Abstract 2721: Linkage of Left Ventricular Outflow Tract Obstruction to Xq28 in 3 French-Canadian Pedigrees
BACKGROUND: Statistical genetic analysis of cohorts with left ventricular outflow tract obstruction (LVOTO) shows high heritability of such lesions. We have identified three X-linked French-Canadian pedigrees with a total of 54 family members with multiple cases of LVOTO and septal defects.
AIMS: The aim of this study was to evaluate the three pedigrees with LVOTO and septal defects for genetic linkage to the X chromosome.
METHODS: Detailed family history, physical exam, ECG, echocardiography and chart review was performed. Informed consent was obtained from all participants. Genomic DNA was isolated from peripheral blood samples. Twenty-four STR markers from the X chromosome were genotyped. We used a dominant genetic model with the following penetrances: 0.99 for homozygous women, 0.75 for heterozygous women, 0.99 for hemizygous men. Phenocopy rate was set to 0.01 and disease allele frequency to 0.001. Reference allele frequencies from the Quebec population were used. Analyses were performed with MLINK and MERLIN.
RESULTS: Sixteen family members were affected (13 males, 3 females). Predominant lesions were atrial (n = 5) and ventricular (n = 6) septal defects, coarctation (n = 4) and aortic lesions (stenosis (n = 4), bicuspid/abnormal aortic valve (n = 6)), as well as mitral valve lesions (n = 4). Males had a high incidence of supraventricular arrhythmias postoperatively (4 with atrial flutter/fibrillation, one with ICD implantation). LOD scores above 2 were obtained in parametric two-point linkage analysis for 3 markers in the Xq28 region. Multipoint non-parametric linkage analysis confirmed these results with a NPL score of 9.1 (P < .00001) over a STR marker in intron 13 of the F8C gene. Haplotype analysis allowed the definition of a candidate interval flanked by marker DXS8069 spanning to the telomeric end of Xq.
CONCLUSIONS: By analysing 3 multi-generation French-Canadian pedigrees, we mapped a syndrome of LVOTO and septal defects to the Xq28 region. Further work will refine our candidate region with dense SNP coverage to search for a shared haplotype identical by descent between the three French Canadian families, to complete the sequencing of candidate genes including FLNA, and to search for a possible founder effect in our population.