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Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.

  • Harel, Tamar1
  • Griffin, John N2, 3
  • Arbogast, Thomas2
  • Monroe, Tanner O4, 5
  • Palombo, Flavia6
  • Martinelli, Marcella7
  • Seri, Marco8, 9
  • Pippucci, Tommaso9
  • Elpeleg, Orly10
  • Katsanis, Nicholas4, 5
  • 1 Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. , (Israel)
  • 2 Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA.
  • 3 School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom. , (United Kingdom)
  • 4 Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
  • 5 Advanced Center for Translational and Genetic Medicine (ACT-GeM), Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 East Chicago Avenue, Box 205, Chicago, IL 60611, USA.
  • 6 IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, 40138 Bologna, Italy. , (Italy)
  • 7 Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, 40138 Bologna, Italy. , (Italy)
  • 8 Dipartimento di Scienze Mediche e Chirurgiche, Università Di Bologna, 40138 Bologna, Italy. , (Italy)
  • 9 U.O. Genetica Medica, Policlinico S. Orsola-Malpighi, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy. , (Italy)
  • 10 Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, 91120, Jerusalem, Israel. , (Israel)
Published Article
Human Molecular Genetics
Oxford University Press
Publication Date
Apr 20, 2020
DOI: 10.1093/hmg/ddaa073
PMID: 32307552


Despite the wide use of genomics to investigate the molecular basis of rare congenital malformations, a significant fraction of patients remains bereft of diagnosis. As part of our continuous effort to recruit and perform genomic and functional studies on such cohorts, we investigated the genetic and mechanistic cause of disease in two independent consanguineous families affected by overlapping craniofacial, cardiac, laterality, and neurodevelopmental anomalies. Using whole exome sequencing, we identified homozygous frameshift CCDC32 variants in three affected individuals. Functional analysis in a zebrafish model revealed that ccdc32 depletion recapitulates the human phenotypes. Because some of the patient phenotypes overlap defects common to ciliopathies, we asked if loss of CCDC32 might contribute to the dysfunction of this organelle. Consistent with this hypothesis, we show that ccdc32 is required for normal cilia formation in zebrafish embryos and mammalian cell culture, arguing that ciliary defects are at least partially involved in the pathomechanism of this disorder. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

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