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.
N1 - Funding Information:
We would like to thank all the individuals and families for their participation in this study. We also thank D. Kunig, B. Bunke, D.J. Cutler, M.K. Rudd, M.R. Rossi, M. Hegde, C.T. Stauss, A. Moreno De Luca, and J.F. Cubells for technical and editorial assistance. This work was funded in part by NIH grants MH074090 (D.H.L. and C.L.M.), HD064525 (D.H.L. and C.L.M.), MH080583 (J.G.M.), MH080129 (S.T.W.), and MH071425 (K. Stefansson). The SGENE project was sponsored by EU grant LSHM-CT-2006-037761 (Project SGENE).
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.
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U2 - 10.1016/j.ajhg.2010.10.004
DO - 10.1016/j.ajhg.2010.10.004
M3 - Article
C2 - 21055719
AN - SCOPUS:78249281977
SN - 0002-9297
VL - 87
SP - 618
EP - 630
JO - American journal of human genetics
JF - American journal of human genetics
IS - 5
ER -