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The actin cytoskeleton is regulated by many proteins including capping proteins that stabilize actin filaments (F-actin) by inhibiting actin polymerization and depolymerization. Here, we report two pediatric probands who carry damaging heterozygous  de novo  mutations in  CAPZA2  (HGNC: 1490) and exhibit neurological symptoms with shared phenotypes including global motor development delay, speech delay, intellectual disability, hypotonia and a history of seizures.  CAPZA2  encodes a subunit of an F-actin-capping protein complex (CapZ). CapZ is an obligate heterodimer consisting of α and β heterodimer conserved from yeast to human. Vertebrate genomes contain three α subunits encoded by three different genes and  CAPZA2  encodes the α2 subunit. The single orthologue of  CAPZA  genes in  Drosophila  is  cpa . Loss of  cpa  leads to lethality in early development and expression of the human reference;  CAPZA2  rescues this lethality. However, the two  CAPZA2  variants identified in the probands rescue this lethality at lower efficiency than the reference. Moreover, expression of the  CAPZA2  variants affects bristle morphogenesis, a process that requires extensive actin polymerization and bundling during development. Taken together, our findings suggest that variants in  CAPZA2  lead to a non-syndromic neurodevelopmental disorder in children.

Variants in CAPZA2, a member of an F-actin capping complex, cause intellectual disability and developmental delay