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

Hui Guo*, Qiumeng Zhang, Rujia Dai, Bin Yu, Kendra Hoekzema, Jieqiong Tan, Senwei Tan, Xiangbin Jia, Wendy K. Chung, Rebecca Hernan, Fowzan S. Alkuraya, Ahood Alsulaiman, Mohammad A. Al-Muhaizea, Gaetan Lesca, Linda Pons, Audrey Labalme, Linda Laux, Emily Bryant, Natasha J. Brown, Elena SavvaSamantha Ayres, Dhamidhu Eratne, Hilde Peeters, Frédéric Bilan, Lucile Letienne-Cejudo, Brigitte Gilbert-Dussardier, Inge Lore Ruiz-Arana, Jenny Meylan Merlini, Alexia Boizot, Lucia Bartoloni, Federico Santoni, Danielle Karlowicz, Marie McDonald, Huidan Wu, Zhengmao Hu, Guodong Chen, Jianjun Ou, Charlotte Brasch-Andersen, Christina R. Fagerberg, Inken Dreyer, Anne chun-hui Tsai, Valerie Slegesky, Rose B. McGee, Brina Daniels, Elizabeth A. Sellars, Lori A. Carpenter, Bradley Schaefer, Maria J.Guillen Sacoto, Amber Begtrup, Rhonda E. Schnur, Sumit Punj, Ingrid M. Wentzensen, Lindsay Rhodes, Qian Pan, Raphael A. Bernier, Chao Chen, Evan E. Eichler, Kun Xia

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)963-976
Number of pages14
JournalAmerican journal of human genetics
Volume107
Issue number5
DOIs
StatePublished - Nov 5 2020

Keywords

  • NCKAP1
  • autism spectrum disorder
  • de novo variants
  • disruptive variant
  • genotype-phenotype correlation
  • neurodevelopmental disorder

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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