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AP-517-03 WHOLE EXOME SEQUENCING IDENTIFIES TWO NOVEL EXTREMELY RARE CANDIDATE VARIANTS ASSOCIATED WITH THE SHORT QT SYNDROME IN TWO LARGE PEDIGREES

      Background

      Short QT syndrome (SQTS) is caused by pathogenic variants predominantly in the KCNQ1, KCNH2, KCNJ2 genes and genes encoding for different subunits of the L-type calcium channel. Recently, a variant in the SLC4A3 gene has been associated with the SQTS as well.

      Objective

      To identify the genetic background causing SQTS using whole exome sequencing (WES) and co-segregation analysis in two large pedigrees.

      Methods

      Genetic testing of the index patient 1 and molecular autopsy of the index patient two was performed using NGS. Family screening was performed with cardiologic work-up and genetic cascade screening.

      Results

      Index case 1 was diagnosed with SQTS at the age of 28 years after a syncopal event. Work-up revealed a markedly shortened QTc interval (340ms). Family history revealed peripartum death of one relative. Genetic testing of all known implicated genes was initially negative. WES was performed, which revealed a novel rare heterozygous missense variant (p.(Arg370Cys)) in a highly conserved region of the SLC4A3 gene. Cardiac and genetic work-up of 5 relatives suggested co-segregation of the candidate variant (pedigree 1) with the SQTS. Index case 2 had sudden cardiac death (SCD) at 17 years of age and had a positive family history for SCD before the age of 40 in three cases. A previously recorded 12-lead ECG revealed a QTc of 340ms in the index patient. Post-mortem genetic testing of all known implicated genes was initially negative. In light of our previous findings, reanalysis was performed including the SLC4A3gene, which revealed a second rare novel heterozygous missense variant(p.(Ser1039Arg)). Cardiac and genetic work-up of 10 relatives suggested co-segregation of the candidate variant with the SQTS (pedigree 2).