O2048: Early Detection of LQTS with KCNQ1 Cascade Screening in the Amish Population

Background: Long QT syndrome (LQTS) is an autosomal dominant disease associated with increased risk for syncope and sudden cardiac death. Sudden death is the first presenting symptom in ~10% of individuals with LQTS. A new pathogenic variant in KCNQ1, T224M, is present in ~3% of the Amish population. Genetic testing of at-risk individuals may allow for earlier life-saving preventative therapy with beta-blockers.

Methods: Family members of KCNQ1, T224M propands in the Amish community were offered cascade genetic testing and clinical assessment. Letters were sent to families to participate in the screening which included genetic testing, medical history, family history, symptom questionnaires and supine and standing ECGs. QTc was calculated using Bazett’’s formula by a cardiologist. Symptoms were scored as 0=no symptoms, 1=symptom at rest, and 2=symptom with activity. We considered the threshold for prolonged QTc >450 ms in males, >460 ms in females, and >460 ms under 16 years of age. QTc intervals and symptom scores were compared by student’s T-test. Proportion of individuals with prolonged QTc and with fainting or seizures was compared with Fisher’s Exact test.

Results: Of 131 individuals tested, 28 KCNQ1- and 18 KCNQ1+ agreed to an at-home ECG and their characteristics are shown in Table 1. Distribution of QTc by genotypes is shown in Figure 1. An important proportion of individuals who are KCNQ1+ did not meet the threshold for prolonged QTc, demonstrating the inability of the ECG to capture the phenotype of prolongation of QTc intervals. Mean supine and standing QTc intervals were significantly longer in KCNQ1+ individuals than KCNQ1- (Table 1). Using supine QTc, 6/18 (33%) KCNQ1+ were prolonged compared to 1/28 (3.6%) KCNQ1-. Using standing QTc 10/18 (55%) KCNQ1+ were prolonged compared to 6/28 (21%) KCNQ1- (Table 1). The average score for all symptoms trended toward being higher in KCNQ1+ (p=0.125, Table 1). Fainting with activity was reported in 16.7% of KCNQ1+ and 10.7% in KCNQ1-.

Conclusion: This is, to our knowledge, the first clinical phenotypic evaluation of a (mainly pediatric) population in the Amish community with this new KCNQ1 T224M mutation. While average QTc was prolonged in genotype positive individuals, our results also demonstrated that not all KCNQ1+ met the threshold for QTc prolongation, while at the same time tending to be more symptomatic as compared to KCNQ1-, thus highlighting the importance of cascade genetic testing to identify patients with congenital LQTS. Change of position revealed prolonged QTc which exemplifies obtaining both supine and standing ECGs. Since we lacked longitudinal follow up, we could not correlate symptom severity with duration of QTc interval on the EKG. Our study is limited by our small sample size and lack of long term follow-up.