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Two novel CCDC88C mutations confirm the role of DAPLE in autosomal recessive congenital hydrocephalus
  1. Anais Drielsma1,2,
  2. Chaim Jalas3,
  3. Nicolas Simonis4,
  4. Julie Désir2,
  5. Natalia Simanovsky5,
  6. Isabelle Pirson1,
  7. Orly Elpeleg6,
  8. Marc Abramowicz2,
  9. Simon Edvardson6
  1. 1Institute of Interdisciplinary Research – IRIBHM, Université Libre de Bruxelles, Brussels, Belgium
  2. 2Department Medical Genetics, Hôpital Erasme – ULB, Université Libre de Bruxelles, Brussels, Belgium
  3. 3Bonei Olam Center for Rare Jewish Diseases, Brooklyn, New York, New York, USA
  4. 4Bioinformatics of Genome and Networks (BiGRe), Université Libre de Bruxelles, Brussels, Belgium
  5. 5Department of Medical Imaging, Hadassah Hebrew University Medical Center, Jerusalem, Israel
  6. 6Monique and Jacques Roboh Department of Genetic Research, Hadassah Hebrew University Medical Center, Jerusalem, Israel
  1. Correspondence to Professor Marc Abramowicz, Department Medical Genetics, Hôpital Erasme – ULB, Université Libre de Bruxelles, 808 Route de Lennik, Brussels 1070, Belgium; Marc.Abramowicz{at}


Background Human congenital non-syndromic hydrocephalus is a vastly heterogeneous condition. A subgroup of cases are not secondary to a specific cause (eg, a neural tube defect), and within this subgroup, autosomal recessive inheritance has been described. One homozygous mutation in the DAPLE (Dvl-associating protein with a high frequency of leucine residues) protein-encoding gene CCDC88C (coiled-coil domain containing 88C) has recently been reported in a single family. The role of this gene has not been validated in another family, and no other autosomal recessive gene has been reported.

Methods We used homozygosity mapping and whole exome sequencing in two families with primary, non-syndromic congenital hydrocephalus from two different ethnic backgrounds.

Results In each family, we identified a novel homozygous mutation of CCDC88C. One mutation produced a premature stop codon at position 312 of the protein, while the second mutation induced a frameshift in the last exon, producing a stop codon that truncated the extreme C-terminus of DAPLE, including the 2026-2028 Gly-Cys-Val motif known to bind the post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein (zo-1) (PDZ) domain of Dishevelled.

Conclusions Our data validate CCDC88C as causing autosomal recessive, primary non-syndromic congenital hydrocephalus, suggesting this gene may be an important cause of congenital hydrocephalus, and underscore the important role of the C-terminal PDZ domain-binding motif in the DAPLE protein.

  • Developmental
  • Genetics
  • Hydrocephalus
  • Molecular genetics
  • Neurosciences

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