Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test

Abstract

Background: Long QT syndrome (LQTS) is a potentially lethal, highly treatable cardiac channelopathy for which genetic testing has matured from discovery to translation and now clinical implementation.

Objectives: Here we examine the spectrum and prevalence of mutations found in the first 2,500 unrelated cases referred for the FAMILION LQTS clinical genetic test.

Methods: Retrospective analysis of the first 2,500 cases (1,515 female patients, average age at testing 23 +/- 17 years, range 0 to 90 years) scanned for mutations in 5 of the LQTS-susceptibility genes: KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6).

Results: Overall, 903 referral cases (36%) hosted a possible LQTS-causing mutation that was absent in >2,600 reference alleles; 821 (91%) of the mutation-positive cases had single genotypes, whereas the remaining 82 patients (9%) had >1 mutation in > or =1 gene, including 52 cases that were compound heterozygous with mutations in >1 gene. Of the 562 distinct mutations, 394 (70%) were missense, 428 (76%) were seen once, and 336 (60%) are novel, including 92 of 199 in KCNQ1, 159 of 226 in KCNH2, and 70 of 110 in SCN5A.

Conclusion: This cohort increases the publicly available compendium of putative LQTS-associated mutations by >50%, and approximately one-third of the most recently detected mutations continue to be novel. Although control population data suggest that the great majority of these mutations are pathogenic, expert interpretation of genetic test results will remain critical for effective clinical use of LQTS genetic test results.

Figure 1

Mutation detection yield and novelty rate over the life of the test. Comparing 5 consecutive groups of 500 cases, the bar graph in (A) depicts the frequency of positive genetic test results, ranging from 33% to 39%, and in (B) illustrates the novelty rate during the lifetime of the test, ranging from 32% to 35%. Each variant is counted as novel only in the first patient in whom it was discovered. Novelty was assessed relative to the web site (http://www.fsm.it/cardmoc) as of February 1, 2009.

Figure 2

LQTS-associated mutation frequency distribution. This bar graph summarizes the distribution of specific mutations among unrelated patients. The y axis depicts the number of distinct LQTS-associated mutations, and the x axis represents the number of unrelated patients. For example, the first column indicates that there were 166 distinct mutations, each observed only once. The last column indicates that 5 different LQTS-associated mutations were each seen in ≥11 unrelated patients. The inset shows the 5 most common mutations identified and the number of specified unrelated patients in whom they were found. LQTS = long QT syndrome.

Figure 3

Summary of mutation type for LQT1, LQT2, and LQT3. The distribution of mutation type (missense, frame shift, etc.) is summarized for the 3 major LQTS genes. LQTS = long QT syndrome.

Figure 4

Channel topology and location of putative LQTS-causing mutations for the 3 major LQTS genes. Missense mutations are indicated by white circles, whereas mutations other than missense (i.e., frame shift, deletions, splice-site, etc.) are depicted as gray circles. In addition, 3 different circle sizes are used, with the smallest circle indicating a mutation seen only once; a medium-sized circle for mutations observed in 2, 3, or 4 subjects; and the largest circle indicating those mutations observed at least 5 times. See Supplemental Tables 1–3 for details about each mutation depicted here. (A) Channel topology of Kv7.1’s pore-forming alpha subunit encoded by KCNQ1 and location of putative LQT1-causing mutations. (B) Channel topology of Kv11.1’s pore-forming alpha subunit encoded by KCNH2 and location of putative LQT2-causing mutations. (C) Channel topology of Nav1.5’s pore-forming alpha subunit encoded by SCN5A and location of putative LQT3-causing mutations. LQTS = long QT syndrome.