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

Publication ,  Journal Article
Guo, H; Zhang, Q; Dai, R; Yu, B; Hoekzema, K; Tan, J; Tan, S; Jia, X; Chung, WK; Hernan, R; Alkuraya, FS; Alsulaiman, A; Al-Muhaizea, MA ...
Published in: Am J Hum Genet
November 5, 2020

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.

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Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

November 5, 2020

Volume

107

Issue

5

Start / End Page

963 / 976

Location

United States

Related Subject Headings

  • Young Adult
  • Transcriptome
  • RNA, Small Interfering
  • Protein Isoforms
  • Pregnancy
  • Phenotype
  • Pedigree
  • Neurons
  • Neuroglia
  • Mutation
 

Citation

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Guo, H., Zhang, Q., Dai, R., Yu, B., Hoekzema, K., Tan, J., … Xia, K. (2020). NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism. Am J Hum Genet, 107(5), 963–976. https://doi.org/10.1016/j.ajhg.2020.10.002
Guo, Hui, Qiumeng Zhang, Rujia Dai, Bin Yu, Kendra Hoekzema, Jieqiong Tan, Senwei Tan, et al. “NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism.Am J Hum Genet 107, no. 5 (November 5, 2020): 963–76. https://doi.org/10.1016/j.ajhg.2020.10.002.
Guo H, Zhang Q, Dai R, Yu B, Hoekzema K, Tan J, et al. NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism. Am J Hum Genet. 2020 Nov 5;107(5):963–76.
Guo, Hui, et al. “NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism.Am J Hum Genet, vol. 107, no. 5, Nov. 2020, pp. 963–76. Pubmed, doi:10.1016/j.ajhg.2020.10.002.
Guo H, Zhang Q, Dai R, Yu B, Hoekzema K, Tan J, Tan S, Jia X, Chung WK, Hernan R, Alkuraya FS, Alsulaiman A, Al-Muhaizea MA, Lesca G, Pons L, Labalme A, Laux L, Bryant E, Brown NJ, Savva E, Ayres S, Eratne D, Peeters H, Bilan F, Letienne-Cejudo L, Gilbert-Dussardier B, Ruiz-Arana I-L, Merlini JM, Boizot A, Bartoloni L, Santoni F, Karlowicz D, McDonald M, Wu H, Hu Z, Chen G, Ou J, Brasch-Andersen C, Fagerberg CR, Dreyer I, Chun-Hui Tsai A, Slegesky V, McGee RB, Daniels B, Sellars EA, Carpenter LA, Schaefer B, Sacoto MJG, Begtrup A, Schnur RE, Punj S, Wentzensen IM, Rhodes L, Pan Q, Bernier RA, Chen C, Eichler EE, Xia K. NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism. Am J Hum Genet. 2020 Nov 5;107(5):963–976.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

November 5, 2020

Volume

107

Issue

5

Start / End Page

963 / 976

Location

United States

Related Subject Headings

  • Young Adult
  • Transcriptome
  • RNA, Small Interfering
  • Protein Isoforms
  • Pregnancy
  • Phenotype
  • Pedigree
  • Neurons
  • Neuroglia
  • Mutation