CHD7 gene polymorphisms are associated with susceptibility to idiopathic scoliosis.
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 x 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.
Gao
Xiaochong
X
Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA.
Gordon
Derek
D
Zhang
Dongping
D
Browne
Richard
R
Helms
Cynthia
C
Gillum
Joseph
J
Weber
Samuel
S
Devroy
Shonn
S
Swaney
Saralove
S
Dobbs
Matthew
M
Morcuende
Jose
J
Sheffield
Val
V
Lovett
Michael
M
Bowcock
Anne
A
Herring
John
J
Wise
Carol
C
D000015:Abnormalities, Multiple / Q000235:genetics; D002648:Child; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D005260:Female; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D007438:Introns; D008297:Male; D018895:Microsatellite Repeats; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012600:Scoliosis / Q000235:genetics*; D013577:Syndrome
D004268:DNA-Binding Proteins; D004265:DNA Helicases; C491434:CHD7 protein, human