TY - JOUR
T1 - CHD7 gene polymorphisms are associated with susceptibility to idiopathic scoliosis
AU - Gao, Xiaochong
AU - Gordon, Derek
AU - Zhang, Dongping
AU - Browne, Richard
AU - Helms, Cynthia
AU - Gillum, Joseph
AU - Weber, Samuel
AU - Devroy, Shonn
AU - Swaney, Saralove
AU - Dobbs, Matthew
AU - Morcuende, Jose
AU - Sheffield, Val
AU - Lovett, Michael
AU - Bowcock, Anne
AU - Herring, John
AU - Wise, Carol
N1 - Funding Information:
We thank the families for their participation; J. Birch, C. Johnston, L. Karol, K. Rathjen, B. S. Richards, D. Sucato, J. Purvis, for patient referrals; N. Ritter, L. Edwards, and L. Macleod, for help with the families; and J. Bainbridge-Smith for help in analysis. For help with genotyping and sequencing, we thank the McDermott Center Sequencing Core at University of Texas Southwestern Medical Center and the Division of Human Genetics Core Genotyping Facility at Washington University School of Medicine in St. Louis. Support from the Scoliosis Research Society, Fondation Cotrel, and TSRHC Research Fund grant 12-96-381 (to C.W.) is gratefully acknowledged.
PY - 2007/5
Y1 - 2007/5
N2 - Idiopathic scoliosis (IS) is the most common spinal deformity in children, and its etiology is unknown. To refine the search for genes underlying IS susceptibility, we ascertained a new cohort of 52 families and conducted a follow-up study of genomewide scans that produced evidence of linkage and association with 8q12 loci (multipoint LOD 2.77; P = .0028). Further fine mapping in the region revealed significant evidence of disease-associated haplotypes (P < 1.0 × 10-4) centering over exons 2-4 of the CHD7 gene associated with the CHARGE (coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness) syndrome of multiple developmental anomalies. Resequencing CHD7 exons and conserved intronic sequence blocks excluded coding changes but revealed at least one potentially functional polymorphism that is overtransmitted (P = .005) to affected offspring and predicts disruption of a caudal-type (cdx) transcription-factor binding site. Our results identify the first gene associated with IS susceptibility and suggest etiological overlap between the rare, early-onset CHARGE syndrome and common, later-onset IS.
AB - Idiopathic scoliosis (IS) is the most common spinal deformity in children, and its etiology is unknown. To refine the search for genes underlying IS susceptibility, we ascertained a new cohort of 52 families and conducted a follow-up study of genomewide scans that produced evidence of linkage and association with 8q12 loci (multipoint LOD 2.77; P = .0028). Further fine mapping in the region revealed significant evidence of disease-associated haplotypes (P < 1.0 × 10-4) centering over exons 2-4 of the CHD7 gene associated with the CHARGE (coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness) syndrome of multiple developmental anomalies. Resequencing CHD7 exons and conserved intronic sequence blocks excluded coding changes but revealed at least one potentially functional polymorphism that is overtransmitted (P = .005) to affected offspring and predicts disruption of a caudal-type (cdx) transcription-factor binding site. Our results identify the first gene associated with IS susceptibility and suggest etiological overlap between the rare, early-onset CHARGE syndrome and common, later-onset IS.
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U2 - 10.1086/513571
DO - 10.1086/513571
M3 - Article
C2 - 17436250
AN - SCOPUS:34247584973
SN - 0002-9297
VL - 80
SP - 957
EP - 965
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -