Long QT molecular autopsy in sudden unexplained death in the young (1-40 years old): Lessons learnt from an eight year experience in New Zealand

Abstract

BackgroundTo review long QT syndrome molecular autopsy results in sudden unexplained death in young (SUDY) between 2006 and 2013 in New Zealand.MethodsAudit of the LQTS molecular autopsy results, cardiac investigations and family screening data from gene-positive families.ResultsDuring the study period, 365 SUDY cases were referred for molecular autopsy. 128 cases (35%) underwent LQTS genetic testing. 31 likely pathogenic variants were identified in 27 cases (21%); SCN5A (14/31, 45%), KCNH2 (7/31, 22%), KCNQ1 (4/31, 13%), KCNE2 (3/31, 10%), KCNE1 (2/31, 7%), KCNJ2 (1/31, 3%). Thirteen variants (13/128, 10%) were ultimately classified as pathogenic. Most deaths (63%) occurred during sleep. Gene variant carriage was more likely with a positive medical history (mostly seizures, 63% vs 36%, p = 0.01), amongst females (36% vs 12%, p = 0.001) and whites more than Maori (31% vs 0, p = 0.0009). Children 1–12 years were more likely to be gene-positive (33% vs 14%, p = 0.02). Family screening identified 42 gene-positive relatives, 18 with definitive phenotypic expression of LQTS/Brugada. 76% of the variants were maternally inherited (p = 0.007). Further family investigations and research now support pathogenicity of the variant in 13/27 (48%) of gene-positive cases.ConclusionIn New Zealand, variants in SCN5A and KCNH2, with maternal inheritance, predominate. A rare variant in LQTS genes is more likely in whites rather than Maori, females, children 1–12 years and those with a positive personal and family history of seizures, syncope or SUDY. Family screening supported the diagnosis in a third of the cases. The changing classification of variants creates a significant challenge.

<p>Spotlight on sudden arrhythmic death syndrome</p>

“…The fluid definition of pathogenicity due to expanding understanding of variants has been a common problem such as for investigators in New Zealand who reviewed molecular autopsies performed on 365 sudden unexplained death in the young (SUDY) cases between 2006 and 2013 for variants in LQTS genes. 63 Whilst 27 cases of gene variants were identified over an 8-year period, with the change in understanding of pathogenicity over time, only 13 of these remained as likely pathogenic with the rest being downgraded to VUS or polymorphisms by the Cardiac Inherited Disease Group. 63 The authors highlight the challenge of studying this population in the absence of whole exome control populations and the difficulty of defining pathogenicity.…”

“…63 Whilst 27 cases of gene variants were identified over an 8-year period, with the change in understanding of pathogenicity over time, only 13 of these remained as likely pathogenic with the rest being downgraded to VUS or polymorphisms by the Cardiac Inherited Disease Group. 63 The authors highlight the challenge of studying this population in the absence of whole exome control populations and the difficulty of defining pathogenicity. 63 In 2015, the American College of Medical Genetics (ACMG) published guidelines to tackle the challenge of a rapidly growing number of variants being detected through application of high-throughput next-generation sequencing.…”

“…63 The authors highlight the challenge of studying this population in the absence of whole exome control populations and the difficulty of defining pathogenicity. 63 In 2015, the American College of Medical Genetics (ACMG) published guidelines to tackle the challenge of a rapidly growing number of variants being detected through application of high-throughput next-generation sequencing. 64 They sought to standardize the terminology used to describe a variant's pathogenicity and provide guidance on how to assign variants into "pathogenic", "likely pathogenic", "uncertain significance", "likely benign" and "benign" categories.…”

Clinical and genetic profile of congenital long QT syndrome in Hong Kong: a 20-year experience in paediatrics

“…We believe that the total number of symptomatic and asymptomatic young patients with LQTS in Hong Kong is much higher than what we have studied in our single tertiary referral centre. 10,11 Long QT syndrome presentation Congenital LQTS is usually diagnosed in patients presenting with syncope, unexplained seizure, and aborted cardiac arrest. The mean QTc of our patients was 504 ± 47 ms, and median Schwartz score of the entire cohort was 4 points (range, 1-6 points).…”

Molecular genetic basis of sudden cardiac death in the young with cardiomyopathy of various origins

“…Мутации генов KCNQ1, KCNH2 и SCN5A, вызывающие LQTS1, 2 и 3 соответственно, являются так называемыми основными генами LQTS, а мутации в них предполагают высокую вероятность врожденного LQTS и имеют важное значение для стратификации риска [24]. Следует отметить различия в частоте встречаемости мутантных вариантов в зависимости от популяции [49].…”