1. NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism.
- Author
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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 IL, 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, and Xia K
- Subjects
- Adaptor Proteins, Signal Transducing deficiency, Adolescent, Animals, Autism Spectrum Disorder diagnosis, Autism Spectrum Disorder pathology, Cerebral Cortex metabolism, Cerebral Cortex pathology, Child, Female, Gene Expression, Genotype, HEK293 Cells, Humans, Intellectual Disability diagnosis, Intellectual Disability pathology, Learning Disabilities diagnosis, Learning Disabilities pathology, Male, Mice, Mice, Knockout, 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 genetics, Autism Spectrum Disorder genetics, Intellectual Disability genetics, Learning Disabilities genetics, Mutation
- Abstract
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., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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