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

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

  • Hum Mol Genet. 2020 Jun 3;29(9):1489-1497. doi: 10.1093/hmg/ddaa073.
Tamar Harel 1,  John N Griffin 2 3,  Thomas Arbogast 2,  Tanner O Monroe 4 5,  Flavia Palombo 6,  Marcella Martinelli 7,  Marco Seri 8 9,  Tommaso Pippucci 9,  Orly Elpeleg 10,  Nicholas Katsanis 4 5
Affiliations

Affiliations

  • 1 Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, 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, UK.
  • 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, Chicago, IL 60611, USA.
  • 6 IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy.
  • 7 Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Alma Mater Studiorum - Università di Bologna, Bologna 40138, Italy.
  • 8 Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum - Università di Bologna, Bologna 40138, Italy.
  • 9 U.O. Genetica Medica, Policlinico S. Orsola-Malpighi, Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy.
  • 10 Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
PMID: 32307552 DOI: 10.1093/hmg/ddaa073
Abstract

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.

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