Genetic linkage localizes an adolescent idiopathic scoliosis and pectus excavatum gene to chromosome 18 q

A single large family, in which adolescent idiopathic scoliosis (AIS) and pectus excavatum (PE) segregate as an autosomal dominant condition, was evaluated. Genome-wide linkage analysis and candidate gene sequencing were performed. To map the disease-causing locus in a large white family in which AIS and PE cosegregate. AIS and PE are common musculoskeletal conditions known to have a genetic component, though few genes have been identified for either. Genetic studies have been confounded by a lack of large families in which the disorders segregate. Clinical examinations were performed on the proband, who underwent posterior spinal fusion, and 12 additional affected family members. To map a gene causing AIS and PE, a genome-wide linkage analysis was performed with the Affymetrix Mapping 10 K XbaI array on 13 affected and 10 unaffected family members. Candidate genes were sequenced. AIS was present in 13 female family members and PE was present in 3 males and 1 female. Genome-wide linkage analysis resulted in a linkage peak on chromosome 18 q with a maximum parametric multipoint logarithm of the odds score of 3.86. Recombinants delineated the critical genetic region to an interval of 6.4 cM between SNP_A-1519369 and SNP_A-1507702, corresponding to a 7.06-Mb region (hg18: chr18:26342508-34395660). The chromosome 18 q linkage region contains more than 30 genes. Resequencing of the coding regions of 21 candidate genes in the region did not reveal any causative mutation. Linkage analysis in this large family demonstrated a novel locus for AIS and PE on chromosome 18 q. Because of the increased frequency of PE in family members of AIS patients, consideration of family members with PE as affected may increase the power of AIS genetic linkage studies.