Abstract

Exome Analysis of Long QT Syndrome

Toshihiro Tanaka, Professor, Tokyo Medical and Dental University (TMDU)

As we understand from variations in individual's height, weight, character or looks, HUMAN is DIVERSE in every aspect.  From the clinical point of view, it is one form of the expression of human diversity that every patient diagnosed as the same disease does not respond equally to the same therapy.  While human diversity is composed of complex combination of differences in environmental and genetic factors, genetic epidemiology focuses on revealing genetic backgrounds of clinical status including the disease itself, drug responses or adverse effects.  Genome-wide association study (GWAS) and comprehensive sequencing approaches including Whole Exome Sequencing Analysis (WES) have been among the main analytic tools in this methodology.  Recent progress in the genetic fields of arrhythmias have revealed the potent roles of genetic factors in the pathogenesis of both inherited and common arrhythmias, and some of the research results have been applied to clinical fields.  In this talk, genetic analyses of long QT syndrome (LQTS), an arrhythmogenic disorder that can lead to sudden death will be shown as one example.  To date, mutations in 15 LQTS-susceptibility genes have been implicated.  However, the genetic cause for approximately 40% of LQTS patients remains elusive.  We performed whole-exome sequencing analyses on 59 LQTS and 61 unaffected individuals in 35 families and 138 unrelated LQTS cases.  Although no novel commonly mutated gene was identified other than known LQTS genes, protein-protein interaction (PPI) network analyses revealed ten new pathogenic candidates that directly or indirectly interact with proteins encoded by known LQTS genes.  Five of the newly identified candidates directly interact with calmodulin.  These results suggest an important role of calmodulin and its interacting proteins in the pathogenesis of LQTS that might be an anchoring point for novel drug development as well as novel diagnosis.