NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism
Open accessAbstract
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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Among these NCKAP1 variants, 13 were found to be de novo, four were transmitted, and three had an unknown inheritance pattern.
“Among them, 13 were found to be de novo, four were transmitted, and three had an unknown inheritance pattern129.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [129]
The Results section (page unavailable) describes 18 individuals with putative disruptive NCKAP1 variants: 14 with LGD variants (8 de novo, 4 inherited, 2 undetermined), two with de novo structural variants, and two with intronic variants (one de novo and one inherited). That yields 11 de novo, 5 inherited, and 2 of undetermined inheritance—not the claimed 13, 4, and 3. (LLM, conf=0.88)
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Experimental — accuracy not yet measuredA 240 kb de novo microdeletion encompassing three genes including NCKAP1 at 2q32.1, and one de novo balanced chromosome inversion truncating NCKAP1 at the 2q32.1 genomic inversion breakpoint, were identified.
“Additionally, a 240 kb de novo microdeletion encompassing three genes, including NCKAP1 at 2q32.1, and one de novo balanced chromosome inversion [46,XX,inv(2)(p23.1q32.1)dn] truncating NCKAP1 at the 2q32.1 genomic inversion breakpoint were identified.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [129]
The Results section reports a de novo microdeletion involving NCKAP1 and two other genes, plus a de novo inversion with a breakpoint in NCKAP1’s first intron. The passages in our copy do not give the deletion’s 240 kb size, describe the inversion as balanced, or specify the chromosome bands and karyotype stated in the claim. (LLM, conf=0.86)
Experimental — accuracy not yet measuredA total of 19 predicted deleterious variants in NCKAP1 were reported across 20 unrelated families, including four frameshift, five nonsense, five splice, and three missense variants.
“A total of 19 predicted deleterious variants in NCKAP1 were reported across 20 unrelated families. These variants include four frameshift variants, five nonsense variants, five splice variants, and three missense variants (Table 2t).”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [129]
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The WAVE complex in developmental and adulthood brain disorders
Kim, H.-G., Berdasco, C., Nairn, A. C., & Kim, Y. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01386-w · Cited by 8 · see citing works
- Authors
- Guo, H., Zhang, Q., Dai, R., Yu, B., Hoekzema, K., Tan, J., Tan, S., Jia, X., Chung, W. K., Hernan, R., Alkuraya, F. S., Alsulaiman, A., Al-Muhaizea, M. A., Lesca, G., Pons, L., Labalme, A., Laux, L., Bryant, E., Brown, N. J., Savva, E., Ayres, S., Eratne, D., Peeters, H., Bilan, F., Letienne-Cejudo, L., Gilbert-Dussardier, B., Ruiz-Arana, I.-L., Merlini, J. M., Boizot, A., Bartoloni, L., Santoni, F., Karlowicz, D., McDonald, M., Wu, H., Hu, Z., Chen, G., Ou, J., Brasch-Andersen, C., Fagerberg, C. R., Dreyer, I., chun-hui Tsai, A., Slegesky, V., McGee, R. B., Daniels, B., Sellars, E. A., Carpenter, L. A., Schaefer, B., Sacoto, M. J. G., Begtrup, A., Schnur, R. E., Punj, S., Wentzensen, I. M., Rhodes, L., Pan, Q., Bernier, R. A., Chen, C., Eichler, E. E., & Xia, K.
- Affiliations
- Central South University (CN)
- University of Washington (US)
- Columbia University (US)
- King Faisal Specialist Hospital & Research Centre (SA)
- Hospices Civils de Lyon (FR)
- Lurie Children's Hospital (US)
- Royal Children's Hospital (AU)
- Victorian Clinical Genetics Services (AU)
- The Royal Melbourne Hospital (AU)
- KU Leuven (BE)
- Centre Hospitalier Universitaire de Poitiers (FR)
- Centre Hospitalier Universitaire Vaudois (CH)
- Duke Medical Center (US)
- Odense University Hospital (DK)
- Sygehus Sønderjylland (DK)
- Children's Hospital Colorado (US)
- St. Jude Children's Research Hospital (US)
- University of Arkansas for Medical Sciences (US)
- Saint Francis Health System (US)
- Arkansas Children's Hospital (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Guo, Hui
- Xia, Kun
- ORCID
- Guo, Hui
- Zhang, Qiumeng
- Dai, Rujia
- Yu, Bin
- Hoekzema, Kendra
- Tan, Jieqiong
- Tan, Senwei
- Jia, Xiangbin
- Chung, Wendy K.
- Hernan, Rebecca
- Alkuraya, Fowzan S.
- Pons, Linda
- Labalme, Audrey
- Laux, Linda
- Bryant, Emily
- Brown, Natasha J.
- Savva, Elena
- Ayres, Samantha
- Eratne, Dhamidhu
- Peeters, Hilde
- Bilan, Frédéric
- Merlini, Jenny Meylan
- Bartoloni, Lucia
- Santoni, Federico
- McDonald, Marie
- Hu, Zhengmao
- Chen, Guodong
- Ou, Jianjun
- Fagerberg, Christina R.
- McGee, Rose B.
- Sellars, Elizabeth A.
- Begtrup, Amber
- Schnur, Rhonda E.
- Punj, Sumit
- Wentzensen, Ingrid M.
- Pan, Qian
- Bernier, Raphael A.
- Chen, Chao
- Eichler, Evan E.
- Xia, Kun
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2020-11
- Volume
- 107
- Issue
- 5
- Pages
- 963-976
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC7674997
- OpenAlex
- W3097947115
- Cited by
- 38
- References
- 10
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 9 · 2023: 6 · 2022: 5 · 2021: 4
- FWCI
- 2.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, other-oa)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- Central South University (2020CX042)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_185292)
- National Natural Science Foundation of China (81330027, 81871079, 81671122, 8173000779, 81525007)
- Simons Foundation
- Howard Hughes Medical Institute
- National Institutes of Health (MH101221)
- State Government of Victoria
- JPB Foundation
- U.S. Department of Health and Human Services
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- NCKAP1, NAP1, autism spectrum disorder, neurodevelopmental disorders, intellectual disability, de novo mutations, truncating mutations, missense mutations, structural variants, neuronal migration, cortical development, excitatory neurons, radial glia, inhibitory neurons, genotype-phenotype correlation
- MeSH terms
- Autism Spectrum Disorder, Adolescent, Animals, Cerebral Cortex, Child, Female, Genotype, Humans, Learning Disabilities, Male, Intellectual Disability, Mutation, Neuroglia, Neurons, Pedigree, Phenotype, Pregnancy, Gene Expression, Mice, Knockout, Protein Isoforms, RNA, Small Interfering, Adaptor Proteins, Signal Transducing, Mice, Young Adult, HEK293 Cells, Transcriptome
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