Key result
Five different variants in KCNQ1, including a novel compound heterozygous mutation containing a large deletion and a missense variant, were identified as the genetic cause of Long QT syndrome or Jervell and Lange-Nielsen syndrome in three pedigrees.
Why the study?
LQTS is a primary cause of sudden cardiac death in youth, but the specific genetic etiology in individual families remains unknown.
Case Report (n=3)
No
The study expands the genetic spectrum of LQTS and JLNS by identifying novel KCNQ1 variants, including a first-reported compound heterozygous mutation with a large deletion and missense variant.
Answers are grounded in this paper and cite their sources.
May inform family-specific LQTS counseling; hypothesis-generating for novel variants pending larger validation.
OBJECTIVES: Long QT syndrome (LQTS) is one of the primary causes of sudden cardiac death (SCD) in youth. Studies have identified mutations in ion channel genes as key players in the pathogenesis of LQTS. However, the specific etiology in individual families remains unknown. METHODS: Three unrelated Chinese pedigrees diagnosed with LQTS or Jervell and Lange-Nielsen syndrome (JLNS) were recruited clinically. Whole exome sequencing (WES) was performed and further validated by multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing. RESULTS: All of the probands in our study experienced syncope episodes and featured typically prolonged QTc-intervals. Two probands also presented with congenital hearing loss and iron-deficiency anemia and thus were diagnosed with JLNS. A total of five different variants in KCNQ1, encoding a subunit of the voltage-gated potassium channel, were identified in 3 probands. The heterozygous variants, KCNQ1 c.749T > C was responsible for LQTS in Case 1, transmitting in an autosomal dominant pattern. Two patterns of compound heterozygous variants were responsible for JLNS, including a large deletion causing loss of the exon 16 and missense variant c.1663 C > T in Case 2, and splicing variant c.605-2 A > G and frame-shift variant c.1265del in Case 3. To our knowledge, the compound heterozygous mutations containing a large deletion and missense variant were first reported in patients with JLNS. CONCLUSION: Our study expanded the LQTS genetic spectrum, thus favoring disease screening and diagnosis, personalized treatment, and genetic consultation.
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Zhao et al. (2023) conducted a case report in Long QT syndrome (LQTS) and Jervell and Lange-Nielsen syndrome (JLNS) (n=3). KCNQ1 genetic variants was evaluated on Identification of pathogenic genetic variants via whole exome sequencing. Five different variants in KCNQ1, including a novel compound heterozygous mutation containing a large deletion and a missense variant, were identified as the genetic cause of Long QT syndrome or Jervell and Lange-Nielsen syndrome in three pedigrees.
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