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

Tamar Harel, John N. Griffin, Thomas Arbogast, Tanner O. Monroe, Flavia Palombo, Marcella Martinelli, Marco Seri, Tommaso Pippucci, Orly Elpeleg, Nicholas Katsanis

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1489-1497
Number of pages9
JournalHuman molecular genetics
Volume29
Issue number9
DOIs
StatePublished - Jun 3 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Harel, T., Griffin, J. N., Arbogast, T., Monroe, T. O., Palombo, F., Martinelli, M., Seri, M., Pippucci, T., Elpeleg, O., & Katsanis, N. (2020). Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies. Human molecular genetics, 29(9), 1489-1497. https://doi.org/10.1093/hmg/ddaa073