MUTATIONS ASSOCIATED WITH LONG QT SYNDROME
The invention is based, at least in part, on the observation that the presence of particular biomarkers, e.g., particular mutations in any of the KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 genes as identified in Tables 1-5 (and, in particular, those identified with an asterisk), is associated with Long QT Syndrome (LQTS).
1 . A method for identifying whether a subject suffers from or is predisposed to suffer from congenital long QT syndrome (LQTS) comprising identifying the presence of at least one biomarker in a biological sample obtained from the subject, wherein the biomarker is selected from the group consisting of variants set forth in Tables 1-5.
2 . The method of claim 1 , wherein the biomarker is a variant in at least one of the KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 or KCNE2 genes.
3 . The method of claim 1 , wherein the variant is selected from the group consisting of a mutation, a missense mutation, a nonsense mutation, an insertion, a deletion, or a frameshift mutation.
4 . The method of claim 1 , wherein the variant disrupts the open reading frame of the KCNQ1, KCNH2, SCN5A, KCNE1 or KCNE2 genes.
5 . The method of claim 1 , wherein the variant disrupts the canonical splice site of the KCNQ1, KCNH2, SCN5A, KCNE1 or KCNE2 genes.
6 . The method of claim 5 , wherein the variant disrupts the splice acceptor sequence and/or the splice donor recognition sequence of the KCNQ1, KCNH2, SCN5A, KCNE1 or KCNE2 genes.
7 . The method of claim 1 , wherein the biomarker is selected from the group consisting of a L266P mutation in KCNQ1, a R518X mutation in KCNQ1, a R594Q mutation in KCNQ1, a G168R mutation in KCNQ1, a E1784K mutation in SCN5A, a Q73X nonsense mutation in SCN5A, a R179X nonsense mutation in SCN5A, a R222X nonsense mutation in SCN5A, a Y389X nonsense mutation in SCN5A, and a W1798X nonsense mutation in SCN5A, a V850fs+18X frameshift mutation in SCN5A and a L1786fs+45X frameshift mutation in SCN5A.
8 . The method of claim 1 , wherein the biomarker is a variant identified with an asterisk in Table 1-5.
9 . A method for predicting therapeutic responsiveness of a subject having LQTS or susceptible to having LQTS to LQTS therapy, the method comprising determining the presence or absence of at least one biomarker in a biological sample obtained from the subject, wherein the biomarker is selected from the group consisting of variants set forth in Tables 1-5, and wherein the presence of the at least one biomarker in the sample is an indication that the subject will respond to the LQTS therapy, thereby predicting responsiveness of the subject to the LQTS therapy.
10 . The method of claim 9 , wherein the LQTS therapy comprises a method selected from the group consisting of administration of beta receptor blocking agents, implantation of an implantable cardioverter-defibrillator (ICD), potassium supplementation, administration of a sodium channel blocker such as mexiletine, and amputation of the cervical sympathetic chain.
11 . The method of claim 9 , wherein determining the presence or absence of at least one biomarker is accomplished using a technique selected from the group consisting of polymerase chain reaction (PCR) amplification reaction, reverse-transcriptase PCR analysis, single-strand conformation polymorphism analysis (SSCP), mismatch cleavage detection, heteroduplex analysis, Southern blot analysis, Western blot analysis, deoxyribonucleic acid sequencing, restriction fragment length polymorphism analysis, haplotype analysis, serotyping, and combinations or sub-combinations thereof, of said sample.
12 . The method of claim 9 , wherein the sample from the subject is selected from the group consisting of a fluid, blood fluids, vomit, intra-articular fluid, saliva, lymph, cystic fluid, urine, fluids collected by bronchial lavage, fluids collected by peritoneal rinsing, gynecological fluids, a blood sample or a component thereof, a tissue or component thereof, bone, connective tissue, cartilage, lung, liver, kidney, muscle tissue, heart, pancreas, and skin.
13 . The method of claim 9 , wherein the biomarker is a variant in at least one of the KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 or KCNE2 genes.
14 . The method of claim 9 , wherein the variant is selected from the group consisting of a mutation, a missense mutation, a nonsense mutation, an insertion, a deletion, or a frameshift mutation.
15 . The method of claim 9 , wherein the variant disrupts the open reading frame of the KCNQ1, KCNH2, SCN5A, KCNE1 or KCNE2 genes.
16 . The method of claim 9 , wherein the variant disrupts the canonical splice site, the splice acceptor sequence and/or splice donor recognition sequence of the KCNQ1, KCNH2, SCN5A, KCNE1 or KCNE2 genes.
17 . The method of claim 1 , wherein the biomarker is selected from the group consisting of a L266P mutation in KCNQ1, a R518X mutation in KCNQ1, a R594Q mutation in KCNQ1, a G168R mutation in KCNQ1, a E1784K mutation in SCN5A, a Q73X nonsense mutation in SCN5A, a R179X nonsense mutation in SCN5A, a R222X nonsense mutation in SCN5A, a Y389X nonsense mutation in SCN5A, and a W1798X nonsense mutation in SCN5A, a V850fs+18X frameshift mutation in SCN5A and a L1786fs+45X frameshift mutation in SCN5A.
18 . The method of claim 9 , wherein the biomarker is a variant identified with an asterisk in Table 1-5.
19 . A nucleic acid molecule comprising a variant of the KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 or KCNE2 genes selected from the group consisting of the variants set forth in Tables 1-5.
20 . The nucleic acid molecule of claim 19 , wherein the variant is identified with an asterisk in Table 1-5.