TY - JOUR
T1 - Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder
AU - Girirajan, Santhosh
AU - Dennis, Megan Y.
AU - Baker, Carl
AU - Malig, Maika
AU - Coe, Bradley P.
AU - Campbell, Catarina D.
AU - Mark, Kenneth
AU - Vu, Tiffany H.
AU - Alkan, Can
AU - Cheng, Ze
AU - Biesecker, Leslie G.
AU - Bernier, Raphael
AU - Eichler, Evan E.
N1 - Funding Information:
We thank Tonia Brown, Emre Karakoc, Nik Krumm, Arthur Ko, Daryl Dhanraj, Jason Lu, John Huddleston, and Ben Nelson for valuable discussions and technical assistance. We also thank the Autism Genetic Resource Exchange (AGRE) for providing DNA samples. We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, and E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base. Approved researchers can obtain the SSC population dataset described in this study by applying at Simons Simplex Collection online (see Web Resources ). M.Y.D. is supported by a US National Institutes of Health (NIH) Ruth L. Kirchstein National Research Service Award (NRSA) Fellowship through Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD071698). C.D.C. was supported by NIH National Human Genome Research Institute NRSA (F32HG006070). This work was supported by Simons Foundation Autism Research Initiative award SFARI 137578 (E.E.E.) and NIH grant HD065285 (E.E.E.). E.E.E. is an investigator with the Howard Hughes Medical Institute.
PY - 2013/2/7
Y1 - 2013/2/7
N2 - Rare copy-number variants (CNVs) have been implicated in autism and intellectual disability. These variants are large and affect many genes but lack clear specificity toward autism as opposed to developmental-delay phenotypes. We exploited the repeat architecture of the genome to target segmental duplication-mediated rearrangement hotspots (n = 120, median size 1.78 Mbp, range 240 kbp to 13 Mbp) and smaller hotspots flanked by repetitive sequence (n = 1,247, median size 79 kbp, range 3-96 kbp) in 2,588 autistic individuals from simplex and multiplex families and in 580 controls. Our analysis identified several recurrent large hotspot events, including association with 1q21 duplications, which are more likely to be identified in individuals with autism than in those with developmental delay (p = 0.01; OR = 2.7). Within larger hotspots, we also identified smaller atypical CNVs that implicated CHD1L and ACACA for the 1q21 and 17q12 deletions, respectively. Our analysis, however, suggested no overall increase in the burden of smaller hotspots in autistic individuals as compared to controls. By focusing on gene-disruptive events, we identified recurrent CNVs, including DPP10, PLCB1, TRPM1, NRXN1, FHIT, and HYDIN, that are enriched in autism. We found that as the size of deletions increases, nonverbal IQ significantly decreases, but there is no impact on autism severity; and as the size of duplications increases, autism severity significantly increases but nonverbal IQ is not affected. The absence of an increased burden of smaller CNVs in individuals with autism and the failure of most large hotspots to refine to single genes is consistent with a model where imbalance of multiple genes contributes to a disease state.
AB - Rare copy-number variants (CNVs) have been implicated in autism and intellectual disability. These variants are large and affect many genes but lack clear specificity toward autism as opposed to developmental-delay phenotypes. We exploited the repeat architecture of the genome to target segmental duplication-mediated rearrangement hotspots (n = 120, median size 1.78 Mbp, range 240 kbp to 13 Mbp) and smaller hotspots flanked by repetitive sequence (n = 1,247, median size 79 kbp, range 3-96 kbp) in 2,588 autistic individuals from simplex and multiplex families and in 580 controls. Our analysis identified several recurrent large hotspot events, including association with 1q21 duplications, which are more likely to be identified in individuals with autism than in those with developmental delay (p = 0.01; OR = 2.7). Within larger hotspots, we also identified smaller atypical CNVs that implicated CHD1L and ACACA for the 1q21 and 17q12 deletions, respectively. Our analysis, however, suggested no overall increase in the burden of smaller hotspots in autistic individuals as compared to controls. By focusing on gene-disruptive events, we identified recurrent CNVs, including DPP10, PLCB1, TRPM1, NRXN1, FHIT, and HYDIN, that are enriched in autism. We found that as the size of deletions increases, nonverbal IQ significantly decreases, but there is no impact on autism severity; and as the size of duplications increases, autism severity significantly increases but nonverbal IQ is not affected. The absence of an increased burden of smaller CNVs in individuals with autism and the failure of most large hotspots to refine to single genes is consistent with a model where imbalance of multiple genes contributes to a disease state.
UR - http://www.scopus.com/inward/record.url?scp=84873731200&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84873731200&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2012.12.016
DO - 10.1016/j.ajhg.2012.12.016
M3 - Article
C2 - 23375656
AN - SCOPUS:84873731200
SN - 0002-9297
VL - 92
SP - 221
EP - 237
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -