TY - JOUR
T1 - Disruption of Neurexin 1 Associated with Autism Spectrum Disorder
AU - Kim, Hyung Goo
AU - Kishikawa, Shotaro
AU - Higgins, Anne W.
AU - Seong, Ihn Sik
AU - Donovan, Diana J.
AU - Shen, Yiping
AU - Lally, Eric
AU - Weiss, Lauren A.
AU - Najm, Juliane
AU - Kutsche, Kerstin
AU - Descartes, Maria
AU - Holt, Lynn
AU - Braddock, Stephen
AU - Troxell, Robin
AU - Kaplan, Lee
AU - Volkmar, Fred
AU - Klin, Ami
AU - Tsatsanis, Katherine
AU - Harris, David J.
AU - Noens, Ilse
AU - Pauls, David L.
AU - Daly, Mark J.
AU - MacDonald, Marcy E E.
AU - Morton, Cynthia C.
AU - Quade, Bradley J.
AU - Gusella, James F.
N1 - Funding Information:
We are grateful to the DGAP families and members of the ASD, TS and OCD cohorts for their cooperation and participation in this study. We also gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. We thank Heather Ferguson, Chantal Kelly, and Jill Platko for assistance in obtaining subject samples and phenotypic data, Robert Eisenman for technical support and the CHGR Tissue Culture and Genomics Resources for lymphoblast transformation and DNA sequencing services. This work was supported by National Institutes of Health grants P01-GM061354 (to C.C.M.), U19-HD35482 (to F.V., A.K., and D.L.P), P01-HD00300838 (to F.V., A.K., and D.L.P), and R01-NS16648 (D.L.P.) and by a NARSAD Distinguished Investigator Award (J.F.G.). Y.S. received a Young Investigator Award from the Children's Tumor Foundation. AGRE is a program of Cure Autism Now and is supported, in part, by grant MH64547 from the National Institute of Mental Health to Daniel H. Geschwind (PI).
PY - 2008/1/10
Y1 - 2008/1/10
N2 - Autism is a neurodevelopmental disorder of complex etiology in which genetic factors play a major role. We have implicated the neurexin 1 (NRXN1) gene in two independent subjects who display an autism spectrum disorder (ASD) in association with a balanced chromosomal abnormality involving 2p16.3. In the first, with karyotype 46,XX,ins(16;2)(q22.1;p16.1p16.3)pat, NRXN1 is directly disrupted within intron 5. Importantly, the father possesses the same chromosomal abnormality in the absence of ASD, indicating that the interruption of α-NRXN1 is not fully penetrant and must interact with other factors to produce ASD. The breakpoint in the second subject, with 46,XY,t(1;2)(q31.3;p16.3)dn, occurs ∼750 kb 5′ to NRXN1 within a 2.6 Mb genomic segment that harbors no currently annotated genes. A scan of the NRXN1 coding sequence in a cohort of ASD subjects, relative to non-ASD controls, revealed that amino acid alterations in neurexin 1 are not present at high frequency in ASD. However, a number of rare sequence variants in the coding region, including two missense changes in conserved residues of the α-neurexin 1 leader sequence and of an epidermal growth factor (EGF)-like domain, respectively, suggest that even subtle changes in NRXN1 might contribute to susceptibility to ASD.
AB - Autism is a neurodevelopmental disorder of complex etiology in which genetic factors play a major role. We have implicated the neurexin 1 (NRXN1) gene in two independent subjects who display an autism spectrum disorder (ASD) in association with a balanced chromosomal abnormality involving 2p16.3. In the first, with karyotype 46,XX,ins(16;2)(q22.1;p16.1p16.3)pat, NRXN1 is directly disrupted within intron 5. Importantly, the father possesses the same chromosomal abnormality in the absence of ASD, indicating that the interruption of α-NRXN1 is not fully penetrant and must interact with other factors to produce ASD. The breakpoint in the second subject, with 46,XY,t(1;2)(q31.3;p16.3)dn, occurs ∼750 kb 5′ to NRXN1 within a 2.6 Mb genomic segment that harbors no currently annotated genes. A scan of the NRXN1 coding sequence in a cohort of ASD subjects, relative to non-ASD controls, revealed that amino acid alterations in neurexin 1 are not present at high frequency in ASD. However, a number of rare sequence variants in the coding region, including two missense changes in conserved residues of the α-neurexin 1 leader sequence and of an epidermal growth factor (EGF)-like domain, respectively, suggest that even subtle changes in NRXN1 might contribute to susceptibility to ASD.
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U2 - 10.1016/j.ajhg.2007.09.011
DO - 10.1016/j.ajhg.2007.09.011
M3 - Article
C2 - 18179900
AN - SCOPUS:38749084216
SN - 0002-9297
VL - 82
SP - 199
EP - 207
JO - American journal of human genetics
JF - American journal of human genetics
IS - 1
ER -