Study on Gene Mutations of Hereditary Heart Diseases in Cases of Yunnan Sudden Unexplained Death

ZhaoHuizuo¹1

MaLin¹1

XiYanmei¹1

TangXue¹1

ShenMeifen¹1

SunMengyao¹1

YangYongpeng¹1

WangYuebing¹1✉

YuebingWang1

ChiefPhysician1Phone(0871)67451519Email1430646497@qq.com

1Yunnan Provincial Key Laboratory of Natural Epidemic Disease Prevention and Control TechnologyYunnan Provincial Institute of Endemic Disease Prevention and Control650500Kunming YunnanPeople’s Republic of China

Zhao Huizuo¹, Ma Lin¹, Xi Yanmei¹, Tang Xue¹, Shen Meifen¹, Sun Mengyao¹, Yang Yongpeng¹, Wang Yuebing¹*

Affiliations:

Yunnan Provincial Institute of Endemic Disease Prevention and Control, Yunnan Provincial Key Laboratory of Natural Epidemic Disease Prevention and Control Technology, Kunming Yunnan, People’s Republic of China

* Correspondence to

Yuebing Wang, Chief Physician

Yunnan Provincial Institute of Endemic Disease Prevention and Control, Yunnan Provincial Key Laboratory of Natural Epidemic Disease Prevention and Control Technology, Kunming Yunnan ,650500

Tel: (0871) 67451519 Email: 1430646497@qq.com

Abstract

Background

Yunnan sudden unexplained death (YNSUD) is a regional public health issue with unclear etiology, characterized by temporal, geographical, and familial clustering. This study aimed to identify pathogenic genetic mutations in hereditary heart disease among YNSUD cases and explore their etiological association.

Methods

Whole-exome sequencing was performed on 11 YNSUD cases and 11 healthy controls. Mutations were validated by Sanger sequencing, and functional predictions were conducted using SIFT, PolyPhen2, and Mutation Taster. Family history was investigated for genetic analysis.

Results

Eighty-one point eight percent (9/11) of YNSUD cases carried 39 unique mutations in 14 genes associated with hereditary heart disease, including TTN, DMD, and DSP. Eighty-two point two percent (32/39) of mutations were predicted to be pathogenic. Eight cases (72.7%) had compound mutations (2–16 mutations per case). A novel mutation (DMD:exon49:c.C7151A:p.S2384Y) was identified. Family clustering was observed, e.g., mother-daughter pair LM and LXL shared TTN mutations. No overlapping mutations were found between cases and controls.

Conclusions

YNSUD is closely associated with pathogenic mutations in hereditary heart disease genes, highlighting the need for genetic screening in high-risk populations to reduce sudden death risk.

Keywords:

Yunnan sudden unexplained death

Hereditary heart disease

Gene mutation

Whole-exome sequencing

Pathogenic mutation

1 Background

Sudden cardiac death (SCD) accounts for 70–80% of sudden deaths worldwide, posing a major public health challenge [1, 2]. Sudden unexplained death (SUD) remains poorly understood despite comprehensive post-mortem examinations [3]. YNSUD, a regional SUD variant in southwest China, has caused 421 cases since 1975, with distinct clustering in rainy seasons and impoverished rural areas of central-western Yunnan [4].

Epidemiological studies indicate 75.3% of YNSUD cases show family aggregation, and 42% of familial cases have blood relationships, suggesting genetic factors [5]. Previous research has linked YNSUD to abnormal myocardial enzymes, electrocardiographic repolarization abnormalities, and potential associations with arrhythmogenic right ventricular cardiomyopathy (ARVC) [1, 6]. However, specific pathogenic genetic mutations remain uncharacterized.

Hereditary heart diseases, including ARVC, Brugada syndrome (BrS), and long QT syndrome (LQTS), are major causes of SCD, with pathogenic mutations in genes like DSP, SCN5A, and KCNH2 [7, 8]. This study aimed to screen for mutations in hereditary heart disease genes among YNSUD cases using whole-exome sequencing, to clarify their etiological role and provide a basis for prevention strategies.

2 Methods

2.1 Study participants

Eleven YNSUD cases with collectible blood samples were enrolled from endemic areas in Yunnan for whole-exome sequencing, and their basic information is shown in Table 1. These cases included 2 mother-daughter pairs [LM&LXL], 1 sister pair [ZLS1&ZLS2], and 2 married couples [ZLS2&ZZX, SJZ&SJL].

Table 1
Demographic characteristics of YNSUD cases
No.	Case ID	County	Gender	Age (years)	Time of death
1	WSC	Dayao	Female	39	2007-07-30
2	SJZ	Chuxiong	Female	45	2007-08-08
3	SJL	Chuxiong	Male	49	2007-08-08
4	YJF	Mouding	Female	42	2008-07-06
5	ZLS1	Heqing	Female	32	2009-08-03
6	ZLS2	Heqing	Female	29	2009-08-04
7	ZZX	Heqing	Male	32	2009-08-04
8	WJP	Xiangyun	Male	27	2009-08-18
9	LM	Lufeng	Female	5	2015-07-22
10	LXL	Lufeng	Female	2	2015-07-22
11	LSF	Lufeng	Female	38	2015-07-13

Eleven healthy controls were selected from regions with similar geography, environment, and economy to the endemic areas but without YNSUD cases. Controls had no history of cardiovascular or systemic diseases.

This study was approved by the Medical Ethics Committee of Yunnan Institute for Endemic Disease Control and Prevention (Approval No. Yun Disuo Yilun [2024] No. 04) Informed consent was obtained from all control participants and the relatives of deceased cases. The study complied with the Regulations on the Administration of Human Genetic Resources.

2.2 Sample collection

Peripheral blood samples (0.5 ml per individual) were collected from YNSUD cases and controls, stored at -80°C, and transported to Sangon Biotech (Shanghai) Co., Ltd. for testing. Family history of YNSUD cases was investigated via interviews, and pedigrees were constructed for genetic analysis.

2.3 Reagents and instruments

Hieff NGSR®MaxUp II DNA Library Prep Kit (Yeasen, Shanghai, China; cat. no. 12200ES08)

Qubit™ dsDNA HS Assay Kit (ThermoFisher, Waltham, USA; cat. no. Q32854)

Hieff NGSTM DNA Selection Beads (Yeasen, Shanghai, China; cat. no. 12601ES56)

Covaris S220 Ultrasonic DNA Fragmenter (Covaris, Woburn, USA)

Illumina NovaSeq 6000 Sequencing Platform (Illumina, San Diego, USA)

Thermo Qubit 4.0 Fluorometer (ThermoFisher, Waltham, USA; cat. no. Q33226)

2.4 Whole-exome sequencing

2.4.1 Data processing and quality control

Genomic DNA was extracted and fragmented using ultrasonic disruption. Libraries were constructed and sequenced on the Illumina NovaSeq 6000 platform (PE150). Raw reads were filtered using Fastp software to remove adapter sequences, reads with > 40% low-quality bases (Q ≤ 20), and reads with > 10% undetermined bases. Clean data were aligned to the hg19/hg38 reference genome using BWA software, followed by sorting and deduplication with GATK to obtain sequencing depth and coverage metrics.

2.4.2 Mutation screening and annotation

ANNOVAR software was used to annotate mutations, focusing on genes previously associated with cardiomyopathy and cardiac ion channel diseases. Mutations were filtered against the 1000 Genomes Project, dbSNP, and COSMIC databases to retain rare variants (minor allele frequency ≤ 0.01) and potential pathogenic mutations.

2.4.3 Mutation validation and functional prediction

Functional predictions were conducted using SIFT, PolyPhen2, and Mutation Taster. Considering the small sample size of YNSUD cases in this study, mutations were classified as "pathogenic" if predicted harmful by at least one tool to avoid missing potential disease-related variants.

2.4.4 Statistical analysis

Enrichment analysis of biological processes for pathogenic genes identified in YNSUD cases was performed using the Gene Ontology (GO) database (http://geneontology.org/). The analysis focused on the "Biological Process (BP)" category to explore the functional association of mutated genes. Raw P-value < 0.05 was set as the statistical significance threshold (without false discovery rate [FDR] correction in this stage, aiming to initially highlight the enrichment trend of genes in myocardial function-related pathways; subsequent functional validation will further confirm the authenticity of candidate pathways). The enrichment results were visualized using a bar chart, with the x-axis representing -lg(P-value) (the negative logarithm of raw P-value, higher values indicate stronger enrichment significance) and the y-axis representing enriched biological processes.

3 Results

3.1 Clinical characteristics and family clustering

YNSUD cases occurred between 2007 and 2015, with ages ranging from 2 to 49 years (Table 1). Family pedigrees showed a clustered onset.with 75.3% of cases having familial history (Fig. 1). Sudden death occurred within 24 hours without obvious prodromal symptoms.

Fig. 1

Pedigree of YNSUD families with familial clustering

3.2 Sequencing data quality

All 11 YNSUD cases had high-quality sequencing data, with Q20 > 96% and ≥ 30X coverage ranging from 81.57% to 96.18%, ensuring reliable mutation analysis.

3.3 Mutation spectrum in YNSUD cases

A total of 39 unique mutations in 14 genes associated with hereditary heart disease were identified in 9 YNSUD cases (mutation rate 81.8%). Eight cases (72.7%) carried compound mutations (2–16 mutations per case).

3.4 Key mutations included:

TTN: 6 mutations (e.g., exon154:c.C48874T:p.R16292C) in LM and LXL

DMD: 10 mutations, including a novel mutation (exon49:c.C7151A:p.S2384Y) in ZLS2

DSP: exon9:c.A1049G:p.Y350C (associated with ARVC)

Controls carried 9 unique mutations in 5 genes, with no overlap with cases (Table 2).

Table 2
Genetic mutations in YNSUD cases and their functional predictions
Gene	Mutation site	Case ID	SIFT	Polyphen2	Mutation Taster	Associated disease
TTN	exon154:c.C48874T:p.R16292C、exon155:c.C49249T:p.R16417C、exon155:c.C49450T:p.R16484C、exon275:c.C68365T:p.R22789C、exon276:c.C71146T:p.R23716C、exon326:c.C76069T:p.R25357C	LM、LXL	D	D	D	HCM、DCM、LVNC、ARVC
FLNC	exon18:c.G2686A:p.G896R		D	D	D	DCM、HCM
KIF21B	exon15:c.G2224A:p.E742K		D	P	D	DCM、HCM、LQTS
KCNE5	exon1:c.T241C:p.Y81H		D	B	D	BrS、ARVC
DSP	exon9:c.A1049G:p.Y350C		D	D	D	ARVC、DCM
DMD	exon21:c.C3128A:p.S1043Y、exon21:c.C3119A:p.S1040Y、exon49:c.C7127A:p.S2376Y、exon49:c.C7151A:p.S2384Y* 、exon49:c.C7139A:p.S2380Y、exon49:c.C6782A:p.S2261Y	ZLS2	D	D	D	LQTS、DCM
SIDT1	exon21:c.A2023G:p.K675E、exon22:c.A2125G:p.K709E、exon22:c.A1756G:p.K586E、exon22:c.A1666G:p.K556E、exon22:c.A1453G:p.K485E、exon22:c.A928G:p.K310E、exon22:c.A2194G:p.K732E、exon23:c.A2209G:p.K737E、exon23:c.A2212G:p.K738E	ZLS2、ZLS1	D	D	D	LQTS
CSRP3	exon2:c.G16A:p.G6R	ZZX	D	D	D	DCM、HCM
DSG2	exon15:c.C2470T:p.R824C	ZZX	D	B	N	ARVC、DCM、HCM
JUP	exon7:c.C958T:p.R320C	WJP	D	D	D	ARVC
PRDM16	exon9:c.G1574A:p.R525Q	WJP、YJF	D	D	D	LVNC
DMD	exon11:c.C1462G:p.Q488E、exon11:c.C1453G:p.Q485E、exon39:c.C5461G:p.Q1821E、exon39:c.C5485G:p.Q1829E、exon39:c.C5473G:p.Q1825E、exon39:c.C5116G:p.Q1706E	SJL	D	B	N	LQTS、DCM
SGCD	exon8:c.A845G:p.Q282R、exon9:c.A848G:p.Q283R	SJL	T	D	D	DCM、HCM
AKAP9	exon9:c.T3430C:p.C1144R	YJF	D	D	D	LQTS、BrS、CPVT
EMD	exon5:c.G445C:p.D149H	WSC	D	P	N	DCM
Note: D = Damaging; B = Benign; P = Possibly damaging; N = Polymorphism; T = Tolerated;*Novel mutation identified in this study; ARVC = Arrhythmogenic right ventricular cardiomyopathy; DCM = Dilated cardiomyopathy; HCM = Hypertrophic cardiomyopathy; LQTS = Long QT syndrome༛ LVNC = Left ventricular noncompaction; CPVT = Catecholaminergic polymorphic ventricular tachycardia.

3.5 Functional prediction of mutations

Thirty-two of 39 mutations (82.2%) were predicted pathogenic by at least two tools (SIFT, PolyPhen2, Mutation Taster). TTN and DSP mutations were consistently predicted harmful, suggesting roles in myocardial structural damage and arrhythmogenesis (Table 2).

3.6 Sanger sequencing validation

Seventeen mutations in 7 cases (e.g., TTN exon155:c.C49249T, JUP exon7:c.C958T) were validated as heterozygous true positives. One FLNC mutation was not confirmed due to DNA quality issues.

3.7 Enrichment analysis

GO biological process enrichment analysis of 9 YNSUD cases’ pathogenic genes (including TTN, DSP, DMD, etc.) showed significant functional clustering (Fig. 2). Specifically, the mutated genes were significantly enriched in myocardial function-related pathways (all P < 0.05):Cardiac muscle contraction (P = 0.002, -lgP = 2.698), which is the core pathway maintaining normal heart pumping function;

Fig. 2

GO enrichment analysis of mutated genes in YNSUD cases

X-axis: -log10(P-value);

Y-axis: Biological process;

Bars: Rich factor (number of mutated genes in the process/total number of genes in the process);

Note: Enriched biological processes are shown; P < 0.05 was considered statistically significant.

Heart process (P = 0.005, -lgP = 2.301), involving the regulation of heart development and physiological function;Muscle system process (P = 0.008, -lgP = 2.096), closely related to the structural stability of myocardial cells.In addition, non-cardiac pathways such as "multicellular organismal process" (P = 0.012, -lgP = 1.921) were also slightly enriched, but their -lgP values were lower than those of cardiac-related pathways, indicating that the functional impact of mutations mainly focused on myocardial tissue.

4 Discussion

4.1 Mutation spectrum of YNSUD cases

This study identified high rates of pathogenic mutations in hereditary heart disease genes among YNSUD cases, supporting a genetic etiological component.TTN mutations, found in the mother-daughter pair, are known to cause dilated cardiomyopathy (DCM) and ARVC by disrupting myocardial structural integrity [9, 10]. ARVC-related desmosomal gene mutations (DSP, DSG2, JUP) were prevalent, consistent with previous findings of 37.1% ARVC-related mutation rates in YNSUD endemic areas [1]. These mutations may disrupt myocardial cell junctions, leading to fibrofatty replacement and malignant arrhythmias [11–13].

Compound mutations (e.g., JUP + PRDM16 in WJP) suggest a "two-hit" mechanism, exacerbating myocardial damage and increasing sudden death risk. Family clustering of shared mutations (e.g., TTN in LM&LXL) indicates heritability, possibly autosomal dominant.The novel DMD mutation expands the spectrum of X-linked DCM, which can cause fatal heart failure in female carriers despite absent skeletal muscle symptoms [14, 15].

Cases frequently exhibited the coexistence of multiple gene mutations. For example, case WJP carried mutations in JUP and PRDM16: the former disrupts myocardial cell junctions, while the latter affects myocardial differentiation through transcriptional regulation [16, 17]; case SJL harbored mutations in SGCD and DMD simultaneously, which could synergistically reduce myocyte membrane stability and induce myocardial fibrosis [18, 19]. Such compound mutations may exacerbate myocardial damage via the "two-hit" mechanism, explaining the clinical characteristics of sudden death in Yunnan, namely its acute onset and high mortality rate.

The NUP155 mutation identified in the sudden death family from Lufeng City [8], as well as the SCN5A and MYH6 mutations detected in 25 relatives of sudden death cases in Yunnan [7], all highlight the core role of hereditary heart diseases. As an efficient screening tool, whole-exome sequencing has captured key genetic variants in genes such as TTN and DMD, providing molecular evidence for the etiological research of sudden death in Yunnan [20, 21]. These findings not only support the inference that "hereditary heart diseases are the main cause of some sudden death cases in Yunnan" but also lay a foundation for establishing a prevention and control system encompassing "genetic screening - risk assessment - early intervention".

4.2 Functional implications of mutations

Table 2 shows that YNSUD cases carry multiple pathogenic mutations in heart disease-related genes, such as TTN (associated with HCM, DCM) and DSP (associated with ARVC). These mutations have been reported in previous studies to cause structural or electrical abnormalities of the heart, which may be the genetic basis of sudden death.

To further clarify the functional impact of these mutations, we performed GO biological process enrichment analysis, and the results further supported the pathogenic association between YNSUD and myocardial function defects (Fig. 2). The significant enrichment of mutated genes in "cardiac muscle contraction" and "heart process" (P < 0.05) is consistent with the clinical phenotype of YNSUD (sudden death caused by arrhythmia or cardiomyopathy): for example, TTN mutations (enriched in cardiac muscle contraction pathway) can lead to myocardial structural damage (such as HCM, DCM), while DSP mutations can disrupt myocardial cell adhesion and trigger ARVC—both of which are key pathological mechanisms of sudden death.It should be noted that this study used raw P-values instead of FDR-corrected Q-values to present enrichment trends. Although raw P-values may have potential false positives due to multiple pathway tests, the consistent enrichment of 3 independent cardiac-related pathways (all P < 0.05) and their known association with hereditary heart diseases (as shown in Table 2) reduce the risk of false positive results. In future studies, we will expand the sample size and conduct in vitro functional experiments (e.g., cardiomyocyte mutation transfection) to further verify the pathogenicity of these enriched pathways.

This finding is consistent with Wang et al. (2024), who reported that sudden unexplained death cases in southern China also showed enrichment of myocardial contraction-related mutations

Limitations include small sample size and lack of functional experiments to validate mutation pathogenicity. Future studies with larger cohorts and in vitro functional assays are needed.

5 Conclusions

Yunnan sudden unexplained death is closely associated with pathogenic mutations in hereditary heart disease genes, particularly TTN, DMD, and ARVC-related desmosomal genes. Genetic screening of high-risk populations and family-based interventions may reduce YNSUD incidence.

6 Abbreviations

YNSUD

Yunnan sudden unexplained death

ARVC

Arrhythmogenic right ventricular cardiomyopathy

BrS

Brugada syndrome

CPVT

Catecholaminergic polymorphic ventricular tachycardia

DCM

Dilated cardiomyopathy

HCM

Hypertrophic cardiomyopathy

LQTS

Long QT syndrome

LVNC

Left ventricular noncompaction

Data Availability

The datasets generated and/or analysed during the current study are associated with the NCBI BioProject accession PRJNA1354792 (link: https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1354792). The whole-exome sequencing data of 11 Yunnan Sudden Unexplained Death (YNSUD) cases have been partially deposited in the NCBI Sequence Read Archive (SRA) via the Aspera platform.A total of 22 sequencing files (totaling 52.5 GB) were successfully uploaded to the folder "YNSUD-rawdata" on 2025-10-30 18:05, and these files are currently in the SRA preload system.Five files (e.g., LXL.raw\_1.fastq.gz, SJL.raw\_1.fastq.gz) remain unprocessed due to persistent technical issues, specifically "FTP transfer failures or file compression incompatibilities" as indicated in the SRA submission portal (SUB15732729). All feasible troubleshooting steps have been exhausted, including re-compressing the files using standard gzip protocols and multiple re-upload attempts via Aspera. We will continue to coordinate with our technical team to verify raw data integrity and resolve these issues as soon as possible.All study-related datasets, including genetic polymorphisms, linked genotype-phenotype data of the cases, and mutation functional prediction results, will be publicly accessible via the aforementioned SRA link once full deposition is finalized. For reasonable academic requests, additional supporting materials (e.g., Sanger sequencing validation electropherograms, detailed case metadata) can be obtained from the corresponding author (Yuebing Wang, Email: 1430646497@qq.com) after completing the data access application process required by the repository.

Author Contribution

Zhao Huizuo and Wang Yuebing conceived and designed the study; Ma Lin, Xi Yanmei, Tang Xue, Shen Meifen, Sun Mengyao, and Yang Yongpeng were responsible for data collection; Zhao Huizuo was responsible for data analysis and drafting the manuscript; Wang Yuebing provided guidance for the revision of the draft; all authors critically revised the manuscript for scientific content and approved the final version of the article.

9 Acknowledgements

Thanks to the Yunnan Institute for Endemic Disease Control and Prevention for sample collection, and Sangon Biotech for sequencing support.

10 Funding

National Natural Science Foundation of China (81960573); Project of Training Objects for Technical Innovation Talents in Yunnan Province (202405AD350026);The Special Medical and Health Talent Project of "Talent Support Program in Yunnan"(XDYC-YLWS-2024-0065).

Declarations

11.1 Ethics approval and consent to participate

The study was approved by the Medical Ethics Committee of Yunnan Institute for Endemic Disease Control and Prevention (Approval No. Yundisuo Yilun [2024] No. 04). All procedures involving human participants and human-derived materials (peripheral blood samples of YNSUD cases and healthy controls) were conducted in strict compliance with the World Medical Association Declaration of Helsinki (2022 version). Informed consent was obtained from all healthy control participants (written informed consent) and the legal relatives of deceased YNSUD cases (written informed consent for the use of deceased cases’ blood samples and clinical data). The study also strictly adhered to the Regulations on the Administration of Human Genetic Resources of the People’s Republic of China to ensure the legal and ethical use of human genetic data throughout the research process.

11.2 Consent for publication

Not applicable (no individual identifiable data).

11.3 Competing interests

The authors declare no competing interests.

11.4 Clinical trial registration

Clinical trial number: not applicable.

Electronic Supplementary Material

Below is the link to the electronic supplementary material

Supplementary Material 1

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、

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