C18orf32 loss-of-function is associated with a neurodevelopmental disorder with hypotonia and contractures

Smrithi Salian, Xin Yu Guo, Yoshiko Murakami, Taroh Kinoshita, Parneet Kaur, Anju Shukla, Katta M. Girisha, Morihisa Fujita, Philippe M. Campeau

Research output: Contribution to journalArticlepeer-review


Glycosylphosphatidylinositol (GPI) functions to anchor certain proteins to the cell surface. Although defects in GPI biosynthesis can result in a wide range of phenotypes, most affected patients present with neurological abnormalities and their diseases are grouped as inherited-GPI deficiency disorders. We present two siblings with global developmental delay, brain anomalies, hypotonia, and contractures. Exome sequencing revealed a homozygous variant, NM_001035005.4:c.90dupC (p.Phe31Leufs*3) in C18orf32, a gene not previously associated with any disease in humans. The encoded protein is known to be important for GPI-inositol deacylation. Knockout of C18orf32 in HEK293 cells followed by a transfection rescue assay revealed that the PIPLC (Phosphatidylinositol-Specific Phospholipase C) sensitivity of GPI-APs (GPI-anchored proteins) was restored only by the wild type and not the mutant C18orf32. Immunofluorescence revealed that the mutant C18orf32 was localized to the endoplasmic reticulum and was also found as aggregates in the nucleus. In conclusion, we identified a pathogenic variant in C18orf32 as the cause of a novel autosomal recessive neurodevelopmental disorder with hypotonia and contractures. Our results demonstrate the importance of C18orf32 in the biosynthesis of GPI-anchors, the molecular impact of the variant on the protein function, and add a novel candidate gene to the existing repertoire of genes implicated in neurodevelopmental disorders.

Original languageEnglish
Pages (from-to)1423-1429
Number of pages7
JournalHuman Genetics
Issue number8
Publication statusPublished - 08-2022

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)


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