Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia

Daniel Moreno-De-Luca, Jennifer G. Mulle, Erin B. Kaminsky, Stephan J. Sanders, Scott M. Myers, Margaret P. Adam, Amy T. Pakula, Nancy J. Eisenhauer, Kim Uhas, Luann Weik, Lisa Guy, Melanie E. Care, Chantal F. Morel, Charlotte Boni, Bonnie Anne Salbert, Ashadeep Chandrareddy, Laurie A. Demmer, Eva W.C. Chow, Urvashi Surti, Swaroop AradhyaDiane L. Pickering, Denae M. Golden, Warren G. Sanger, Emily Aston, Arthur R. Brothman, Troy J. Gliem, Erik C. Thorland, Todd Ackley, Ram Iyer, Shuwen Huang, John C. Barber, John A. Crolla, Stephen T. Warren, Christa L. Martin, David H. Ledbetter

Research output: Contribution to journalArticle

199 Citations (Scopus)

Abstract

Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10 -5). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.

Original languageEnglish (US)
Pages (from-to)618-630
Number of pages13
JournalAmerican Journal of Human Genetics
Volume87
Issue number5
DOIs
StatePublished - Nov 12 2010

Fingerprint

Autistic Disorder
Schizophrenia
Megalencephaly
Genes
Kidney
Mutation
Autism Spectrum Disorder
Brain
Renal cysts and diabetes syndrome
Neurodevelopmental Disorders

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Moreno-De-Luca, D., Mulle, J. G., Kaminsky, E. B., Sanders, S. J., Myers, S. M., Adam, M. P., ... Ledbetter, D. H. (2010). Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia. American Journal of Human Genetics, 87(5), 618-630. https://doi.org/10.1016/j.ajhg.2010.10.004

Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia. / Moreno-De-Luca, Daniel; Mulle, Jennifer G.; Kaminsky, Erin B.; Sanders, Stephan J.; Myers, Scott M.; Adam, Margaret P.; Pakula, Amy T.; Eisenhauer, Nancy J.; Uhas, Kim; Weik, Luann; Guy, Lisa; Care, Melanie E.; Morel, Chantal F.; Boni, Charlotte; Salbert, Bonnie Anne; Chandrareddy, Ashadeep; Demmer, Laurie A.; Chow, Eva W.C.; Surti, Urvashi; Aradhya, Swaroop; Pickering, Diane L.; Golden, Denae M.; Sanger, Warren G.; Aston, Emily; Brothman, Arthur R.; Gliem, Troy J.; Thorland, Erik C.; Ackley, Todd; Iyer, Ram; Huang, Shuwen; Barber, John C.; Crolla, John A.; Warren, Stephen T.; Martin, Christa L.; Ledbetter, David H.

In: American Journal of Human Genetics, Vol. 87, No. 5, 12.11.2010, p. 618-630.

Research output: Contribution to journalArticle

Moreno-De-Luca, D, Mulle, JG, Kaminsky, EB, Sanders, SJ, Myers, SM, Adam, MP, Pakula, AT, Eisenhauer, NJ, Uhas, K, Weik, L, Guy, L, Care, ME, Morel, CF, Boni, C, Salbert, BA, Chandrareddy, A, Demmer, LA, Chow, EWC, Surti, U, Aradhya, S, Pickering, DL, Golden, DM, Sanger, WG, Aston, E, Brothman, AR, Gliem, TJ, Thorland, EC, Ackley, T, Iyer, R, Huang, S, Barber, JC, Crolla, JA, Warren, ST, Martin, CL & Ledbetter, DH 2010, 'Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia', American Journal of Human Genetics, vol. 87, no. 5, pp. 618-630. https://doi.org/10.1016/j.ajhg.2010.10.004
Moreno-De-Luca, Daniel ; Mulle, Jennifer G. ; Kaminsky, Erin B. ; Sanders, Stephan J. ; Myers, Scott M. ; Adam, Margaret P. ; Pakula, Amy T. ; Eisenhauer, Nancy J. ; Uhas, Kim ; Weik, Luann ; Guy, Lisa ; Care, Melanie E. ; Morel, Chantal F. ; Boni, Charlotte ; Salbert, Bonnie Anne ; Chandrareddy, Ashadeep ; Demmer, Laurie A. ; Chow, Eva W.C. ; Surti, Urvashi ; Aradhya, Swaroop ; Pickering, Diane L. ; Golden, Denae M. ; Sanger, Warren G. ; Aston, Emily ; Brothman, Arthur R. ; Gliem, Troy J. ; Thorland, Erik C. ; Ackley, Todd ; Iyer, Ram ; Huang, Shuwen ; Barber, John C. ; Crolla, John A. ; Warren, Stephen T. ; Martin, Christa L. ; Ledbetter, David H. / Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia. In: American Journal of Human Genetics. 2010 ; Vol. 87, No. 5. pp. 618-630.
@article{c24f2ecb4b074c42b2ad3ce619d43350,
title = "Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia",
abstract = "Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10 -5). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.",
author = "Daniel Moreno-De-Luca and Mulle, {Jennifer G.} and Kaminsky, {Erin B.} and Sanders, {Stephan J.} and Myers, {Scott M.} and Adam, {Margaret P.} and Pakula, {Amy T.} and Eisenhauer, {Nancy J.} and Kim Uhas and Luann Weik and Lisa Guy and Care, {Melanie E.} and Morel, {Chantal F.} and Charlotte Boni and Salbert, {Bonnie Anne} and Ashadeep Chandrareddy and Demmer, {Laurie A.} and Chow, {Eva W.C.} and Urvashi Surti and Swaroop Aradhya and Pickering, {Diane L.} and Golden, {Denae M.} and Sanger, {Warren G.} and Emily Aston and Brothman, {Arthur R.} and Gliem, {Troy J.} and Thorland, {Erik C.} and Todd Ackley and Ram Iyer and Shuwen Huang and Barber, {John C.} and Crolla, {John A.} and Warren, {Stephen T.} and Martin, {Christa L.} and Ledbetter, {David H.}",
year = "2010",
month = "11",
day = "12",
doi = "10.1016/j.ajhg.2010.10.004",
language = "English (US)",
volume = "87",
pages = "618--630",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "5",

}

TY - JOUR

T1 - Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia

AU - Moreno-De-Luca, Daniel

AU - Mulle, Jennifer G.

AU - Kaminsky, Erin B.

AU - Sanders, Stephan J.

AU - Myers, Scott M.

AU - Adam, Margaret P.

AU - Pakula, Amy T.

AU - Eisenhauer, Nancy J.

AU - Uhas, Kim

AU - Weik, Luann

AU - Guy, Lisa

AU - Care, Melanie E.

AU - Morel, Chantal F.

AU - Boni, Charlotte

AU - Salbert, Bonnie Anne

AU - Chandrareddy, Ashadeep

AU - Demmer, Laurie A.

AU - Chow, Eva W.C.

AU - Surti, Urvashi

AU - Aradhya, Swaroop

AU - Pickering, Diane L.

AU - Golden, Denae M.

AU - Sanger, Warren G.

AU - Aston, Emily

AU - Brothman, Arthur R.

AU - Gliem, Troy J.

AU - Thorland, Erik C.

AU - Ackley, Todd

AU - Iyer, Ram

AU - Huang, Shuwen

AU - Barber, John C.

AU - Crolla, John A.

AU - Warren, Stephen T.

AU - Martin, Christa L.

AU - Ledbetter, David H.

PY - 2010/11/12

Y1 - 2010/11/12

N2 - Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10 -5). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.

AB - Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10 -5). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.

UR - http://www.scopus.com/inward/record.url?scp=78249281977&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78249281977&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2010.10.004

DO - 10.1016/j.ajhg.2010.10.004

M3 - Article

C2 - 21055719

AN - SCOPUS:78249281977

VL - 87

SP - 618

EP - 630

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 5

ER -