Wolff-Parkinson-White Syndrome: De Novo Variants and Evidence for Mutational Burden in Genes Associated with Atrial Fibrillation

BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting ~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population. METHODS: We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, candidate gene approach, and burden testing to explore the genetic contributions to WPW. RESULTS: A heterozygous deleterious variant in PRKAG2 was identified in one subject, accounting for 0.6% (1/151) of the genetic basis of WPW in this study. Another individual with WPW and left ventricular hypertrophy carried a known pathogenic variant in MYH7. We found rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, and PRDM16) in this cohort. There was an increased burden of rare deleterious variants (MAF ≤ 0.005) with CADD score ≥ 25 in genes linked to AF in cases compared to controls (P = .0023). CONCLUSIONS: Our findings show an increased burden of rare deleterious variants in genes linked to AF in WPW syndrome, suggesting that genetic factors that determine the development of accessory pathways may be linked to an increased susceptibility of atrial muscle to AF in a subset of patients

Facile dihydroxylation of styrene using clay based catalysts

Dihydroxylation of styrene to 1-phenyl-1,2-dihydroxyethane is studied using iodosyl benzene as an oxidant and various modified bentonite clays (1 M-H-clay; proton exchange; Fe-exchanged clay; and Mn(III)-salen-exchanged clay) as catalyst. Catalytic activity was found to be higher for Fe-exchanged clay for intermediate epoxide formation. Studies clearly show that free Fe(III) species present in the interlayer space are responsible for its reactivity. The intermediate epoxide is converted to 1-phenyl-1,2-dihydroxy-ethane by Bronsted acidity of the clay and the water present in the reaction media

Oxygenation and carbonylation studies of some ruthenium(III) Schiff base complexes containing nitrogen and oxygen as donor atoms. II

Synthesis and characterization of a series of ruthenium(III) Schiff base complexes of the type [Ru<SUP>III</SUP>LXY] where L=Schiff base viz. bis(naphthaldehyde)-o-phenylenediimine (naphoph), bis(naphthaldehyde)ethylenediimine (naphen), bis(naphthaldehyde)propylenediimine (naphprop) and bis(naphthaldehyde)diethylenetriimine (naphdien); X=Cl and Y=Cl imidazole (Im) or 2-methylimidazole (2-MeIm) are reported. Elemental analysis, conductivity and IR studies of the complexes suggest an octahedral geometry around ruthenium. Magnetic moments of the complexes indicate a single unpaired electron in a low spin d<SUP>5</SUP> configuration. Oxygenation studies in DMF or THF solutions suggest the reversible binding of molecular oxygen to the ruthenium(III) complexes. EPR studies at liquid nitrogen temperature and UV---Vis measurements at room temperature support the formation of a Ru(IV) superoxo species [Ru<SUP>IV</SUP>L(O<SUB>2</SUB>)<SUP>−</SUP>Y]. The EPR spectrum of the Ru(IV) superoxo complex at 77 K (g<SUB>1</SUB>=2.063, g<SUB>2</SUB>=2.047, g<SUB>3</SUB>=2.023) is consistent with the odd electron occupying a highly localized antibonding π<SUP>∗</SUP> orbital of molecular oxygen. The reversible binding of O<SUB>2</SUB> and CO has been carried out in DMF at 10, 25 and 40°C. The complexes show discrimination against the binding of CO over O<SUB>2</SUB> as evinced by values of K<SUB>O<SUB>2</SUB></SUB> and K<SUB>CO</SUB> in the complexes. The thermodynamic paramegers ΔH°, ΔG° and ΔS° for oxygenation and carbonylation reactions are evaluated

Synthesis, characterisation, oxygenation and carbonylation of ruthenium(III) schiff base complexes

Some ruthenium(III) Schiff base complexes of the type [RuLXY]<SUP>n</SUP> where L=Schiff base namely, bis(α-hydroxyacetophenone)-o-phenylenediimine (α-acetop.oph), bis(2-hydroxy-4-methoxyacetophenone) -o-phenylenediimine (4-MeOacetop.oph), bis(α-hydroxyacetophenone)ethylenediimine (α-acetop.en), bis(2-hydroxy-4-methoxyacetophenone)ethylenediimine (4-MeOacetop.en), bis(α-hydroxyacetophenone) propylenediimine (α-acetop.prop), bis(2-hydroxy- 4-methoxyacetophenone)propylendiimine (4-MeOacetop.prop), bis(a-hydroxyacetophenone)diethylenetriimine (α-acetop.dien), bis(2-hydroxy-4-methoxyacetophenone) diethylenetriimine (4-MeOacetop.dien), n=−1 when X=Y=Cl<SUP>−</SUP>, n=0 when X=imidazole (Im), 2-methylimidazole (2-MeIm) and Y=Cl<SUP>−</SUP> were synthesised and characterised by physicochemical methods. The reversible binding of molecular oxygen as well as carbon monoxide was carried out in DMF. The complexes show discrimination against the binding of CO over molecular oxygen as evinced by the values of K<SUB>O<SUB>2</SUB></SUB> and K<SUB>CO</SUB> in the complexes. The thermodynamic parameters ΔH°, ΔG°, ΔS° for the carbonylation and oxygenation reactions at 10, 25 and 40°C are evaluated

Wolff–Parkinson–White

Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting ~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population.We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, candidate gene approach, and burden testing to explore the genetic contributions to WPW.A heterozygous deleterious variant in PRKAG2 was identified in one subject, accounting for 0.6% (1/151) of the genetic basis of WPW in this study. Another individual with WPW and left ventricular hypertrophy carried a known pathogenic variant in MYH7. We found rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, and PRDM16) in this cohort. There was an increased burden of rare deleterious variants (MAF ≤ 0.005) with CADD score ≥ 25 in genes linked to AF in cases compared to controls (P = .0023).Our findings show an increased burden of rare deleterious variants in genes linked to AF in WPW syndrome, suggesting that genetic factors that determine the development of accessory pathways may be linked to an increased susceptibility of atrial muscle to AF in a subset of patients