12, 8952 Schlieren-Zurich, Switzerland. 56 Phone: +41445563300; e-mail: [email protected] 57 58 59 60 John Wiley & Sons, Inc. Human Mutation Page 2 of 22 Stellacci, Steindl, et al. Pag. 2 1 2 3 4 5 Disclosure statement: 6 7 8 The authors declare no conflict of interest. 9 10 11 12 13 Acnowledgements 14 15 16 We are grateful to the families who contributed to this study. We thank Serenella Venanzi for 17 18 technical support. This study was supported by grants from the University of Zurich clinical 19 For Peer Review 20 research priority program radiz (rare disease initiative Zurich), Fondazione Bambino Gesù (Vite 21 22 coraggiose) and Fondazione Umberto Veronesi. 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc. Page 3 of 22 Human Mutation Stellacci, Steindl, et al. Pag. 3 1 2 3 ABSTRACT 4 5 Primrose syndrome (PS) is a rare disorder characterized by macrocephaly, tall stature, intellectual 6 7 disability, autistic traits, and disturbances of glucose metabolism with insulin-resistant diabetes and 8 9 distal muscle wasting occurring in adulthood. The disorder is caused by functional dysregulation of 10 11 ZBTB20, a transcriptional repressor controlling energetic metabolism and developmental programs. 12 13 14 ZBTB20 maps in a genomic region that is deleted in the 3q13.31 microdeletion syndrome, which 15 16 explains the partial clinical overlap between the two disorders. A narrow spectrum of amino acid 17 18 substitutions in a restricted region of ZBTB20 encompassing the first and second zinc-finger motifs 19 For Peer Review 20 have been reported thus far. Here, we characterize clinically and functionally the first truncating 21 22 mutation (c.1024delC; p.Gln342Serfs*42) and a missense change affecting the third zinc-finger 23 24 motif of the protein (c.1931C>T; p.Thr644Ile). Our data document that both mutations have 25 26 27 dominant negative impact on wild-type ZBTB20, providing further evidence of the specific 28 29 behavior of PS-causing mutations on ZBTB20 function. 30 31 32 33 34 35 Keywords: Primrose syndrome, ZBTB20, 3q13.31 microdeletion syndrome, mutation spectrum, 36 37 functional analyses. 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc. Human Mutation Page 4 of 22 Stellacci, Steindl, et al. Pag. 4 1 2 3 MAIN TEXT 4 5 Recognized as a nosologic entity for the first time over 35 years ago (Primrose, 1982), Primrose 6 7 syndrome (PS; MIM #259050) is a rare genetic condition characterized by cognitive deficits often 8 9 associated with autism spectrum disorder, macrocephaly, tall stature, truncal obesity, and a 10 11 distinctive pattern of ectopic calcification. With age, deafness, atrophy of the muscles of the limbs, 12 13 14 disturbed glucose metabolism and onset of diabetes in adults is commonly observed in affected 15 16 individuals (Collacott et al, 1986; Lindor et al, 1996; Battisti et al, 2002; Dalal et al, 2010; Posmyk 17 18 et al, 2011; Carvalho et al, 2011). The assumption of autosomal dominant inheritance of this 19 For Peer Review 20 sporadic condtion was confirmed by the identification of heterozygous de novo missense mutations 21 22 in ZBTB20 as the molecular event underlying the trait (Cordeddu et al, 2014). Consistent with the 23 24 occurrence of intellectual disability, behavioral issues and altered energetic metabolism in PS 25 26 27 patients, ZBTB20 is a transcriptional repressor involved in the control of brain development and 28 29 glucose metabolism (Sutherland et al, 2009; Mitchelmore et al, 2002; Nielsen et al, 2007). The 30 31 protein is a member of the broad complex tramtrack bric-a-brac (BTB) zinc-finger family (Zhang et 32 33 al, 2001; Zhang et al, 2012; Zhang et al, 2015), and is characterized by an N-terminal BTB domain 34 35 that is involved in protein-protein interaction, and five C2H2 zinc fingers at the C-terminus 36 37 mediating protein binding to regulatory sites within promoters of target genes. So far, all mutations 38 39 causing PS have been reported to be missense and affect amino acid residues within a region of the 40 41 42 protein encompassing the first and second zinc-finger (ZnF) motifs (Cordeddu et al, 2014; Mattioli 43 44 et al, 2016) (Figure 1A). ZBTB20 maps in a relatively small region containing a few additional 45 46 protein-coding genes (DRD3, ZNF80, and TIGIT) that is deleted in the 3q13.31 microdeletion 47 48 syndrome (del3q13.31, MIM #615433), a complex condition clinically overlapping PS and 49 50 characterized by postnatal growth in the upper normal range, hypotonia, intellectual disability (ID), 51 52 developmental delay, disturbed behavior and dysmorphic features (Hervé et al, 2016). Of note, we 53 54 55 previously provided evidence for a dominant negative impact of PS-causing mutations, indicating 56 57 that PS and del3q13.31 syndrome may represent allelic disorders resulting from variably impaired 58 59 60 John Wiley & Sons, Inc. Page 5 of 22 Human Mutation Stellacci, Steindl, et al. Pag. 5 1 2 3 ZBTB20 function (Cordeddu et al, 2014). Here, we report on the clinical and functional 4 5 characterization of two novel ZBTB20 mutations, a truncating frameshift (c.1024delC; 6 7 p.Gln342Serfs*42) and a missense substitution (c.1931C>T; p.Thr644Ile) affecting the third ZnF 8 9 motif, identified by whole exome sequencing (WES) in two young individuals with ID, 10 11 macrocephaly and syndromic features. We document that both changes result in stable but 12 13 14 dysfunctional proteins characterized by impaired/defective binding to DNA, and provide further 15 16 evidence for their dominant negative impact on ZBTB20 function. 17 18 The study was approved by the University Children’s Hospital of Zurich, and written 19 For Peer Review 20 informed consent was obtained from each participant for DNA storage and genetic analyses. 21 22 Patient 1 (P1) was an 8.5 year-old boy with mild developmental delay and macrocephaly born to 23 24 non-consanguineous healthy parents from the Dominican Republic (Figure 1B upper panels and 25 26 27 Suppl. Table 1). He was born at 35 + 3/7 weeks of gestation by Caesarean section with a weight of 28 th th th th 29 2465 g (25 centile), length of 44 cm (5 centile), and head circumference of 34.8 cm (75 -90 30 31 centile).The new-born hearing assessment was reported to be normal and confirmed by formal 32 33 testing at 8.5 years.
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