Heart rhythm · 2022
Genome sequencing in a genetically elusive multigenerational long QT syndrome pedigree identifies a novel LQT2-causative deeply intronic KCNH2 variant.
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Tobert Kathryn E, Tester David J, Zhou Wei, Haglund-Turnquist Carla M, Giudicessi John R, Ackerman Michael J
Аннотация
BACKGROUND: Most of the long QT syndrome (LQTS) stems from pathogenic variants in KCNQ1, KCNH2, or SCN5A. However, ∼10%-20% of LQTS index cases remain genotype-negative.
OBJECTIVE: The purpose of this study was to identify and characterize functionally a novel LQTS genetic substrate in a multigenerational, "genotype-negative" LQTS pedigree.
METHODS: The patient was a 40-year-old woman with a history of syncope, seizures, ventricular fibrillation, and a family history of LQTS and sudden death. Commercial genetic testing of all LQTS-causative genes was negative. Genome sequencing was performed on 6 affected family members. Patient-specific and CRISPR/Cas9 "gene-corrected" isogenic control induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated.
RESULTS: No ultrarare, nonsynonymous heterozygous variants cosegregated among the 6 LQTS phenotype-positive individuals. Instead, a deep intronic KCNH2 variant (c.3331-316G>T) was present in all affected individuals. Reverse transcription polymerase chain reaction analysis of patient-specific iPSC-CM-derived RNA revealed that c.3331-316G>T creates a novel 89 base-pair exon that results in a frameshift variant (p.S1112Pfs∗171). Action potential duration (APD90) was significantly longer in p.S1112Pfs∗171-iPSC-CMs (602.4 ± 12.2 ms; n =70) compared to isogenic control iPSC-CMs (425.7 ± 9.3 ms; n = 61; P <.0001). Further, field potential duration was significantly longer in p.S1112Pfs∗171-iPSC-CMs (358.9 ± 7.7 ms; n = 65) compared to isogenic control iPSC-CMs (282.2 ± 10.8 ms; n = 51; P <.0001).
CONCLUSION: A novel deep intronic KCNH2 variant was identified in a multigenerational, genetically elusive LQTS pedigree. The iPSC-CMs establish that the variant is the monogenetic cause for this family's LQTS. Deep intronic variants within the 2 most common LQTS-susceptibility genes should be considered in patients with seemingly genetically elusive LQTS.
OBJECTIVE: The purpose of this study was to identify and characterize functionally a novel LQTS genetic substrate in a multigenerational, "genotype-negative" LQTS pedigree.
METHODS: The patient was a 40-year-old woman with a history of syncope, seizures, ventricular fibrillation, and a family history of LQTS and sudden death. Commercial genetic testing of all LQTS-causative genes was negative. Genome sequencing was performed on 6 affected family members. Patient-specific and CRISPR/Cas9 "gene-corrected" isogenic control induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated.
RESULTS: No ultrarare, nonsynonymous heterozygous variants cosegregated among the 6 LQTS phenotype-positive individuals. Instead, a deep intronic KCNH2 variant (c.3331-316G>T) was present in all affected individuals. Reverse transcription polymerase chain reaction analysis of patient-specific iPSC-CM-derived RNA revealed that c.3331-316G>T creates a novel 89 base-pair exon that results in a frameshift variant (p.S1112Pfs∗171). Action potential duration (APD90) was significantly longer in p.S1112Pfs∗171-iPSC-CMs (602.4 ± 12.2 ms; n =70) compared to isogenic control iPSC-CMs (425.7 ± 9.3 ms; n = 61; P <.0001). Further, field potential duration was significantly longer in p.S1112Pfs∗171-iPSC-CMs (358.9 ± 7.7 ms; n = 65) compared to isogenic control iPSC-CMs (282.2 ± 10.8 ms; n = 51; P <.0001).
CONCLUSION: A novel deep intronic KCNH2 variant was identified in a multigenerational, genetically elusive LQTS pedigree. The iPSC-CMs establish that the variant is the monogenetic cause for this family's LQTS. Deep intronic variants within the 2 most common LQTS-susceptibility genes should be considered in patients with seemingly genetically elusive LQTS.