Genetic neuromuscular diseases (NMDs) represent a heterogeneous group of genetic conditions that primarily affect the peripheral nerves, muscles, and neuromuscular junctions. These diseases manifest as a broad spectrum of clinical symptoms, including muscle weakness, muscle atrophy, joint contractures, cardiomyopathy, exercise intolerance, sensory deficits, fatigue, myalgia, tremors, ataxia, and dysarthria. However, the specific symptoms depend on the disease subtype and implicated genes. Approximately 600 causative genes of NMDs have been identified.1

Epidemiological studies have investigated the occurrence, timing, and causes of diseases within populations.2 These investigations provide essential data on the origin and risk factors of various diseases. The utility of epidemiological studies is multifaceted; they identify disease-associated risk factors, guide disease interventions, reveal disease incidence and prevalence over time, which is critical for recognizing public health threats, and inform the creation of health guidelines and policies. However, conducting epidemiological studies of genetic NMDs is challenging because of the infrequency, widespread distribution, and diagnostic intricacies of these diseases.3 These diagnostic difficulties are compounded by the diverse and intricate processes involved in such studies, including history taking, physical examination, electrodiagnostic testing, pathological evaluation, and genetic analysis. Therefore, many epidemiological studies on NMDs have been conducted using diverse and non-unified diagnostic criteria and research methods.45678

With the advent of next-generation sequencing, public databases including the Genome Aggregation Database (gnomAD) have been established to provide comprehensive information on human exomes and genomes.9 These databases provide the proportion of individuals in the general population who carry pathogenic or likely pathogenic variants (PLPVs) in specific genes. This information is crucial for predicting the carrier frequency and genomic prevalence of autosomal recessive (AR) Mendelian diseases. Compared with previous studies that only analyzed patients diagnosed in hospitals, this epidemiological approach offers the advantage of analyzing wider populations and obtaining accurate genotypic information. Epidemiological studies have been conducted to evaluate several AR Mendelian diseases, including inherited retinal diseases and Upshaw-Schulman syndrome.1011

We recently analyzed the carrier frequency and genetic prevalence of AR-NMDs worldwide using the gnomAD.12 The Korea 1 K dataset contains approximately 1,000 Korean genomes with systematically collected clinical and biochemical data from blood and urine samples, thus providing valuable genomic information.13 This dataset represents the general population, sourced from residents of Ulsan, a major city in South Korea. Given the high mobility characteristic of large urban areas, it is thought to encompass a broader genetic diversity. To evaluate the carrier frequency and predicted genomic prevalence of AR-NMDs, we investigated PLPVs within the genomic data from the Korea 1 K dataset, aiming to better understand the genetic landscape of AR-NMDs specific to Korean population.

We analyzed the carrier frequency and predicted the genetic prevalence of AR-NMDs in the Korean population using 984 whole-genome sequences. We identified 165 PLPVs among 267 AR-NMD-related genes. The pathogenicity of 75 variants was confirmed using databases and the literature, whereas 90 variants were manually verified according to the 2015 ACMG guidelines. Therefore, we revealed the precise pathogenicity of AR-NMDs variants in the Korean population.

Characterization of PLPVs in AR-NMDs revealed that frameshift variants were the most prevalent, accounting for 37.0% of all identified PLPVs. In contrast, literature verified variants encompassed a broad spectrum of variant types; all manually verified variants were null, including frameshift, nonsense, splice, and initial codon variants. This predominance of null variants may be attributed to the relative ease of classifying them as PLPVs, whereas classifying missense variants is challenging because of their complex nature according to the 2015 ACMG guidelines.14 This finding is consistent with that of a previous analysis of the gnomAD.12

The carrier frequency of AR-NMDs in the Korean population is 27.1%, which is lower than the global average of 32.9%.12 Table 2 shows a comparison of the carrier frequencies of the top 20 causative AR-NMDs genes in Korea with those in global and regional populations.12 Both similarities and differences were observed in carrier frequencies between Korean and global populations. Notably, the carrier frequency of individuals with PLPVs in DYSF was highest in Korea (1.63%), surpassing those in the global population (0.46%).12 Our study is the first to analyze the frequency of AR-NMD carriers in Koreans, and there is insufficient evidence to determine whether carriers with PLPVs in DYSF are the most common among AR-NMD carriers. However, we previously reported that dysferlinopathy caused by PLPVs in DYSF was the most common AR genetic myopathy in Korea.151617 The carrier frequency of individuals with PLPVs in GAA in the Korean population (1.55%) was similar to that in the global population (1.31%), including in East Asian (1.58%), non-Finnish European (1.70%), and African/African American (1.26%). Additionally, a separate dataset analysis of the Korean population reported a GAA carrier frequency of 1.7%, consistent with our findings, further validating that our dataset accurately represents the Korean genotype. Furthermore, an independent analysis of another dataset based on the Korean population reported a GAA carrier frequency of 1.7%, consistent with our findings, confirming that our dataset accurately reflects the Korean genotype.18 The similar carrier frequencies of individuals with GAA in the Korean and various other populations indicate that Pompe disease is a prevalent condition caused by PLPVs in GAA across various ethnicities.1219 The carrier frequency of individuals with ADSS1 in the Korean population (0.65%) was high compared with that of the global population (0.28%).12 ADSS1 was first identified as causative gene for genetic myopathy in Korea and is the most common nemaline myopathy in Japan, a neighboring country of Korea.2021 However, the carrier frequency of individuals with PLPVs in ANO5 (0.00%) was low compared with that in global populations (0.88%), including Latino/admixed American (1.43%) and non-Finnish European (1.07%) subpopulations. This result aligns with those of previous studies showing that anoctaminopathy caused by PLPVs in ANO5 has a high prevalence in Northern European populations because of a founder PLPV22 but is rare in Asian and Middle Eastern populations.2324252627

We estimated the predicted genetic prevalence of AR-NMDs to be 38.0 cases per 100,000 individuals in Korea. A previous study of the global prevalence of NMDs using the same method reported a prevalence of 24.3 per 100,000 individuals, which is lower than that in Koreans.12 This discrepancy may be attributed to the small study population (984 cases), potentially leading to over- or underestimation of allele frequencies. Although the carrier frequency of AR-NMDs in Korea (27.1%) is lower than the global average, the higher genetic prevalence could be influenced by the presence of dominant PLPVs in specific genes, particularly in smaller sample sizes. Additionally, high ethnic homogeneity and selective marriages influenced by social stratification may contribute to this higher prevalence.282930 Prevalence studies performed using classical methods showed that the prevalence of total NMDs ranges from 28.6 to 82.8 per 100,000 individuals.3132 Our results, based on PLPVs in causative genes, differ from those obtained in previous studies that relied on clinically diagnosed patients, making direct comparison challenging. Nevertheless, the predicted genetic prevalence of AR-NMDs in our study was higher than expected. This result can be explained by the following reasons. First, many major genes responsible for NMDs, including dystrophinopathy, myotonic dystrophy, facioscapulohumeral muscular dystrophy, and most cases of Charcot-Marie-Tooth diseases, are not inherited in an AR manner.7 Second, we could not evaluate deletions or duplications of exons, including the exon 7 deletion found in 95% of patients with spinal muscular atrophy.33 Third, exome and genome sequencing can only diagnose 30–40% of Mendelian diseases, suggesting that many patients cannot be identified using these methods alone.34 Thus, AR-NMDs may be more prevalent than currently estimated, and further comprehensive studies are needed to better understand their true frequencies in the population.

Our study revealed high allele frequencies of PLPVs in HEXB, GAA, and DYSF in the Korean population. Our results are similar to the previously reported allele frequency of these PLPVs in the East Asian population, which included Koreans.12 The allele frequency of c.1250C>T in HEXB was also very high at 0.00095 in the East Asian group compared with those in other groups in a previous study based on the gnomAD v2.1.1, but was around 1/8 lower than that in our study (0.00764).12 In the most recent version of the gnomAD v.4.1.0 (https://gnomad.broadinstitute.org/), the allele frequency of this variant was highest in the East Asian population, at 0.00354, which is similar to our finding. The allele frequency of the second most common PLPV, c.[752C>T:c.761C>T] in GAA, was 0.00505 in our study. This result is comparable to the high allele frequency in the East Asian population at 0.00261, in contrast to those in other populations: 0.0000 in African/African American, 0.00000 in Latino/Admixed American, 0.00000 in non-Finnish European, 0.00000 in South Asian subpopulations.12 The c.919delA in ADSS1 and c.1400C>G in SLC22A5 also showed much higher allele frequencies in the Korean population (0.00273 and 0.00218, respectively) and East Asian subpopulation (0.00110 and 0.00226, respectively) than in the global population (0.00008 and 0.00017, respectively).12 However, there were some differences between our results and previous results. We identified the c.2055+2T>G variant as the most prevalent PLPV in DYSF. However, the c.2494C>T variant is the most common PLPV in DYSF among Korean patients with dysferlinopathy.16 Our findings have important implications for clinical practice. The high carrier frequencies of certain AR-NMD genes, such as DYSF and GAA, suggest that targeted genetic screening programs in Korea could help with early diagnosis and treatment. This would enable effective genetic counseling for at-risk couples to make informed reproductive decisions. Furthermore, public health policies could focus on AR-NMDs with higher genetic prevalence, improving healthcare planning and resource allocation for these conditions. Identification of common PLPVs specific to the Korean population underscores the importance of regional genetic studies, which are crucial for developing targeted interventions and public health strategies customized for the distinct genetic profiles of specific populations.35

Our study had some limitations. First, our data were derived from a small sample of 984 Korean whole genomes collected from a specific region. Thus, our results may not be representative of the entire Korean population.36 Further studies of larger sample sizes and more diverse regions are needed to enhance the representativeness of the findings. Second, many non-truncating PLPVs that have not been documented in the literature are classified as variants of unknown significance because of a lack of evidence. Comprehensive studies focusing on these variants are required to determine their clinical importance in disease. Third, we did not analyze large deletions or duplications of exons.13 Finally, comparisons of our allele frequencies with global data should be performed with caution because of differences in data sources and methodologies.

We determined the carrier frequency and genetic prevalence of AR-NMDs in the Korean population, highlighting important variants and their potential implications. These findings emphasize the importance of regional genetic studies, expanded carrier screening, and targeted public health strategies for effective management and prevention of genetic NMDs. In conclusion, our results suggest that 27.1% of the Korean population is a healthy carrier of at least one PLPV gene in AR-NMD. This is the first study to analyze the carrier frequency and genetic prevalence of AR-NMDs in a Korean population.