NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism

Am J Hum Genet. 2020 Nov 5;107(5):963-976. doi: 10.1016/j.ajhg.2020.10.002.


NCKAP1/NAP1 regulates neuronal cytoskeletal dynamics and is essential for neuronal differentiation in the developing brain. Deleterious variants in NCKAP1 have been identified in individuals with autism spectrum disorder (ASD) and intellectual disability; however, its clinical significance remains unclear. To determine its significance, we assemble genotype and phenotype data for 21 affected individuals from 20 unrelated families with predicted deleterious variants in NCKAP1. This includes 16 individuals with de novo (n = 8), transmitted (n = 6), or inheritance unknown (n = 2) truncating variants, two individuals with structural variants, and three with potentially disruptive de novo missense variants. We report a de novo and ultra-rare deleterious variant burden of NCKAP1 in individuals with neurodevelopmental disorders which needs further replication. ASD or autistic features, language and motor delay, and variable expression of intellectual or learning disability are common clinical features. Among inherited cases, there is evidence of deleterious variants segregating with neuropsychiatric disorders. Based on available human brain transcriptomic data, we show that NCKAP1 is broadly and highly expressed in both prenatal and postnatal periods and demostrate enriched expression in excitatory neurons and radial glias but depleted expression in inhibitory neurons. Mouse in utero electroporation experiments reveal that Nckap1 loss of function promotes neuronal migration during early cortical development. Combined, these data support a role for disruptive NCKAP1 variants in neurodevelopmental delay/autism, possibly by interfering with neuronal migration early in cortical development.

Keywords: NCKAP1; autism spectrum disorder; de novo variants; disruptive variant; genotype-phenotype correlation; neurodevelopmental disorder.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adolescent
  • Animals
  • Autism Spectrum Disorder / diagnosis
  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / pathology
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Child
  • Female
  • Gene Expression
  • Genotype
  • HEK293 Cells
  • Humans
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Learning Disabilities / diagnosis
  • Learning Disabilities / genetics*
  • Learning Disabilities / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Mutation*
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Pedigree
  • Phenotype
  • Pregnancy
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Transcriptome
  • Young Adult


  • Adaptor Proteins, Signal Transducing
  • NCKAP1 protein, human
  • Protein Isoforms
  • RNA, Small Interfering