Infant sudden death: Mutations responsible for impaired Nav1.5 channel trafficking and function

Abstract

These sudden infant death syndrome (SIDS)-related variants caused a severely dysfunctional Nav1.5 channel, which was mainly due to trafficking defects caused by the Q1832E mutation. The decreased current density is likely to be a major contributing factor to arrhythmogenesis in Brugada syndrome and the sudden death of this SIDS victim.

Molecular autopsy: using the discovery of a novel de novo pathogenic variant in the KCNH2 gene to inform healthcare of surviving family

“…In a published cohort of 28 sudden death in the young (SDY) [23], about 50% of pathogenic variants resulted from de novo alterations. Besides de novo variants, the identification of an inherited variant would also enable targeted cascade variant testing in family members and genotype-phenotype correlation through clinical evaluations as we have previously reported [1, 2, 3].…”

“…The National Institute of Justice has also substantially supported the technology expansion to massive parallel sequencing, functional study and genetic counseling through several research grants. We have published our work on testing for thrombophilia [6, 32] and for cardiac arrhythmogenic genes [1, 3, 4, 5], and we expect to add testing for other inheritable conditions at risks for sudden death, such as epilepsy and aortopathy soon. Joining other studies that described recommendations for molecular autopsy [31, 33], we have outlined an example of best practice of postmortem diagnosis and effective care for the survival family members in this manuscript.…”

“…One of the overlooked areas is postmortem genetic testing of decedents who died naturally, suddenly, and unexpectedly at young ages (molecular autopsy). The value of molecular autopsy in the determination of underlying natural causes of death, and the subsequently improved healthcare of surviving family members has been shown in numerous case reports [1, 2, 3]and cohort studies [4, 5, 6]. However, primarily due to lack of coverage from medical insurance, genetic testing of the deceased is not routinely performed in most of the United States, as it is in our Office in the City of New York, leaving thousands of cases unsolved each year and at-risk family members on the hook.…”

SCN5A Variants: Association With Cardiac Disorders

“…Variants in SCN5A led to severe trafficking defects and a severely dysfunctional Na v 1.5 channel in a structurally normal heart. The decreased current density was likely to be a major contributing factor to the lethal arrhythmia in SIDS victim (Gando et al, 2017 ). Given the potential risk of inherited cardiac conditions caused by ultra-rare gene variants, current experts has made consensus statement on post-mortem genetic testing (molecular autopsy) and clinical investigation of surviving blood relatives.…”

Variants of RBM20 gene in pediatric patients with dilated cardiomyopathy

“…При помощи высокопроизводительной целевой панели у пациента была идентифицирована мутация в гене RBM20. Ранее она была описана у пациента с ДКМП (RBM20 Chr10: 112581114, rs397516607, NM_001134363.2: c.G2737A: p.Glu913Lys) [7], в связи с чем по классификации ACMG выявленный генетический вариант был определен как патогенный. Область, в которой находится найденный вариант Glu913Lys, является высококонсервативной среди ортологов, что указывает на функциональную значимость данного участка (рис.…”