Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes

Anath C. Lionel, Kristiina Tammimies, Andrea K. Vaags, Jill A. Rosenfeld, Joo Wook Ahn, Daniele Merico, Abdul Noor, Cassandra K. Runke, Vamsee K. Pillalamarri, Melissa T. Carter, Matthew J. Gazzellone, Bhooma Thiruvahindrapuram, Christina Fagerberg, Lone W. Laulund, Giovanna Pellecchia, Sylvia Lamoureux, Charu Deshpande, Jill Clayton-Smith, Ann C. White, Susan LeatherJohn Trounce, H. Melanie Bedford, Eli Hatchwell, Peggy S. Eis, Ryan K C Yuen, Susan Walker, Mohammed Uddin, Michael T. Geraghty, Sarah M. Nikkel, Eva M. Tomiak, Bridget A. Fernandez, Noam Soreni, Jennifer Crosbie, Paul D. Arnold, Russell J. Schachar, Wendy Roberts, Andrew D. Paterson, Joyce So, Peter Szatmari, Christina Chrysler, Marc Woodbury-Smith, R. Brian Lowry, Lonnie Zwaigenbaum, Divya Mandyam, John Wei, Jeffrey R. MacDonald, Jennifer L. Howe, Thomas Nalpathamkalam, Zhuozhi Wang, Daniel Tolson, David S. Cobb, Timothy M. Wilks, Mark J. Sorensen, Patricia I. Bader, Yu An, Bai Lin Wu, Sebastiano Antonino Musumeci, Corrado Romano, Diana Postorivo, Anna M. Nardone, Matteo Della Monica, Gioacchino Scarano, Leonardo Zoccante, Francesca Novara, Orsetta Zuffardi, Roberto Ciccone, Vincenzo Antona, Massimo Carella, Leopoldo Zelante, Pietro Cavalli, Carlo Poggiani, Ugo Cavallari, Bob Argiropoulos, Judy Chernos, Charlotte Brasch-Andersen, Marsha Speevak, Marco Fichera, Caroline Mackie Ogilvie, Yiping Shen, Jennelle C. Hodge, Michael E. Talkowski, Dimitri J. Stavropoulos, Christian R. Marshall, Stephen W. Scherer

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.

Original languageEnglish (US)
Article numberddt669
Pages (from-to)2752-2768
Number of pages17
JournalHuman Molecular Genetics
Volume23
Issue number10
DOIs
StatePublished - 2014

Fingerprint

Attention Deficit Disorder with Hyperactivity
Phenotype
Protein Isoforms
Brain
Language Development Disorders
Cerebellar Cortex
Population Control
Transcription Initiation Site
Obsessive-Compulsive Disorder
Neocortex
Psychopathology
Neuroglia
Vertebrates
Anxiety
Genome
RNA
Mutation
Autism Spectrum Disorder
Neurodevelopmental Disorders

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology
  • Medicine(all)

Cite this

Lionel, A. C., Tammimies, K., Vaags, A. K., Rosenfeld, J. A., Ahn, J. W., Merico, D., ... Scherer, S. W. (2014). Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes. Human Molecular Genetics, 23(10), 2752-2768. [ddt669]. https://doi.org/10.1093/hmg/ddt669

Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes. / Lionel, Anath C.; Tammimies, Kristiina; Vaags, Andrea K.; Rosenfeld, Jill A.; Ahn, Joo Wook; Merico, Daniele; Noor, Abdul; Runke, Cassandra K.; Pillalamarri, Vamsee K.; Carter, Melissa T.; Gazzellone, Matthew J.; Thiruvahindrapuram, Bhooma; Fagerberg, Christina; Laulund, Lone W.; Pellecchia, Giovanna; Lamoureux, Sylvia; Deshpande, Charu; Clayton-Smith, Jill; White, Ann C.; Leather, Susan; Trounce, John; Bedford, H. Melanie; Hatchwell, Eli; Eis, Peggy S.; Yuen, Ryan K C; Walker, Susan; Uddin, Mohammed; Geraghty, Michael T.; Nikkel, Sarah M.; Tomiak, Eva M.; Fernandez, Bridget A.; Soreni, Noam; Crosbie, Jennifer; Arnold, Paul D.; Schachar, Russell J.; Roberts, Wendy; Paterson, Andrew D.; So, Joyce; Szatmari, Peter; Chrysler, Christina; Woodbury-Smith, Marc; Lowry, R. Brian; Zwaigenbaum, Lonnie; Mandyam, Divya; Wei, John; MacDonald, Jeffrey R.; Howe, Jennifer L.; Nalpathamkalam, Thomas; Wang, Zhuozhi; Tolson, Daniel; Cobb, David S.; Wilks, Timothy M.; Sorensen, Mark J.; Bader, Patricia I.; An, Yu; Wu, Bai Lin; Musumeci, Sebastiano Antonino; Romano, Corrado; Postorivo, Diana; Nardone, Anna M.; Monica, Matteo Della; Scarano, Gioacchino; Zoccante, Leonardo; Novara, Francesca; Zuffardi, Orsetta; Ciccone, Roberto; Antona, Vincenzo; Carella, Massimo; Zelante, Leopoldo; Cavalli, Pietro; Poggiani, Carlo; Cavallari, Ugo; Argiropoulos, Bob; Chernos, Judy; Brasch-Andersen, Charlotte; Speevak, Marsha; Fichera, Marco; Ogilvie, Caroline Mackie; Shen, Yiping; Hodge, Jennelle C.; Talkowski, Michael E.; Stavropoulos, Dimitri J.; Marshall, Christian R.; Scherer, Stephen W.

In: Human Molecular Genetics, Vol. 23, No. 10, ddt669, 2014, p. 2752-2768.

Research output: Contribution to journalArticle

Lionel, AC, Tammimies, K, Vaags, AK, Rosenfeld, JA, Ahn, JW, Merico, D, Noor, A, Runke, CK, Pillalamarri, VK, Carter, MT, Gazzellone, MJ, Thiruvahindrapuram, B, Fagerberg, C, Laulund, LW, Pellecchia, G, Lamoureux, S, Deshpande, C, Clayton-Smith, J, White, AC, Leather, S, Trounce, J, Bedford, HM, Hatchwell, E, Eis, PS, Yuen, RKC, Walker, S, Uddin, M, Geraghty, MT, Nikkel, SM, Tomiak, EM, Fernandez, BA, Soreni, N, Crosbie, J, Arnold, PD, Schachar, RJ, Roberts, W, Paterson, AD, So, J, Szatmari, P, Chrysler, C, Woodbury-Smith, M, Lowry, RB, Zwaigenbaum, L, Mandyam, D, Wei, J, MacDonald, JR, Howe, JL, Nalpathamkalam, T, Wang, Z, Tolson, D, Cobb, DS, Wilks, TM, Sorensen, MJ, Bader, PI, An, Y, Wu, BL, Musumeci, SA, Romano, C, Postorivo, D, Nardone, AM, Monica, MD, Scarano, G, Zoccante, L, Novara, F, Zuffardi, O, Ciccone, R, Antona, V, Carella, M, Zelante, L, Cavalli, P, Poggiani, C, Cavallari, U, Argiropoulos, B, Chernos, J, Brasch-Andersen, C, Speevak, M, Fichera, M, Ogilvie, CM, Shen, Y, Hodge, JC, Talkowski, ME, Stavropoulos, DJ, Marshall, CR & Scherer, SW 2014, 'Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes', Human Molecular Genetics, vol. 23, no. 10, ddt669, pp. 2752-2768. https://doi.org/10.1093/hmg/ddt669
Lionel, Anath C. ; Tammimies, Kristiina ; Vaags, Andrea K. ; Rosenfeld, Jill A. ; Ahn, Joo Wook ; Merico, Daniele ; Noor, Abdul ; Runke, Cassandra K. ; Pillalamarri, Vamsee K. ; Carter, Melissa T. ; Gazzellone, Matthew J. ; Thiruvahindrapuram, Bhooma ; Fagerberg, Christina ; Laulund, Lone W. ; Pellecchia, Giovanna ; Lamoureux, Sylvia ; Deshpande, Charu ; Clayton-Smith, Jill ; White, Ann C. ; Leather, Susan ; Trounce, John ; Bedford, H. Melanie ; Hatchwell, Eli ; Eis, Peggy S. ; Yuen, Ryan K C ; Walker, Susan ; Uddin, Mohammed ; Geraghty, Michael T. ; Nikkel, Sarah M. ; Tomiak, Eva M. ; Fernandez, Bridget A. ; Soreni, Noam ; Crosbie, Jennifer ; Arnold, Paul D. ; Schachar, Russell J. ; Roberts, Wendy ; Paterson, Andrew D. ; So, Joyce ; Szatmari, Peter ; Chrysler, Christina ; Woodbury-Smith, Marc ; Lowry, R. Brian ; Zwaigenbaum, Lonnie ; Mandyam, Divya ; Wei, John ; MacDonald, Jeffrey R. ; Howe, Jennifer L. ; Nalpathamkalam, Thomas ; Wang, Zhuozhi ; Tolson, Daniel ; Cobb, David S. ; Wilks, Timothy M. ; Sorensen, Mark J. ; Bader, Patricia I. ; An, Yu ; Wu, Bai Lin ; Musumeci, Sebastiano Antonino ; Romano, Corrado ; Postorivo, Diana ; Nardone, Anna M. ; Monica, Matteo Della ; Scarano, Gioacchino ; Zoccante, Leonardo ; Novara, Francesca ; Zuffardi, Orsetta ; Ciccone, Roberto ; Antona, Vincenzo ; Carella, Massimo ; Zelante, Leopoldo ; Cavalli, Pietro ; Poggiani, Carlo ; Cavallari, Ugo ; Argiropoulos, Bob ; Chernos, Judy ; Brasch-Andersen, Charlotte ; Speevak, Marsha ; Fichera, Marco ; Ogilvie, Caroline Mackie ; Shen, Yiping ; Hodge, Jennelle C. ; Talkowski, Michael E. ; Stavropoulos, Dimitri J. ; Marshall, Christian R. ; Scherer, Stephen W. / Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 10. pp. 2752-2768.
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title = "Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes",
abstract = "Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.",
author = "Lionel, {Anath C.} and Kristiina Tammimies and Vaags, {Andrea K.} and Rosenfeld, {Jill A.} and Ahn, {Joo Wook} and Daniele Merico and Abdul Noor and Runke, {Cassandra K.} and Pillalamarri, {Vamsee K.} and Carter, {Melissa T.} and Gazzellone, {Matthew J.} and Bhooma Thiruvahindrapuram and Christina Fagerberg and Laulund, {Lone W.} and Giovanna Pellecchia and Sylvia Lamoureux and Charu Deshpande and Jill Clayton-Smith and White, {Ann C.} and Susan Leather and John Trounce and Bedford, {H. Melanie} and Eli Hatchwell and Eis, {Peggy S.} and Yuen, {Ryan K C} and Susan Walker and Mohammed Uddin and Geraghty, {Michael T.} and Nikkel, {Sarah M.} and Tomiak, {Eva M.} and Fernandez, {Bridget A.} and Noam Soreni and Jennifer Crosbie and Arnold, {Paul D.} and Schachar, {Russell J.} and Wendy Roberts and Paterson, {Andrew D.} and Joyce So and Peter Szatmari and Christina Chrysler and Marc Woodbury-Smith and Lowry, {R. Brian} and Lonnie Zwaigenbaum and Divya Mandyam and John Wei and MacDonald, {Jeffrey R.} and Howe, {Jennifer L.} and Thomas Nalpathamkalam and Zhuozhi Wang and Daniel Tolson and Cobb, {David S.} and Wilks, {Timothy M.} and Sorensen, {Mark J.} and Bader, {Patricia I.} and Yu An and Wu, {Bai Lin} and Musumeci, {Sebastiano Antonino} and Corrado Romano and Diana Postorivo and Nardone, {Anna M.} and Monica, {Matteo Della} and Gioacchino Scarano and Leonardo Zoccante and Francesca Novara and Orsetta Zuffardi and Roberto Ciccone and Vincenzo Antona and Massimo Carella and Leopoldo Zelante and Pietro Cavalli and Carlo Poggiani and Ugo Cavallari and Bob Argiropoulos and Judy Chernos and Charlotte Brasch-Andersen and Marsha Speevak and Marco Fichera and Ogilvie, {Caroline Mackie} and Yiping Shen and Hodge, {Jennelle C.} and Talkowski, {Michael E.} and Stavropoulos, {Dimitri J.} and Marshall, {Christian R.} and Scherer, {Stephen W.}",
year = "2014",
doi = "10.1093/hmg/ddt669",
language = "English (US)",
volume = "23",
pages = "2752--2768",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "10",

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TY - JOUR

T1 - Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes

AU - Lionel, Anath C.

AU - Tammimies, Kristiina

AU - Vaags, Andrea K.

AU - Rosenfeld, Jill A.

AU - Ahn, Joo Wook

AU - Merico, Daniele

AU - Noor, Abdul

AU - Runke, Cassandra K.

AU - Pillalamarri, Vamsee K.

AU - Carter, Melissa T.

AU - Gazzellone, Matthew J.

AU - Thiruvahindrapuram, Bhooma

AU - Fagerberg, Christina

AU - Laulund, Lone W.

AU - Pellecchia, Giovanna

AU - Lamoureux, Sylvia

AU - Deshpande, Charu

AU - Clayton-Smith, Jill

AU - White, Ann C.

AU - Leather, Susan

AU - Trounce, John

AU - Bedford, H. Melanie

AU - Hatchwell, Eli

AU - Eis, Peggy S.

AU - Yuen, Ryan K C

AU - Walker, Susan

AU - Uddin, Mohammed

AU - Geraghty, Michael T.

AU - Nikkel, Sarah M.

AU - Tomiak, Eva M.

AU - Fernandez, Bridget A.

AU - Soreni, Noam

AU - Crosbie, Jennifer

AU - Arnold, Paul D.

AU - Schachar, Russell J.

AU - Roberts, Wendy

AU - Paterson, Andrew D.

AU - So, Joyce

AU - Szatmari, Peter

AU - Chrysler, Christina

AU - Woodbury-Smith, Marc

AU - Lowry, R. Brian

AU - Zwaigenbaum, Lonnie

AU - Mandyam, Divya

AU - Wei, John

AU - MacDonald, Jeffrey R.

AU - Howe, Jennifer L.

AU - Nalpathamkalam, Thomas

AU - Wang, Zhuozhi

AU - Tolson, Daniel

AU - Cobb, David S.

AU - Wilks, Timothy M.

AU - Sorensen, Mark J.

AU - Bader, Patricia I.

AU - An, Yu

AU - Wu, Bai Lin

AU - Musumeci, Sebastiano Antonino

AU - Romano, Corrado

AU - Postorivo, Diana

AU - Nardone, Anna M.

AU - Monica, Matteo Della

AU - Scarano, Gioacchino

AU - Zoccante, Leonardo

AU - Novara, Francesca

AU - Zuffardi, Orsetta

AU - Ciccone, Roberto

AU - Antona, Vincenzo

AU - Carella, Massimo

AU - Zelante, Leopoldo

AU - Cavalli, Pietro

AU - Poggiani, Carlo

AU - Cavallari, Ugo

AU - Argiropoulos, Bob

AU - Chernos, Judy

AU - Brasch-Andersen, Charlotte

AU - Speevak, Marsha

AU - Fichera, Marco

AU - Ogilvie, Caroline Mackie

AU - Shen, Yiping

AU - Hodge, Jennelle C.

AU - Talkowski, Michael E.

AU - Stavropoulos, Dimitri J.

AU - Marshall, Christian R.

AU - Scherer, Stephen W.

PY - 2014

Y1 - 2014

N2 - Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.

AB - Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.

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