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.
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.
UR - http://www.scopus.com/inward/record.url?scp=38749084216&partnerID=8YFLogxK
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 -