Linkage analysis of in this large family resulted in the identification of a novel locus for AIS and PE on chromosome 18q12.1–q12.2. The typical female predominance of AIS was present in this pedigree, and therefore this locus may represent a locus for common forms of AIS. A larger region of chromosome 18q, encompassing the current locus, was previously identified in a genome-wide linkage scan involving a large family with AIS9
, although the linkage peak in that family was considerably more telomeric (70–120cM). However, it is possible that this represents the same locus that is described here in the current study of AIS and PE.
Although scoliosis is increased in frequency in patients with PE and their familiy members22
, to our knowledge no study has previously determined the incidence of PE in AIS. An increased incidence of PE was noted both in family 6061 as well as in a clinic population of AIS patients, where a family history of PE was present in 20%, which is considerably higher than would be expected given the rate of PE in the general populations (1 out of every 400 children)23 24
. PE and scoliosis are also common in connective tissue disorders including Ehlers-Danlos and Marfan syndrome. However, additional evidence of connective tissue disorders (long extremities, nearsightedness, aortic dilatation, mitral valve prolapse, easy bruising, lax joints, loose or excess skin, arthritis, and hernias) was absent in family 6061 and the 65 AIS patients surveyed. Furthermore, there was no evidence of linkage to chromosomal loci containing genes for Ehlers Danlos syndrome and Marfan syndrome in family 6061. Because our data show an increased incidence of PE in family members of AIS patients, it is likely that at least some of the genetic susceptibility genes for AIS may also contribute to the susceptibility to PE.
There are well known, significant, and nearly opposite gender differences in the incidence of PE and AIS that were also seen in our study. PE is more common in males (4:1 male to female ratio)24
and this is consistent with inheritance of PE in family 6061 in which three out of four affected were male. In family 6061, all individuals affected with AIS were female and there were no individuals with both AIS and PE. However, the eleven year-old sister of the proband has PE and inherited the common haplotype on chromosome 18q, and based on her age, remains at risk for developing AIS. Identification of the genes responsible for AIS and PE may eventually allow us to better understand these gender specific effects on skeletal development.
Because of the large number of affected individuals in family 6061, we were able to narrow the candidate interval to a relatively small region [6.6cM (7.3 Mb)] of chromosome 18q12.1–q12.2 Mb, containing <40 genes. There are several interesting candidate genes on chromosome 18q, including DTNA and B4GALT7. DTNA encodes alpha-dystrobrevin and is a member of the dystrophin family. Duchenne muscular dystrophy is an X-linked neuromuscular condition that results from mutations in dystrophin, which is often associated with scoliosis25
. Recessive mutations in B4GALT7 (xylosylprotein 4-beta-galactosyltrasferase I) results in the progeroid form of Ehlers-Danlos syndrome26 27
and is therefore a likely candidate for AIS and PE. Although the exons of these genes and 19 other candidate genes were sequenced and mutations not identified, we did not evaluate for mutations within noncoding, regulatory regions surrounding these genes. For many common diseases such as AIS, disease associated variants have been identified in the noncoding sequence. This was recently demonstrated in the association of AIS with a single nucleotide polymorphism (SNP) on chromosome 8q12.2 that is located in an intron of CHD713
, the gene responsible for CHARGE syndrome. Despite finding an association of AIS with this intronic SNP, mutations in CHD7 were not identified, and the functional effects of this SNP remain unknown. Disease-causative noncoding mutations are much more difficult to identify given the large amount of conserved DNA sequence flanking most genes and it is currently not cost effective to sequence all of these noncoding regions.
To summarize, we have identified an increased incidence of PE in a large multigenerational family with AIS as well as in an independent cohort of AIS patients. Because the etiology of these two conditions are likely related, we considered both phenotypes as affected in our linkage analysis, and were therefore able to identify a novel genetic locus for AIS and PE on chromosome 18q. Although familial cases of PE have been reported22
, linkage studies have not been published and it will be interesting to see if PE is linked to the same region on chromosome 18q. Confirmation of linkage in additional AIS families will be needed to determine if the chromosome 18 locus represents a common locus for AIS. In the near future, genome-wide association studies including hundreds or thousands of AIS patients may also identify SNPs within the chromosome 18q region that are associated with AIS, thus confirming our linkage findings, and identifying the genetic basis for these common musculoskeletal disorders.