The search strategy used was modified from previous study (16). The literature search was restricted to articles published in English. Two authors (K.H. and FF.B.) independently searched the PubMed (1966–2021), MEDLINE (1950–2021), Web of Science (1864–2021), and Cochrane Library (2021) databases. The search strategy in PubMed was as follows: ([(congenital myopathy) OR (genetic muscle disease) OR (nemaline) OR (core myopathy) OR (centronuclear myopathy) OR (congenital fiber-type disproportion myopathy)] AND [(epidemiology) OR (prevalence)]). This retrieval also works for the other three databases. The most recent search was performed on July 30, 2021. In addition, a manual search was carried out to identify references in the identified studies to identify possible other studies. This meta-analysis followed the guidelines recommended by the PRISMA statement (Preferred Reporting Items for Systematic reviews and Meta-Analysis) (17). The PRISMA chart for the search strategy is shown in Figure 1. The studies were read thoroughly to assess the eligibility to be included in the meta-analysis.

Only English-written original studies that reported a numerical and well-defined measure of congenital myopathy epidemiology, such as prevalence or occurrence, birth prevalence and/or incidence, were included. Briefly, articles were included in our review if they (1) presented data on the prevalence, (2) clearly specified how many cases were diagnosed and the total population involved, and (3) established a certain diagnosis of congenital myopathy through muscle pathology or gene mutations. No restrictions regarding age, gender, ethnicity, or geography were imposed. Narrative or systematic reviews, meta-analyses, book chapters, editorials, and personal opinions were not included; however, the reference lists of reviews and meta-analyses were screened to potentially identify further studies to include.

The following data were extracted: authors, year of publication, geographic zone, data source (administrative databases, hospital and clinics medical reviews, surveys and other registries), study population (all living individuals, patients, and newborns), study period (the year at which prevalence was measured), congenital myopathy definition (ascertained by clinical examination, muscle biopsy, and genetic screening), and prevalence estimates. Original authors were contacted when further clarification and additional data were necessary. All measures of the prevalence of congenital myopathy identified in the articles were classified as either overall or child prevalence. All studies reporting the prevalence or epidemiology of congenital myopathy were carefully reviewed. Two authors (K.H. and FF-B) independently screened the titles and abstracts of all records identified by the search strategy for potential inclusion in the review. Afterward, full-text copies of articles deemed potentially relevant were retrieved, and their eligibility was assessed. Any disagreements were discussed until we reached a consensus.

To assess the quality of reporting of the published studies, the adapted STrengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were used in our study (see Supplementary Material 2). The adapted STROBE was modified from 22 elaborate items of STROBE (18) by selecting the five essential items most relevant to rare diseases, which is more frequently used in the research of orphan diseases (19, 20). The quality of the included studies was independently assessed by all the authors. Study quality was classified as low, medium, or high based on the following five criteria: description of study design and setting, description of eligibility criteria, study population, description of outcomes, and description of the study participants (20). An overall score of low, medium, and high was then assigned to each study. The full criteria used to assess study quality are found in Supplementary Material 2. Disagreements were resolved through discussion or the intervention of all the authors.

For each included study, the overall and child prevalence of congenital myopathy per 100,000 individuals was considered the primary outcome for the meta-analysis. The overall and child prevalence of each subtype of congenital myopathy per 100,000 individuals was the secondary outcome. In addition, the proportion of mutant genes for every subtype of congenital myopathy was calculated by dividing the number of patients who had the indicated mutant genes by the total number of patients who had genetic information of certain congenital myopathies. Estimates used the population as the denominator. To be included in the meta-analysis, studies must have reported the number of cases and sample size, an estimate with confidence intervals, or the information needed to calculate the required information. As significant heterogeneity was expected, we decided to employ random effects models to complete stratified analysis along with meta-regression to investigate sources of heterogeneity. To assess significant between-study heterogeneity, the Cochrane Q statistic was calculated, and I², a statistic describing the proportion of variation in point estimates due to heterogeneity of studies rather than to sampling error, was used to quantify the amount of between-study heterogeneity. Potential heterogeneity included continent, country, diagnostic criteria, and the definition of condition.

Study-specific prevalence estimates (along with their 95% CI) as well as the summary prevalence estimates were graphically represented with a forest plot: for each study, ordered by the publication year, a square was plotted whose center projection corresponded to the study-specific estimate. A diamond was used to plot the summary prevalence, the center of which represents the point estimate, whereas the extremes of the summary estimate show the 95% CI. For all tests, p < 0.05 was deemed significant. All statistical analyses were carried out in Review Manager 5.4 software.

The flow chart for study selection is shown in Figure 1. Overall, the initial literature search identified 10,584 studies. Following the removal of duplicates (n = 6,477); 4,107 abstracts were initially screened, and only 479 (11.7%) full text articles were reviewed for further evaluation. A total of 468 studies were excluded, and the reasons for exclusion after full-text assessment are listed in Supplementary Table 1. Of these, based on a literature review, 11 (2.3%) studies containing information on the prevalence of congenital myopathy met the eligibility criteria and were therefore included for qualitative and quantitative analysis in this systematic review. The detailed characteristics of the included studies are summarized in Table 1. Eleven studies reported the prevalence of congenital myopathy (21, 22, 25, 27–29, 31, 34, 35, 37, 38). Eight studies examined the prevalence of nemaline myopathy (21, 22, 25, 28, 29, 34, 37, 38). Nine studies showed the prevalence of core myopathy (21, 22, 25, 28, 29, 31, 34, 37, 38). Five studies detected the prevalence of centronuclear myopathy (21, 28, 34, 37, 38). Seven studies calculated the prevalence of congenital fiber-type disproportion myopathy (21, 22, 25, 28, 31, 37, 38). Seven studies examined the prevalence of other congenital myopathies, such as myosin storage myopathy and other unspecified myopathies (21, 22, 25, 28, 31, 37, 38).

Overall, the quality of 11 studies was evaluated. In total, 10 (90.9%) studies were considered medium-quality, one (9.1%) was considered low-quality, and no study was assessed as having a high overall quality. More details about the quality of each included study are reported in Supplementary Table 2.

Eleven studies examined the prevalence of congenital myopathy (21, 22, 25, 27–29, 31, 34, 35, 37, 38). Eight studies examined European populations, and Asian, Oceanian, and North American populations were each examined in one study separately. All the studies included service-based (including hospital records, physician surveys, and/or use of administrative databases) prevalence estimates. Four studies were based on the total population without specifying the age range, and two studies were based on the adult population specifying the age over 18 years old or 5 years old. We put these six studies into the “all” group. Five other studies were based on the child population specifying ages <15–19 years old. We categorized these five studies as the “children” group. The prevalence from the studies ranged from 0.96 to 3.62 per 100,000 in the “overall” group and 0.52–5.01 per 100,000 in the “children” group.

A meta-analysis was performed by pooling data from the 11 studies (21, 22, 25, 27–29, 31, 34, 35, 37, 38) to estimate the prevalence. Forest plots of individual studies and pooled prevalence estimates of congenital myopathy (stratified by studies including pediatric-only populations) are presented in Figure 2. Six studies were conducted in all-age populations; the overall pooled estimate on the prevalence was 1.62 (95% CI, 1.13–2.11) per 100,000. Random effects models on the meta-analyses performed showed statistically significant heterogeneity (I² = 88%, p < 0.00001). Five studies were conducted in child populations; the overall prevalence was 2.76 (95% CI, 1.34–4.18) per 100,000. Random effects models on the meta-analyses performed showed statistically significant heterogeneity (I² = 94%, p < 0.00001).

Interestingly, the majority of the included studies (N = 8; 73%) were conducted in Europe (Table 1). In addition, we pooled the prevalence of geographically adjacent countries or districts to compare the geographical prevalence. However, no significant difference was found (chi-square test, p = 0.448, 0.291 for the all-age and child populations, respectively). The geographical prevalence of congenital myopathy is presented in Figure 3.

Eight studies examined the prevalence of nemaline myopathy (21, 22, 25, 28, 29, 34, 37, 38). Four studies were based on the total population without specifying the age range or on the adult population specifying ages over 18 years old or 5 years old. Four studies were based on the child population. The prevalence of nemaline myopathy in the studies ranged from 0.14 to 0.26 per 100,000 in the “all” group and 0.08–0.56 per 100,000 in the “children” group. Forest plots of individual studies and pooled prevalence estimates of nemaline myopathy are presented in Figure 4 and Supplementary Figure 1. Four studies were conducted in all-age populations; the overall pooled estimate on the prevalence was 0.20 (95% CI, 0.10–0.35) per 100,000. Random effects models on the meta-analyses performed did not show statistically significant heterogeneity (I² = 0%, p = 0.65). Another four studies were conducted in child populations; the overall prevalence was 0.22 (95% CI, 0.03–0.40) per 100,000. Random effects models on the meta-analyses performed did not show statistically significant heterogeneity (I² = 48%, p = 0.13).

Core myopathy is a clinically and genetically heterogeneous group of congenital myopathies, including central core myopathy, minicore myopathy, multicore myopathy, and multi-minicore myopathy. Nine studies examined the prevalence of core myopathy (21, 22, 25, 28, 29, 31, 34, 37, 38). Five studies were based on the total population without specifying the age range or on the adult population specifying the age over 18 years old or 5 years old. Another four studies were based on the child population. The prevalence from the studies ranged from 0.23 to 0.71 per 100,000 in the “all” group and 0.08–1.23 per 100,000 in the “children” group. Forest plots of individual studies and pooled prevalence estimates of core myopathy are presented in Figure 4 and Supplementary Figure 2. The overall pooled estimate on the prevalence of all-age populations was 0.37 (95% CI, 0.21–0.53) per 100,000. Random effects models on the meta-analyses performed showed statistically significant heterogeneity (I² = 67%, p = 0.02). In addition, the overall prevalence of the child population was 0.46 (95% CI, 0.03–0.90) per 100,000. Random effects models on the meta-analyses performed showed statistically significant heterogeneity (I² = 83%, p = 0.0005).

Five studies examined the prevalence of centronuclear myopathy (21, 28, 34, 37, 38). Each study was based on the total population without specifying the age range and on the adult population specifying the age over 18 years old and 5 years old. Two studies were based on child populations. Three patients with myotubular myopathy were diagnosed in one study (34). Since myotubular myopathy is a subtype of centronuclear myopathy, we included these three patients as having centronuclear myopathy (12). The prevalence of centronuclear myopathy in the studies ranged from 0.02 to 0.28 per 100,000 in the “all” group and 0.25 to 0.66 per 100,000 in the “children” group. Forest plots of individual studies and pooled prevalence estimates of core myopathy are presented in Figure 4 and Supplementary Figure 3. The overall pooled estimate of the prevalence of centronuclear myopathy among the all-age population was 0.08 (95% CI, −0.01 to 0.18) per 100,000. Random effects models on the meta-analyses performed showed statistically significant heterogeneity (I² = 83%, p = 0.003). In addition, the overall prevalence of centronuclear myopathy among the child population was 0.44 (95% CI, 0.03–0.84) per 100,000. Random effects models on the meta-analyses performed showed statistically significant heterogeneity (I² = 67%, p = 0.04).

Seven studies examined the prevalence of congenital fiber-type disproportion myopathy (21, 22, 25, 28, 31, 37, 38). Five studies were based on the total population without specifying the age range or on the adult population specifying the age over 18 years old or 5 years old. Three studies were based on the child population. The prevalence from the studies ranged from 0.06 to 0.50 per 100,000 in the “all” group and 0.08 to 0.56 per 100,000 in the “children” group. Forest plots of individual studies and pooled prevalence estimates of congenital fiber-type disproportion myopathy are presented in Figure 4 and Supplementary Figure 4. The overall pooled estimate on the prevalence of the all-age population was 0.23 (95% CI, 0.04–0.42) per 100,000. Random effects models on the meta-analyses performed showed statistically significant heterogeneity (I² = 85%, p = 0.0001). In addition, the overall prevalence of the child population was 0.25 (95% CI, −0.05 to 0.54) per 100,000. Random effects models on the meta-analyses performed did not show statistically significant heterogeneity (I² = 53%, p = 0.12).

Seven studies examined the prevalence of unspecified congenital myopathies (21, 22, 25, 28, 37, 38). Three studies were based on the total population without specifying the age range or on the adult population specifying the age over 18 years old or 5 years old. Three studies were based on the child population. The prevalence from the studies ranged from 0.26 to 0.42 per 100,000 in the “all” group and 1.82 to 3.61 per 100,000 in the “children” group. Forest plots of individual studies and pooled prevalence estimates of unspecified congenital myopathies are presented in Figure 4 and Supplementary Figure 5. The overall pooled estimate on the prevalence of the all-age population was 0.34 (95% CI, 0.24–0.44) per 100,000. Random effects models on the meta-analyses performed showed statistically significant heterogeneity (I² = 10%, p < 0.00001). In addition, the overall prevalence of the child population was 2.63 (95% CI, 1.64–3.62) per 100,000. Random effects models on the meta-analyses performed showed statistically significant heterogeneity (I² = 71%, p < 0.00001).

More than 30 genes were found to be associated with congenital myopathy (39–41). In the 11 enrolled studies, three studies included genetic information (28, 31, 38). A total of 123 congenital myopathies were included, 59 (48.0%) of which had genetic information. In nemaline myopathy, ACTA1 mutations (41.2%) were the most common mutations. RYR1 mutations account for 93.3% of core myopathy mutations. In centronuclear myopathy and congenital fiber-type disproportion myopathy, DNM2 (46.2%) and RYR1 (66.7%) were the most common mutations, respectively. Overall, RYR1 (40.7%) is likely to be the most common gene causing congenital myopathy, which is consistent with other previous studies (42). Details of genetics are shown in Table 2.