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 language | English (US) |
|---|---|
| Article number | ddt669 |
| Pages (from-to) | 2752-2768 |
| Number of pages | 17 |
| Journal | Human Molecular Genetics |
| Volume | 23 |
| Issue number | 10 |
| DOIs | |
| State | Published - 2014 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
- Molecular Biology
- Medicine(all)
Cite this
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 journal › Article
}
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.
UR - http://www.scopus.com/inward/record.url?scp=84898772564&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84898772564&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddt669
DO - 10.1093/hmg/ddt669
M3 - Article
C2 - 24381304
AN - SCOPUS:84898772564
VL - 23
SP - 2752
EP - 2768
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 10
M1 - ddt669
ER -