Monoallelic and bi-allelic variants in NCDN cause neurodevelopmental delay, intellectual disability, and epilepsy

Ambrin Fatima, Jan Hoeber, Jens Schuster, Eriko Koshimizu, Carolina Maya-Gonzalez, Boris Keren, Cyril Mignot, Talia Akram, Zafar Ali, Satoko Miyatake, Junpei Tanigawa, Takayoshi Koike, Mitsuhiro Kato, Yoshiko Murakami, Uzma Abdullah, Muhammad Akhtar Ali, Rein Fadoul, Loora Laan, Casimiro Castillejo-López, Maarika LiikZhe Jin, Bryndis Birnir, Naomichi Matsumoto, Shahid M. Baig, Joakim Klar, Niklas Dahl

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


Neurochondrin (NCDN) is a cytoplasmatic neural protein of importance for neural growth, glutamate receptor (mGluR) signaling, and synaptic plasticity. Conditional loss of Ncdn in mice neural tissue causes depressive-like behaviors, impaired spatial learning, and epileptic seizures. We report on NCDN missense variants in six affected individuals with variable degrees of developmental delay, intellectual disability (ID), and seizures. Three siblings were found homozygous for a NCDN missense variant, whereas another three unrelated individuals carried different de novo missense variants in NCDN. We assayed the missense variants for their capability to rescue impaired neurite formation in human neuroblastoma (SH-SY5Y) cells depleted of NCDN. Overexpression of wild-type NCDN rescued the neurite-phenotype in contrast to expression of NCDN containing the variants of affected individuals. Two missense variants, associated with severe neurodevelopmental features and epilepsy, were unable to restore mGluR5-induced ERK phosphorylation. Electrophysiological analysis of SH-SY5Y cells depleted of NCDN exhibited altered membrane potential and impaired action potentials at repolarization, suggesting NCDN to be required for normal biophysical properties. Using available transcriptome data from human fetal cortex, we show that NCDN is highly expressed in maturing excitatory neurons. In combination, our data provide evidence that bi-allelic and de novo variants in NCDN cause a clinically variable form of neurodevelopmental delay and epilepsy, highlighting a critical role for NCDN in human brain development.

Original languageEnglish
Pages (from-to)739-748
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - 1 Apr 2021
Externally publishedYes


  • NCDN gene
  • de novo variant
  • epilepsy
  • intellectual disability
  • mGluR5 signaling
  • missense variant
  • neurite formation
  • neurodevelopmental delay
  • speech delay


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