Searching for Genes Responsible for AIS

• c, e - Axial Biotech LLC

Searching for Genes Responsible for Adolescent Idiopathic Scoliosis

Background: Adolescent idiopathic scoliosis (AIS) has a strong genetic pattern of inheritance as evidenced by the tendency for familial clustering. The exact gene(s) involved in AIS have not been identified, although linkage regions have been suggested. It is not clearly established whether more than one gene is involved. The disease is most likely multifactorial due to the decreased expected prevalence observed in at-risk individuals. Using a large sample set and unique genealogy resources our objectives were to 1) quantify the genetic effect in scoliosis and 2) examine large scoliosis pedigrees for evidence of multiple scoliosis genes.

Method: A cohort of 145 patients affected with AIS were identified and contacted to ascertain whether they had a family history of scoliosis. The results from these interviews yielded 100 AIS families. Using an internal genealogical database, these 100 families as well as the 45 apparent sporadic cases were screened for potential connections that would produce larger extended pedigrees.

Results: The genealogical search in the 100 AIS families yielded 114 connections that linked the families into multiple extended pedigrees. The 45 “sporadic” cases were also searched against this database for connections to each other or to the other 100 scoliosis families. Only, 14 of the 145 original patients could not be found in our genealogy database, reducing the patient set to 131. Most of the sporadic individuals showed connections to the other scoliosis families. Overall, 127/131 (97%) of the patients were connected to scoliosis families. These results suggest a major scoliosis gene, as over 50% of our patients were connected by founders that all resided in England in the mid 1500’s. Two large families, with no apparent genealogical relationship, were compared to each other to examine whether there were significant differences in penetrance (percent affected with scoliosis) and expressivity (severity of scoliosis), something that could offer insights into the number of AIS genes. In family E-F, 47 of 114 at-risk family members were affected with scoliosis (41%) and 18 of 47 required either bracing or surgery (38%). In family S, 23 of 67 at-risk individuals were affected (34%) and 14 of those 23 were treated with either brace or surgery (61%). The difference in penetrance (41% v. 34%) and expressivity (38% v. 61%) along with the lack of a detectable genealogical connection might suggest two different genes as the major influence for idiopathic scoliosis in these families.

Conclusion: From our studies we would conclude that nearly all AIS patients have familial origins. In addition, there appears to be at least one major gene and the differences in penetrance and expressivity in two large unconnected pedigrees might suggest the presence of more than 1 major scoliosis gene. AIS is clearly a familial disease that lends itself to identification of major genes that eventually should lead to diagnostic/prognostic tests.

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