Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus

Gea Beunders; Els Voorhoeve; Christelle Golzio; Luba M. Pardo; Jill A. Rosenfeld; Michael E. Talkowski; Ingrid Simonic; Anath C. Lionel; Sarah Vergult; Robert E. Pyatt; Jiddeke Van De Kamp; Aggie Nieuwint; Marjan M. Weiss; Patrizia Rizzu; Lucilla E.N.I. Verwer; Rosalina M.L. Van Spaendonk; Yiping Shen; Bai Lin Wu; Tingting Yu; Yongguo Yu; Colby Chiang; James F. Gusella; Amelia M. Lindgren; Cynthia C. Morton; Ellen Van Binsbergen; Saskia Bulk; Els Van Rossem; Olivier Vanakker; Ruth Armstrong; Soo Mi Park; Lynn Greenhalgh; Una Maye; Nicholas J. Neill; Kristin M. Abbott; Susan Sell; Roger Ladda; Darren M. Farber; Patricia I. Bader; Tom Cushing; Joanne M. Drautz; Laura Konczal; Patricia Nash; Emily De Los Reyes; Melissa T. Carter; Elizabeth Hopkins; Christian R. Marshall; Lucy R. Osborne; Karen W. Gripp; Devon Lamb Thrush; Sayaka Hashimoto; Julie M. Gastier-Foster; Caroline Astbury; Bauke Ylstra; Hanne Meijers-Heijboer; Danielle Posthuma; Björn Menten; Geert Mortier; Stephen W. Scherer; Evan E. Eichler; Santhosh Girirajan; Nicholas Katsanis; Alexander J. Groffen; Erik A. Sistermans

doi:10.1016/j.ajhg.2012.12.011

Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus

Gea Beunders, Els Voorhoeve, Christelle Golzio, Luba M. Pardo, Jill A. Rosenfeld, Michael E. Talkowski, Ingrid Simonic, Anath C. Lionel, Sarah Vergult, Robert E. Pyatt, Jiddeke Van De Kamp, Aggie Nieuwint, Marjan M. Weiss, Patrizia Rizzu, Lucilla E.N.I. Verwer, Rosalina M.L. Van Spaendonk, Yiping Shen, Bai Lin Wu, Tingting Yu, Yongguo YuColby Chiang, James F. Gusella, Amelia M. Lindgren, Cynthia C. Morton, Ellen Van Binsbergen, Saskia Bulk, Els Van Rossem, Olivier Vanakker, Ruth Armstrong, Soo Mi Park, Lynn Greenhalgh, Una Maye, Nicholas J. Neill, Kristin M. Abbott, Susan Sell, Roger Ladda, Darren M. Farber, Patricia I. Bader, Tom Cushing, Joanne M. Drautz, Laura Konczal, Patricia Nash, Emily De Los Reyes, Melissa T. Carter, Elizabeth Hopkins, Christian R. Marshall, Lucy R. Osborne, Karen W. Gripp, Devon Lamb Thrush, Sayaka Hashimoto, Julie M. Gastier-Foster, Caroline Astbury, Bauke Ylstra, Hanne Meijers-Heijboer, Danielle Posthuma, Björn Menten, Geert Mortier, Stephen W. Scherer, Evan E. Eichler, Santhosh Girirajan, Nicholas Katsanis, Alexander J. Groffen, Erik A. Sistermans

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Abstract

Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3′ AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.

Original language	English (US)
Pages (from-to)	210-220
Number of pages	11
Journal	American Journal of Human Genetics
Volume	92
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2012.12.011
State	Published - Feb 7 2013

All Science Journal Classification (ASJC) codes

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2012.12.011

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Beunders, G., Voorhoeve, E., Golzio, C., Pardo, L. M., Rosenfeld, J. A., Talkowski, M. E., Simonic, I., Lionel, A. C., Vergult, S., Pyatt, R. E., Van De Kamp, J., Nieuwint, A., Weiss, M. M., Rizzu, P., Verwer, L. E. N. I., Van Spaendonk, R. M. L., Shen, Y., Wu, B. L., Yu, T., ... Sistermans, E. A. (2013). Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus. American Journal of Human Genetics, 92(2), 210-220. https://doi.org/10.1016/j.ajhg.2012.12.011

@article{d822b5b8fb0e4bca99e6370d2ae42cee,

title = "Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus",

abstract = "Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3′ AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.",

author = "Gea Beunders and Els Voorhoeve and Christelle Golzio and Pardo, {Luba M.} and Rosenfeld, {Jill A.} and Talkowski, {Michael E.} and Ingrid Simonic and Lionel, {Anath C.} and Sarah Vergult and Pyatt, {Robert E.} and {Van De Kamp}, Jiddeke and Aggie Nieuwint and Weiss, {Marjan M.} and Patrizia Rizzu and Verwer, {Lucilla E.N.I.} and {Van Spaendonk}, {Rosalina M.L.} and Yiping Shen and Wu, {Bai Lin} and Tingting Yu and Yongguo Yu and Colby Chiang and Gusella, {James F.} and Lindgren, {Amelia M.} and Morton, {Cynthia C.} and {Van Binsbergen}, Ellen and Saskia Bulk and {Van Rossem}, Els and Olivier Vanakker and Ruth Armstrong and Park, {Soo Mi} and Lynn Greenhalgh and Una Maye and Neill, {Nicholas J.} and Abbott, {Kristin M.} and Susan Sell and Roger Ladda and Farber, {Darren M.} and Bader, {Patricia I.} and Tom Cushing and Drautz, {Joanne M.} and Laura Konczal and Patricia Nash and {De Los Reyes}, Emily and Carter, {Melissa T.} and Elizabeth Hopkins and Marshall, {Christian R.} and Osborne, {Lucy R.} and Gripp, {Karen W.} and Thrush, {Devon Lamb} and Sayaka Hashimoto and Gastier-Foster, {Julie M.} and Caroline Astbury and Bauke Ylstra and Hanne Meijers-Heijboer and Danielle Posthuma and Bj{\"o}rn Menten and Geert Mortier and Scherer, {Stephen W.} and Eichler, {Evan E.} and Santhosh Girirajan and Nicholas Katsanis and Groffen, {Alexander J.} and Sistermans, {Erik A.}",

note = "Funding Information: The authors would like to thank all patients and their families for their major contribution; without them, we would not have been able to describe this syndrome. We thank Marjolein van de Mespel, Desiree Linders, Stefan Strijbis, Amanda Clarkson, and Carrie Hanscom for their contribution to the laboratory work in this project and Shahrin Pereira for clinical coordination. This study made use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available at www.wtccc.org.uk . Funding for this project was provided by the Wellcome Trust under awards 076113 and 085475, as well as by the National Institutes of Health (GM061354, HD065286, and MH095867), the American Heart Association (11POST7160006), and a Distinguished Brumley Professorship to N.K. Evan Eichler is a Howards Hughes Medical Institute investigator. The authors thank Klaas Kok for making available the control data of The Low-Lands Consortium for this study and for developing the custom design of the 180K Agilent oligo array used in The Netherlands. We acknowledge Soheil Shams from BioDiscovery for his help with processing the different array data files. J.A.R. and N.J.N. are employees of Signature Genomic Laboratories, a subsidiary of PerkinElmer, and E.E.E. is on the scientific advisory boards for Pacific Biosciences, SynapDx, and DNAnexus. ",

year = "2013",

month = feb,

day = "7",

doi = "10.1016/j.ajhg.2012.12.011",

language = "English (US)",

volume = "92",

pages = "210--220",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "2",

}

Beunders, G, Voorhoeve, E, Golzio, C, Pardo, LM, Rosenfeld, JA, Talkowski, ME, Simonic, I, Lionel, AC, Vergult, S, Pyatt, RE, Van De Kamp, J, Nieuwint, A, Weiss, MM, Rizzu, P, Verwer, LENI, Van Spaendonk, RML, Shen, Y, Wu, BL, Yu, T, Yu, Y, Chiang, C, Gusella, JF, Lindgren, AM, Morton, CC, Van Binsbergen, E, Bulk, S, Van Rossem, E, Vanakker, O, Armstrong, R, Park, SM, Greenhalgh, L, Maye, U, Neill, NJ, Abbott, KM, Sell, S, Ladda, R, Farber, DM, Bader, PI, Cushing, T, Drautz, JM, Konczal, L, Nash, P, De Los Reyes, E, Carter, MT, Hopkins, E, Marshall, CR, Osborne, LR, Gripp, KW, Thrush, DL, Hashimoto, S, Gastier-Foster, JM, Astbury, C, Ylstra, B, Meijers-Heijboer, H, Posthuma, D, Menten, B, Mortier, G, Scherer, SW, Eichler, EE, Girirajan, S, Katsanis, N, Groffen, AJ & Sistermans, EA 2013, 'Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus', American Journal of Human Genetics, vol. 92, no. 2, pp. 210-220. https://doi.org/10.1016/j.ajhg.2012.12.011

TY - JOUR

T1 - Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus

AU - Beunders, Gea

AU - Voorhoeve, Els

AU - Golzio, Christelle

AU - Pardo, Luba M.

AU - Rosenfeld, Jill A.

AU - Talkowski, Michael E.

AU - Simonic, Ingrid

AU - Lionel, Anath C.

AU - Vergult, Sarah

AU - Pyatt, Robert E.

AU - Van De Kamp, Jiddeke

AU - Nieuwint, Aggie

AU - Weiss, Marjan M.

AU - Rizzu, Patrizia

AU - Verwer, Lucilla E.N.I.

AU - Van Spaendonk, Rosalina M.L.

AU - Shen, Yiping

AU - Wu, Bai Lin

AU - Yu, Tingting

AU - Yu, Yongguo

AU - Chiang, Colby

AU - Gusella, James F.

AU - Lindgren, Amelia M.

AU - Morton, Cynthia C.

AU - Van Binsbergen, Ellen

AU - Bulk, Saskia

AU - Van Rossem, Els

AU - Vanakker, Olivier

AU - Armstrong, Ruth

AU - Park, Soo Mi

AU - Greenhalgh, Lynn

AU - Maye, Una

AU - Neill, Nicholas J.

AU - Abbott, Kristin M.

AU - Sell, Susan

AU - Ladda, Roger

AU - Farber, Darren M.

AU - Bader, Patricia I.

AU - Cushing, Tom

AU - Drautz, Joanne M.

AU - Konczal, Laura

AU - Nash, Patricia

AU - De Los Reyes, Emily

AU - Carter, Melissa T.

AU - Hopkins, Elizabeth

AU - Marshall, Christian R.

AU - Osborne, Lucy R.

AU - Gripp, Karen W.

AU - Thrush, Devon Lamb

AU - Hashimoto, Sayaka

AU - Gastier-Foster, Julie M.

AU - Astbury, Caroline

AU - Ylstra, Bauke

AU - Meijers-Heijboer, Hanne

AU - Posthuma, Danielle

AU - Menten, Björn

AU - Mortier, Geert

AU - Scherer, Stephen W.

AU - Eichler, Evan E.

AU - Girirajan, Santhosh

AU - Katsanis, Nicholas

AU - Groffen, Alexander J.

AU - Sistermans, Erik A.

N1 - Funding Information: The authors would like to thank all patients and their families for their major contribution; without them, we would not have been able to describe this syndrome. We thank Marjolein van de Mespel, Desiree Linders, Stefan Strijbis, Amanda Clarkson, and Carrie Hanscom for their contribution to the laboratory work in this project and Shahrin Pereira for clinical coordination. This study made use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available at www.wtccc.org.uk . Funding for this project was provided by the Wellcome Trust under awards 076113 and 085475, as well as by the National Institutes of Health (GM061354, HD065286, and MH095867), the American Heart Association (11POST7160006), and a Distinguished Brumley Professorship to N.K. Evan Eichler is a Howards Hughes Medical Institute investigator. The authors thank Klaas Kok for making available the control data of The Low-Lands Consortium for this study and for developing the custom design of the 180K Agilent oligo array used in The Netherlands. We acknowledge Soheil Shams from BioDiscovery for his help with processing the different array data files. J.A.R. and N.J.N. are employees of Signature Genomic Laboratories, a subsidiary of PerkinElmer, and E.E.E. is on the scientific advisory boards for Pacific Biosciences, SynapDx, and DNAnexus.

PY - 2013/2/7

Y1 - 2013/2/7

N2 - Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3′ AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.

AB - Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3′ AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.

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UR - http://www.scopus.com/inward/citedby.url?scp=84873732078&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2012.12.011

DO - 10.1016/j.ajhg.2012.12.011

M3 - Article

C2 - 23332918

AN - SCOPUS:84873732078

SN - 0002-9297

VL - 92

SP - 210

EP - 220

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -

Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus

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