Background: The short QT syndrome (SQTS) is a rare channelopathy associated with an increased risk of sudden cardiac death (SCD). Here, we report 3 unrelated SQTS families with an identical mutation associated with SCD and sudden infant death (SIDS). Methods: KCNH2 was screened by direct sequencing of all exons and intron borders in 22 probands with SQTS. Results: A mutation, T618I, in the pore region of KCNH2 gene, previously shown to produced a gain of function in IKr, was identified in 6 patients of 3 unrelated families diagnosed with SQTS+SCD (2) or SQTS+SIDS (1). Threonine (T) at position 618 is a highly conserved residue. Family 1 had a family history of SCD. The proband was symptomatic with palpitations, and inducible VF during EP study. Both proband and his son carried the mutation together with a K897T-KCNH2 polymorphism. Affected family members were all treated with quinidine. In family 2, the first child (II-1) died of SIDS. The proband, her brother and father, all diagnosed with SQTS, carried the T618I mutation together with a R1047L-KCNH2 polymorphism. The father of the proband in family 3 died of SCD at age 45. The proband carried the T618I mutation. Family members carrying modifier gene variants (K897T-KCNH2 and R1047L-KCNH2), previously shown to likely reduce IKr, had longer QT intervals. The average QT/QTc of all mutant carriers is 274±9ms/310±16ms. The pedigrees for the three families are shown below. Conclusion: We report a potential hotspot in KCNH2 contributing to the development of Type1 SQTS, SCD and SIDS.
A Mutation Hotspot in KCNH2 associated with Short QT Syndrome, SCD and SIDS
GIUSTETTO, Carla;GAITA, Fiorenzo;
2011-01-01
Abstract
Background: The short QT syndrome (SQTS) is a rare channelopathy associated with an increased risk of sudden cardiac death (SCD). Here, we report 3 unrelated SQTS families with an identical mutation associated with SCD and sudden infant death (SIDS). Methods: KCNH2 was screened by direct sequencing of all exons and intron borders in 22 probands with SQTS. Results: A mutation, T618I, in the pore region of KCNH2 gene, previously shown to produced a gain of function in IKr, was identified in 6 patients of 3 unrelated families diagnosed with SQTS+SCD (2) or SQTS+SIDS (1). Threonine (T) at position 618 is a highly conserved residue. Family 1 had a family history of SCD. The proband was symptomatic with palpitations, and inducible VF during EP study. Both proband and his son carried the mutation together with a K897T-KCNH2 polymorphism. Affected family members were all treated with quinidine. In family 2, the first child (II-1) died of SIDS. The proband, her brother and father, all diagnosed with SQTS, carried the T618I mutation together with a R1047L-KCNH2 polymorphism. The father of the proband in family 3 died of SCD at age 45. The proband carried the T618I mutation. Family members carrying modifier gene variants (K897T-KCNH2 and R1047L-KCNH2), previously shown to likely reduce IKr, had longer QT intervals. The average QT/QTc of all mutant carriers is 274±9ms/310±16ms. The pedigrees for the three families are shown below. Conclusion: We report a potential hotspot in KCNH2 contributing to the development of Type1 SQTS, SCD and SIDS.
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