Relevance to Autism

Two de novo LoF variants in the NCKAP1 gene (one nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). Transmission and de novo association (TADA) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) in Sanders et al., 2015 identified NCKAP1 as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) 0.01. A third de novo LoF variant in NCKAP1 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. Guo et al., 2020 assembled genotype and phenotype data for 21 affected individuals from 20 unrelated families with predicted deleterious variants in NCKAP1 (including previously reported individuals from the Simons Simplex Collection and the ACGC cohorts) and found that affected individuals presented with a neurodevelopmental disorder characterized by ASD or autistic features, language and motor delay, and variable expression of intellectual or learning disability; of the 15 individuals in this cohort assessed for ASD, 10 individuals were formally diagnosed.

Molecular Function

Part of the WAVE complex that regulates lamellipodia formation. The WAVE complex regulates actin filament reorganization via its interaction with the Arp2/3 complex.

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Model Summary

Both Hem mutants showed a habituation deficit.

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