Sudden Unexplained Nocturnal Death Syndrome: The Hundred Years' Enigma

Figures

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  Figure 1. Milestones in SUNDS. It has been 100 years since the first description of SUNDS in 1917 in Philippines. There were 2 major active periods of studies on SUNDS: The early stage mainly focused on collecting the epidemiological characteristics and revealing the probable external environmental risk factors; the later stage was aimed at uncovering the intrinsic gene susceptibility. BrS indicates Brugada Syndrome; CCS, cardiac conduction system; CDC, Centers for Disease Control and Prevention; SUNDS, sudden unexplained nocturnal death syndrome; US, the United States; VF, ventricular fibrillation.

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  Figure 2. Predicted protein topology of ion channels and the location of variations responsible for SUNDS. A, Cardiac sodium channel comprises a pore‐forming ion‐conducting α‐subunit Nav1.5 and ancillary β‐subunits. B through D, Predicted protein topology of Nav1.8 (SCN10A), Kv11.1 (KCNH2), Kv7.1 (KCNQ1), MinK (KCNE1), MiRP1 (KCNE2), CaV1.2 (CACNA1C), and RyR2. Pathogenicity is determined by ACMG guideline. ACMG indicates American College of Medical Genetics; SUNDS, sudden unexplained nocturnal death syndrome.

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  Figure 3. Protein‐to‐protein interaction of the 33 genes responsible for SUNDS. We conducted a protein‐to‐protein interaction using STRING (https://string-db.org) and found that most of these proteins have a direct or indirect interaction with SCN5A. Line thickness indicates the strength of data support. SUNDS indicates sudden unexplained nocturnal death syndrome.

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  Figure 4. Triple‐risk hypothesis of SUNDS. We propose that SUNDS occurs when 3 factors coincide: a vulnerable young person carrying susceptible variants; stressors caused by environmental or social factors; and finally a disturbance in action potential production and propagation in nocturnal sleep. The final pathway of SUNDS is commonly accepted as lethal ventricular arrhythmia. Cardiac structural changes may also be potential but unnecessary structure substrates for SUNDS. Whether the structural changes are a primary cause or a secondary change is still unknown. Certain associations between potential structure substrate, genetic risk factors, and impaired action potential production and propagation have yet to be demonstrated (dashed arrow). AP indicates action potential; REM, rapid eye movement; SUNDS, sudden unexplained nocturnal death syndrome.

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  Figure 5. The multifactorial model of SUNDS. In this model, we set a supposed threshold for the multifactorial disease. The 2 major parts, namely, intrinsic genetic susceptibility and extrinsic risk burden, determine whether SUNDS occurs or not. People with different genetic background show different intrinsic genetic susceptibility to SUNDS. SUNDS indicates sudden unexplained nocturnal death syndrome.