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 Savva; Samantha 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

doi:10.1016/j.ajhg.2020.10.002

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

Pediatrics

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

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 language	English (US)
Pages (from-to)	963-976
Number of pages	14
Journal	American journal of human genetics
Volume	107
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2020.10.002
State	Published - Nov 5 2020

Funding

We are grateful to the families involved in this study. We thank Tonia Brown for assistance in editing this manuscript. We thank Mais Hashem, Egidio Spinelli, and John J. Millichap for coordinating data collection. This work was supported by the following grants: the National Natural Science Foundation of China ( 81871079 , 81330027 , 81525007 , 8173000779 , 81671122 ) to H.G., K.X., and Z.H.; The US National Institutes of Health (NIH) grant ( MH101221 ) to E.E.E.; and the Hunan Provincial grants ( 2018SK1030 , 2018DK2016 , 2019SK1015 , 2019RS2005 ) to K.X., Z.H., and H.G. H.G. was also supported by the Innovation-Driven Project of Central South University ( 2020CX042 ). N.J.B., E.S., S.A., and D.E. was supported by the State Government of Victoria (Department of Health and Human Services, Melbourne Genomics Health Alliance). J.M.M. and F.S. are supported by the Swiss National Science Foundation ( 310030_185292 ). W.K.C. is supported by grants from the Simons Foundation and the JPB Foundation. E.E.E. is an investigator of the Howard Hughes Medical Institute . We are grateful to the families involved in this study. We thank Tonia Brown for assistance in editing this manuscript. We thank Mais Hashem, Egidio Spinelli, and John J. Millichap for coordinating data collection. This work was supported by the following grants: the National Natural Science Foundation of China (81871079, 81330027, 81525007, 8173000779, 81671122) to H.G. K.X. and Z.H.; The US National Institutes of Health (NIH) grant (MH101221) to E.E.E.; and the Hunan Provincial grants (2018SK1030, 2018DK2016, 2019SK1015, 2019RS2005) to K.X. Z.H. and H.G. H.G. was also supported by the Innovation-Driven Project of Central South University (2020CX042). N.J.B. E.S. S.A. and D.E. was supported by the State Government of Victoria (Department of Health and Human Services, Melbourne Genomics Health Alliance). J.M.M. and F.S. are supported by the Swiss National Science Foundation (310030_185292). W.K.C. is supported by grants from the Simons Foundation and the JPB Foundation. E.E.E. is an investigator of the Howard Hughes Medical Institute.

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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10.1016/j.ajhg.2020.10.002

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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., ... Xia, K. (2020). NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism. American journal of human genetics, 107(5), 963-976. https://doi.org/10.1016/j.ajhg.2020.10.002

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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.",

keywords = "NCKAP1, autism spectrum disorder, de novo variants, disruptive variant, genotype-phenotype correlation, neurodevelopmental disorder",

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

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year = "2020",

month = nov,

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doi = "10.1016/j.ajhg.2020.10.002",

language = "English (US)",

volume = "107",

pages = "963--976",

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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 & Xia, K 2020, 'NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism', American journal of human genetics, vol. 107, no. 5, pp. 963-976. https://doi.org/10.1016/j.ajhg.2020.10.002

TY - JOUR

T1 - NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism

AU - Guo, Hui

AU - Zhang, Qiumeng

AU - Dai, Rujia

AU - Yu, Bin

AU - Hoekzema, Kendra

AU - Tan, Jieqiong

AU - Tan, Senwei

AU - Jia, Xiangbin

AU - Chung, Wendy K.

AU - Hernan, Rebecca

AU - Alkuraya, Fowzan S.

AU - Alsulaiman, Ahood

AU - Al-Muhaizea, Mohammad A.

AU - Lesca, Gaetan

AU - Pons, Linda

AU - Labalme, Audrey

AU - Laux, Linda

AU - Bryant, Emily

AU - Brown, Natasha J.

AU - Savva, Elena

AU - Ayres, Samantha

AU - Eratne, Dhamidhu

AU - Peeters, Hilde

AU - Bilan, Frédéric

AU - Letienne-Cejudo, Lucile

AU - Gilbert-Dussardier, Brigitte

AU - Ruiz-Arana, Inge Lore

AU - Merlini, Jenny Meylan

AU - Boizot, Alexia

AU - Bartoloni, Lucia

AU - Santoni, Federico

AU - Karlowicz, Danielle

AU - McDonald, Marie

AU - Wu, Huidan

AU - Hu, Zhengmao

AU - Chen, Guodong

AU - Ou, Jianjun

AU - Brasch-Andersen, Charlotte

AU - Fagerberg, Christina R.

AU - Dreyer, Inken

AU - chun-hui Tsai, Anne

AU - Slegesky, Valerie

AU - McGee, Rose B.

AU - Daniels, Brina

AU - Sellars, Elizabeth A.

AU - Carpenter, Lori A.

AU - Schaefer, Bradley

AU - Sacoto, Maria J.Guillen

AU - Begtrup, Amber

AU - Schnur, Rhonda E.

AU - Punj, Sumit

AU - Wentzensen, Ingrid M.

AU - Rhodes, Lindsay

AU - Pan, Qian

AU - Bernier, Raphael A.

AU - Chen, Chao

AU - Eichler, Evan E.

AU - Xia, Kun

PY - 2020/11/5

Y1 - 2020/11/5

N2 - 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.

AB - 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.

KW - NCKAP1

KW - autism spectrum disorder

KW - de novo variants

KW - disruptive variant

KW - genotype-phenotype correlation

KW - neurodevelopmental disorder

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

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