A genetic locus for adolescent idiopathic scoliosis linked to chromosome 19p13.3

Abstract

Adolescent idiopathic scoliosis (AIS) is one of the most common orthopedic disorders, affecting up to 4% of schoolchildren worldwide. We studied seven unrelated multiplex families of southern Chinese descent with AIS, consisting of 25 affected members. A genomewide scan with >400 fluorescent microsatellite markers was performed. Multipoint linkage analysis by GENEHUNTER revealed significant linkage of the abnormal phenotype to the distal short arm of chromosome 19, with both a maximum multipoint LOD score and a nonparametric LOD score of 4.93. Two-point linkage analysis by MLINK gave a LOD score of 3.63 (recombination fraction theta[m=f]=0.00) at D19S216. Further high-density mapping and informative recombinations defined the AIS critical region in the vicinity of D19S216, flanked by D19S894 and D19S1034, spanning 5.2 cM on the sex-averaged genetic map on chromosome 19p13.3.

Figure 1

Multipoint linkage analysis of AIS to microsatellite markers on chromosome 19. The X-axis represents the relative location of these markers, and the Y-axis represents the multipoint LOD (solid line ) and NPL (broken line) scores from parametric and nonparametric linkage analyses, respectively, for all seven kindreds.

Figure 2

Abbreviated family pedigree and chromosome 19 haplotypes of four kindreds with AIS with informative recombinations. Affected individuals are denoted by blackened symbols, unaffected individuals are denoted by unblackened symbols, and individuals with unknown phenotype are indicated by a question mark. The identity of each microsatellite marker is shown to the left of each haplotype; their relative position along chromosome 19 is given in the top panel of family 3, and numbers on the far left are the sex-averaged chromosome distances (in cM) from the telomere of chromosome 19p. The individual number and haplotype is given under the symbol of each subject. The affected haplotype shared by relatives is boxed. An allele number represents a unique allele size across all families in the present study. Arrowheads indicate informative recombinations.