Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries

Michael E. Talkowski, Jill A. Rosenfeld, Ian Blumenthal, Vamsee Pillalamarri, Colby Chiang, Adrian Heilbut, Carl Ernst, Carrie Hanscom, Elizabeth Rossin, Amelia M. Lindgren, Shahrin Pereira, Douglas Ruderfer, Andrew Kirby, Stephan Ripke, David J. Harris, Ji Hyun Lee, Kyungsoo Ha, Hyung Goo Kim, Benjamin D. Solomon, Andrea L. Gropman & 15 others Diane Lucente, Katherine Sims, Toshiro K. Ohsumi, Mark L. Borowsky, Stephanie Loranger, Bradley Quade, Kasper Lage, Judith Miles, Bai Lin Wu, Yiping Shen, Benjamin Neale, Lisa G. Shaffer, Mark J. Daly, Cynthia C. Morton, James F. Gusella

Research output: Contribution to journalArticle

318 Citations (Scopus)

Abstract

Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g.; AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g.; CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g.; TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.

Original languageEnglish (US)
Pages (from-to)525-537
Number of pages13
JournalCell
Volume149
Issue number3
DOIs
StatePublished - Apr 27 2012

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Chromosome Aberrations
Genes
Autistic Disorder
snRNP Core Proteins
Genome-Wide Association Study
Psychiatry
Schizophrenia
Alleles
Neurodevelopmental Disorders

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Talkowski, M. E., Rosenfeld, J. A., Blumenthal, I., Pillalamarri, V., Chiang, C., Heilbut, A., ... Gusella, J. F. (2012). Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell, 149(3), 525-537. https://doi.org/10.1016/j.cell.2012.03.028

Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. / Talkowski, Michael E.; Rosenfeld, Jill A.; Blumenthal, Ian; Pillalamarri, Vamsee; Chiang, Colby; Heilbut, Adrian; Ernst, Carl; Hanscom, Carrie; Rossin, Elizabeth; Lindgren, Amelia M.; Pereira, Shahrin; Ruderfer, Douglas; Kirby, Andrew; Ripke, Stephan; Harris, David J.; Lee, Ji Hyun; Ha, Kyungsoo; Kim, Hyung Goo; Solomon, Benjamin D.; Gropman, Andrea L.; Lucente, Diane; Sims, Katherine; Ohsumi, Toshiro K.; Borowsky, Mark L.; Loranger, Stephanie; Quade, Bradley; Lage, Kasper; Miles, Judith; Wu, Bai Lin; Shen, Yiping; Neale, Benjamin; Shaffer, Lisa G.; Daly, Mark J.; Morton, Cynthia C.; Gusella, James F.

In: Cell, Vol. 149, No. 3, 27.04.2012, p. 525-537.

Research output: Contribution to journalArticle

Talkowski, ME, Rosenfeld, JA, Blumenthal, I, Pillalamarri, V, Chiang, C, Heilbut, A, Ernst, C, Hanscom, C, Rossin, E, Lindgren, AM, Pereira, S, Ruderfer, D, Kirby, A, Ripke, S, Harris, DJ, Lee, JH, Ha, K, Kim, HG, Solomon, BD, Gropman, AL, Lucente, D, Sims, K, Ohsumi, TK, Borowsky, ML, Loranger, S, Quade, B, Lage, K, Miles, J, Wu, BL, Shen, Y, Neale, B, Shaffer, LG, Daly, MJ, Morton, CC & Gusella, JF 2012, 'Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries', Cell, vol. 149, no. 3, pp. 525-537. https://doi.org/10.1016/j.cell.2012.03.028
Talkowski ME, Rosenfeld JA, Blumenthal I, Pillalamarri V, Chiang C, Heilbut A et al. Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell. 2012 Apr 27;149(3):525-537. https://doi.org/10.1016/j.cell.2012.03.028
Talkowski, Michael E. ; Rosenfeld, Jill A. ; Blumenthal, Ian ; Pillalamarri, Vamsee ; Chiang, Colby ; Heilbut, Adrian ; Ernst, Carl ; Hanscom, Carrie ; Rossin, Elizabeth ; Lindgren, Amelia M. ; Pereira, Shahrin ; Ruderfer, Douglas ; Kirby, Andrew ; Ripke, Stephan ; Harris, David J. ; Lee, Ji Hyun ; Ha, Kyungsoo ; Kim, Hyung Goo ; Solomon, Benjamin D. ; Gropman, Andrea L. ; Lucente, Diane ; Sims, Katherine ; Ohsumi, Toshiro K. ; Borowsky, Mark L. ; Loranger, Stephanie ; Quade, Bradley ; Lage, Kasper ; Miles, Judith ; Wu, Bai Lin ; Shen, Yiping ; Neale, Benjamin ; Shaffer, Lisa G. ; Daly, Mark J. ; Morton, Cynthia C. ; Gusella, James F. / Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. In: Cell. 2012 ; Vol. 149, No. 3. pp. 525-537.
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AU - Heilbut, Adrian

AU - Ernst, Carl

AU - Hanscom, Carrie

AU - Rossin, Elizabeth

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AU - Pereira, Shahrin

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AU - Kirby, Andrew

AU - Ripke, Stephan

AU - Harris, David J.

AU - Lee, Ji Hyun

AU - Ha, Kyungsoo

AU - Kim, Hyung Goo

AU - Solomon, Benjamin D.

AU - Gropman, Andrea L.

AU - Lucente, Diane

AU - Sims, Katherine

AU - Ohsumi, Toshiro K.

AU - Borowsky, Mark L.

AU - Loranger, Stephanie

AU - Quade, Bradley

AU - Lage, Kasper

AU - Miles, Judith

AU - Wu, Bai Lin

AU - Shen, Yiping

AU - Neale, Benjamin

AU - Shaffer, Lisa G.

AU - Daly, Mark J.

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AU - Gusella, James F.

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