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 Ringmann Fagerberg, Lone W Laulund, Giovanna Pellecchia, Sylvia Lamoureux, Charu Deshpande, Jill Clayton-Smith, Ann C White, Susan Leather & 64 andre John 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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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. 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 neurodevelopmental disorder 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 neurodevelopmental disorder subjects (p=0.002) compared with 44,085 population-based controls. Frequent phenotypes observed in individuals with such deletions included Autism Spectrum Disorders (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 neurodevelopmental disorders, 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.
OriginalsprogEngelsk
TidsskriftHuman Molecular Genetics
Vol/bind23
Udgave nummer10
Sider (fra-til)2752-2768
ISSN0964-6906
DOI
StatusUdgivet - 14. jan. 2014

Fingeraftryk

Protein Isoforms
Language Development Disorders
Population Control
Transcription Initiation Site
Neocortex
Psychopathology
Neuroglia
Vertebrates
RNA
Mutation
Autism Spectrum Disorder
Datasets

Citer dette

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 Ringmann ; 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 ; Della Monica, Matteo ; 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. I: Human Molecular Genetics. 2014 ; Bind 23, Nr. 10. s. 2752-2768.
@article{d617e94495e34e2086568ea74a5c3ed2,
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. 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 neurodevelopmental disorder 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 neurodevelopmental disorder subjects (p=0.002) compared with 44,085 population-based controls. Frequent phenotypes observed in individuals with such deletions included Autism Spectrum Disorders (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 neurodevelopmental disorders, 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 Fagerberg, {Christina Ringmann} 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 Bai-Lin Wu and Musumeci, {Sebastiano Antonino} and Corrado Romano and Diana Postorivo and Nardone, {Anna M} and {Della Monica}, Matteo 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}",
note = ".",
year = "2014",
month = "1",
day = "14",
doi = "10.1093/hmg/ddt669",
language = "English",
volume = "23",
pages = "2752--2768",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Heinemann",
number = "10",

}

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, CR, 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, B-L, Musumeci, SA, Romano, C, Postorivo, D, Nardone, AM, Della Monica, M, 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, bind 23, nr. 10, s. 2752-2768. 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 Ringmann; 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; Della Monica, Matteo; 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.

I: Human Molecular Genetics, Bind 23, Nr. 10, 14.01.2014, s. 2752-2768.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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 Ringmann

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 - Della Monica, Matteo

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

N1 - .

PY - 2014/1/14

Y1 - 2014/1/14

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. 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 neurodevelopmental disorder 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 neurodevelopmental disorder subjects (p=0.002) compared with 44,085 population-based controls. Frequent phenotypes observed in individuals with such deletions included Autism Spectrum Disorders (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 neurodevelopmental disorders, 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. 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 neurodevelopmental disorder 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 neurodevelopmental disorder subjects (p=0.002) compared with 44,085 population-based controls. Frequent phenotypes observed in individuals with such deletions included Autism Spectrum Disorders (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 neurodevelopmental disorders, 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.

U2 - 10.1093/hmg/ddt669

DO - 10.1093/hmg/ddt669

M3 - Journal article

VL - 23

SP - 2752

EP - 2768

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 10

ER -