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Molecular pathological study on LRRC10 in sudden unexplained nocturnal death syndrome in the Chinese Han population.

ABSTRACT: Sudden unexplained nocturnal death syndrome (SUNDS) is a perplexing disorder to both forensic pathologists and clinic physicians. Clinical features of SUNDS survivors suggested that SUNDS is similar to Brugada syndrome (BrS). Leucine-rich repeat containing 10 (LRRC10) gene was a newly identified gene linked to dilated cardiomyopathy, a disease associated with sudden cardiac death. To investigate the prevalence and spectrum of genetic variants of LRRC10 gene in SUNDS and BrS, the coding regions of LRRC10 were genetically screened in 113 sporadic SUNDS victims (from January 2005 to December 2015, 30.7 ± 7.5 years) and ten BrS patients (during January 2010 to December 2014, 38.7 ± 10.3 years) using direct Sanger sequencing. Afterwards, LRRC10 missense variant carriers were screened for a panel of 80 genes known to be associated with inherited cardiac arrhythmia/cardiomyopathy using target-captured next-generation sequencing. In this study, an in silico-predicted malignant LRRC10 mutation p.E129K was detected in one SUNDS victim without pathogenic rare variant in a panel of 80 arrhythmia/cardiomyopathy-related genes. We also provided evidence to show that rare variant p.P69L might contribute to the genetic cause for one SUNDS victim and two BrS family members. This is the first report of genetic screening of LRRC10 in Chinese SUNDS victims and BrS patients. LRRC10 may be a new susceptible gene for SUNDS, and LRRC10 variant was initially and genetically linked to BrS-associated arrhythmia.

SUBMITTER: Huang L

PROVIDER: S-EPMC5603906 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Molecular pathological study on LRRC10 in sudden unexplained nocturnal death syndrome in the Chinese Han population.

Huang Lei L Tang Shuangbo S Chen Yili Y Zhang Liyong L Yin Kun K Wu Yeda Y Zheng Jinxiang J Wu Qiuping Q Makielski Jonathan C JC Cheng Jianding J

International journal of legal medicine 20161228 3

Sudden unexplained nocturnal death syndrome (SUNDS) is a perplexing disorder to both forensic pathologists and clinic physicians. Clinical features of SUNDS survivors suggested that SUNDS is similar to Brugada syndrome (BrS). Leucine-rich repeat containing 10 (LRRC10) gene was a newly identified gene linked to dilated cardiomyopathy, a disease associated with sudden cardiac death. To investigate the prevalence and spectrum of genetic variants of LRRC10 gene in SUNDS and BrS, the coding regions o ...[more]

PMID: 28032242

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Project description:Increasing evidence observed in clinical phenotypes show that abrupt breathing disorders during sleep may play an important role in the pathogenesis of sudden unexplained nocturnal death syndrome (SUNDS). The reported Brugada syndrome causing mutation R1512W in cardiac sodium channel ? subunit encoded gene SCN5A, without obvious loss of function of cardiac sodium channel in previous in vitro study, was identified as the first genetic cause of Chinese SUNDS by us. The R1512W carrier was a 38-year-old male SUNDS victim who died suddenly after tachypnea in nocturnal sleep without any structural heart disease. To test our hypothesis that slight acidosis conditions may contribute to the significant loss of function of mutant cardiac sodium channels underlying SUNDS, the biophysical characterization of SCN5A mutation R1512W was performed under both extracellular and intracellular slight acidosis at pH 7.0. The cDNA of R1512W was created using site-directed mutagenesis methods in the pcDNA3 plasmid vector. The wild type (WT) or mutant cardiac sodium channel R1512W was transiently transfected into HEK293 cells. Macroscopic voltage-gated sodium current (INa) was measured 24?hours after transfection with the whole-cell patch clamp method at room temperature in the HEK293 cells. Under the baseline conditions at pH 7.4, R1512W (-175?±?15?pA/pF) showed about 30% of reduction in peak INa compared to WT (-254?±?23?pA/pF, P?<?0.05). Under the acidosis condition at pH 7.0, R1512W (-130?±?17?pA/pF) significantly decreased the peak INa by nearly 50% compared to WT (-243?±?23?pA/pF, P?<?0.005). Compared to baseline condition at pH 7.4, the acidosis at pH 7.0 did not affect the peak INa in WT (P?>?0.05) but decreased peak INa in R1512W (P?<?0.05). This initial functional study for SCN5A mutation in the Chinese SUNDS victim revealed that the acidosis aggravated the loss of function of mutant channel R1512W and suggested that nocturnal sleep disorders-associated slight acidosis may trigger the lethal arrhythmia underlying the sudden death of SUNDS cases in the setting of genetic defect.

Project description:ObjectiveTo look for previously unrecognized cardiac structural abnormalities and address the genetic cause for sudden unexplained nocturnal death syndrome (SUNDS).MethodsData for 148 SUNDS victims and 444 controls (matched 1:3 on sex, race, and age of death within 1 year) were collected from Sun Yat-sen University from January 1, 1998, to December 31, 2014, to search morphological changes. An additional 17 patients with Brugada syndrome (BrS) collected from January 1, 2006, to December 31, 2014, served as a comparative disease cohort. Target-captured next-generation sequencing for 80 genes associated with arrhythmia/cardiomyopathy was performed in 44 SUNDS victims and 17 patients with BrS to characterize the molecular spectrum.ResultsThe SUNDS victims had slight but statistically significant increased heart weight and valve circumference compared with controls. Twelve of 44 SUNDS victims (SCN5A, SCN1B, CACNB2, CACNA1C, AKAP9, KCNQ1, KCNH2, KCNJ5, GATA4, NUP155, ABCC9) and 6 of 17 patients with BrS (SCN5A, CACNA1C; P>.05) carried rare variants in primary arrhythmia-susceptibility genes. Only 2 of 44 SUNDS cases compared with 5 of 17 patients with BrS hosted a rare variant in the most common BrS-causing gene, SCN5A (P=.01). Using the strict American College of Medical Genetics guideline-based definition, it was found that only 2 of 44 (KCNQ1) SUNDS and 3 of 17 (SCN5A) patients with BrS hosted a "(likely) pathogenic" variant. Fourteen of 44 SUNDS cases with cardiomyopathy-related variants had a subtle but significantly decreased circumference of cardiac valves, and tended to die on average 5 to 6 years younger compared with the remaining 30 cases (P=.02).ConclusionWe present the first comprehensive autopsy evidence that SUNDS victims may have concealed cardiac morphological changes. SUNDS and BrS may result from different molecular pathological underpinnings. The distinct association between cardiomyopathy-related rare variants and SUNDS warrants further investigation.

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Molecular pathological study on LRRC10 in sudden unexplained nocturnal death syndrome in the Chinese Han population.

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Molecular pathological study on LRRC10 in sudden unexplained nocturnal death syndrome in the Chinese Han population.

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