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Abstract

Background:

Congenital myopathies are a group of neuromuscular disorders that typically present at birth or early childhood with hypotonia and non-progressive or slowly progressive muscle weakness. They are classically subclassified by characteristic structural changes and histopathological findings in skeletal muscle. Variants in over 40 genes have been described to date in patients with various forms of congenital myopathy with overlapping phenotypic and histological features, which poses a challenge for laboratories and clinicians in interpreting genetic findings.

Objective:

The purpose of this study was to evaluate the evidence supporting each gene-disease relationship and provide an expert-reviewed classification for the clinical validity of genes involved in congenital myopathies.

Methods:

The ClinGen Neurological Disorders Clinical Domain Working Group assembled the Congenital Myopathies Gene Curation Expert Panel (CongenMyopathy-GCEP), a group of clinicians and geneticists with expertise in congenital myopathies tasked to perform evidence-based curation of 50 gene-disease relationships using the ClinGen semiquantitative framework to assign clinical validity.

Results:

Our curation effort resulted in 35 (70%) Definitive, eight (16%) Moderate, six (12%) Limited, and one (2%) Disputed disease relationship classifications. The summary of each curation is made publicly available on the ClinGen website.

Conclusions:

Expert-reviewed assignment of gene-disease relationships by the CongenMyopathy-GCEP facilitates accurate molecular diagnoses for congenital myopathies and can allow genetic testing to focus on genes with a validated role in disease.

Keywords

Genetics neuromuscular disease congenital myopathy genetic testing

Introduction

With the integration of next-generation sequencing (NGS) in clinical molecular diagnostics, laboratories can test multiple genes that have been reported in association with a disorder on their diagnostic gene panels.¹ Multi-gene panels that allow simultaneous testing of multiple diseases with shared clinical presentations are beneficial in the diagnosis of conditions with phenotypic overlap.^2,3 However, NGS panels that include genes with limited or ambiguous role in a disease may lead to uncertain results and variants identified in such genes may be misinterpreted as causative, resulting in misdiagnosis and potentially unnecessary or detrimental therapeutic intervention.¹ Variants in a gene cannot be accurately interpreted if there is uncertainty in the gene's role in a particular disorder.^4,5 Therefore, careful assessment and stringent classification of a gene's causative role in disease is a crucial step for correct molecular diagnosis of patients.⁵ This is particularly important for diseases that have high genetic heterogeneity with wide phenotypic overlap between implicated genes, as the diagnosis that directs clinical management and genetic counseling of family members relies on the genetic finding.

Congenital myopathies are a group of neuromuscular disorders that typically present at birth with hypotonia and muscle weakness.⁶ Patients may also have respiratory insufficiency and feeding difficulties. Cardiac muscle involvement leading to cardiomyopathy and/or arrhythmias is less common but may also be observed in some forms.^7–9 As opposed to muscular dystrophies that are characterized by progressive muscle degeneration and wasting, congenital myopathies tend to be nonprogressive or slowly progressive and do not involve continuous degeneration and regeneration in the muscle. Congenital myopathies are classically defined by characteristic structural changes in the skeletal muscle, which can be referred to as the “histotype”, that forms the basis for their clinicopathologic sub-classification, such as nemaline myopathy, centronuclear myopathy, central core disease, multiminicore disease, and congenital fiber type disproportion.¹⁰ Many patients may have a combination of multiple features and overlapping muscle biopsy findings. To date, more than 40 genes have been reported as causal for various forms of congenital myopathies.^11,12 A single gene may be associated with more than one clinicopathologic presentation and many genes have been associated with a wide phenotypic as well as histological spectrum, including overlapping features with other related genes.^11,12 All this complexity adds challenges to interpreting genetic findings. Establishing the validity of each reported gene's role in congenital myopathies by clinicians and geneticists with expertise in this field would be beneficial to facilitate accurate molecular diagnoses. Towards this goal, the Clinical Genome Resource (ClinGen),¹³ a National Institute of Health (NIH)-funded initiative, has assembled a group of congenital myopathy experts to curate disease-implicated genes using a systematic evidence-based framework.⁵ Here we present the classification of 50 gene-disease relationships for congenital myopathies by the ClinGen Congenital Myopathies Gene Curation Expert Panel (CongenMyopathy-GCEP).

Materials and methods

Clingen congenital myopathies gene curation expert panel (CongenMyopathy-GCEP)

The CongenMyopathy-GCEP (https://www.clinicalgenome.org/affiliation/40031/) consists of a coordinator, experts with substantial knowledge of congenital myopathies from both clinical and research settings, as well as of biocurators trained in ClinGen methodology to curate evidence and apply the ClinGen gene-disease validity framework in the classification of genes related to congenital myopathies. These roles are filled by an international panel providing diverse experience, including members from the United States, Canada, the United Kingdom, France, Italy, Estonia, and Finland, representing 14 institutions.

Selection of genes and diseases for analysis

In total, 37 genes that have been reported as potentially associated with congenital myopathies were prioritized for curation based on expert knowledge and literature search by the CongenMyopathy-GCEP. Four genes that are often related to dystrophic changes on muscle biopsies but have a predominant congenital myopathy phenotype (COL6A1, COL6A2, COL6A3, and LAMA2) were also included in curation by the CongenMyopathy-GCEP, following consultation with the Limb Girdle Muscular Dystrophy GCEP.

The CongenMyopathy-GCEP implemented standard ClinGen practice for genes with assertions relating to multiple diseases in the Online Mendelian Inheritance in Man (OMIM) database and/or the literature. Following the guidelines from the ClinGen Lumping and Splitting Working Group¹⁴ the CongenMyopathy-GCEP evaluated the mechanism of disease, phenotypic features, and mode of inheritance of each condition to determine whether they should be lumped into one curation record or to split into individual records. Genes that were considered to be associated with a broad spectrum of histological findings (the histotype), rather than specific forms, were linked to disorders based on their histological features. Unique identifiers from the Mondo disease ontology (https://mondo.monarchinitiative.org/) were assigned to each curated disease entity. To include the wide spectrum of phenotypes associated with such genes, their associated diseases were given protein- or gene-based names, such as Actinopathy (for ACTA1-related myopathies) or SELENON-related myopathy.

Clingen gene-disease clinical validity assessment for congenital myopathy genes

The CongenMyopathy-GCEP assessed the clinical validity for 37 genes in relation to congenital myopathies using the ClinGen Gene Curation Standard Operating Procedure, Versions 6–9 (https://clinicalgenome.org/docs/gene-disease-validity-standard-operating-procedure-version-9/) based on the framework described in Strande & Riggs et al..⁵ In short, a structured and evidence-based evaluation of genetic data, such as variants in the gene identified in patients with disease of interest, including case reports, family studies, and case-control studies, and experimental data, including biochemical assays on protein function or expression and animal models available in the literature was performed. A maximum of 12 points and six points were assigned for genetic and experimental evidence, respectively, for a combined maximum total of 18 points. Gene-disease relationships were classified based on the strength of supportive evidence as follows: Definitive (12–18 points, with replication over time), Strong (12–18 points), Moderate (7–11 points), Limited (0.1–6 points), “No known disease relationship” (no reports have directly implicated the gene in human disease cases), Disputed and Refuted (gene-disease relationship has conflicting evidence). To classify a gene-disease relationship as “Definitive” the disease role of the gene with Strong evidence would need to be repeatedly demonstrated in research and clinical diagnostic settings and upheld over time (minimum of three years). The evaluated evidence and scores assigned by the expert group for each gene-disease relationship were recorded in ClinGen's gene curation interface and a summary was published on the ClinGen website (https://search.clinicalgenome.org/kb/affiliate/10031) upon expert approval.

The ClinGen gene curation framework provides guidance, and each expert panel is allowed to adjust scoring or final classifications based on the relevant disease area and the judgment of the expert panel members. For this purpose and to maintain consistency across multiple biocurators, the CongenMyopathy-GCEP developed a guidance document to highlight the salient information for curators to record and consider during scoring (Supplemental Table 1). Genetic evidence scores were reduced when adequate clinical details and previous testing results were not available.

Once the relevant gene-disease relationships were identified, a preliminary evaluation was performed to determine the strategy for curation and review (Supplemental Figure 1). Curations underwent either expedited or standard review processes, following the methods outlined in Ross et al., 2023.¹⁵

Variant classification analysis in ClinVar database

Classification of variants in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/; accessed 10/28/2024) were assessed for each gene. Only single-gene variants that had classifications associated with myopathy-related conditions were included in the analysis; variants that only had classifications related to central or peripheral nervous system disorders or cardiac disorders were not included. For genes that have been classified by the CongenMyopathy-GCEP for more than one congenital myopathy-related condition, the highest level of evidence classification was considered for this analysis.

Results

Thirty-seven genes were curated in association with congenital myopathy disorders. The summary of each curation is made publicly available on the ClinGen website (https://clinicalgenome.org/affiliation/40031/). Each gene was evaluated to determine the most appropriate gene-disease relationship for curation (Table 1). Thirteen of the 37 genes were determined to be related to a broad histotype spectrum of disease that encompassed two or more histological features, including the presence of nemaline rods, cores, centralized nuclei, and/or fiber-type disproportion. Eleven genes (ACTA1, BIN1, COL6A1, COL6A2, COL6A3, MYH2, NEB, RYR1, TNNT1, TPM3, TTN) were considered to be associated with diseases that encompass both autosomal dominant (AD) and autosomal recessive (AR) modes of inheritance. Eight genes were defined in relation to nemaline myopathy, six to centronuclear myopathy, and three to congenital myopathy without notable defining features. Two genes that encode critical components of calcium release-activated calcium (CRAC) channels (STIM1 and ORAI1) were evaluated in association with a combined spectrum of tubular aggregate myopathy with varying severity. Others, such as MYO18B, were associated with a disorder phenotypically distinct from other congenital myopathies, such as fusion of the cervical spine combined with myopathy in Klippel-Feil syndrome. For genes that have been implicated in other disorders not representing a continuum of congenital myopathy phenotypes, such as DNM2 with Charcot-Marie-Tooth Disease, the CongenMyopathy-GCEP focused only on the gene's association with congenital myopathies (Table 1).

Table 1.

Establishment of gene-disease relationship and mode of inheritance for each curation record.

Gene	Disease Assertions (OMIM (Inheritance, MIM number))	Lumping/Splitting Comments	Curated Disease (Inheritance)	MONDO ID
ACTA1	Congenital myopathy 2A, typical, autosomal dominant/Nemaline myopathy 3/Myopathy, actin, congenital, with cores/Myopathy, actin, congenital, with excess of thin myofilaments (AD, 161800)	Alpha-actinopathy is a musculoskeletal system disorder that covers a wide spectrum of phenotypes and is caused by pathogenic variants in the skeletal muscle α-actin gene, ACTA1. These variants lead to a variety of overlapping adult onset and congenital myopathies characterized by muscle weakness, hypotonia, myopathic facies, respiratory dysfunction, and rarely cardiac involvement. While nemaline myopathy is the most common presentation, several other myopathies have been reported in association with ACTA1. Specific skeletal muscle structural lesions visible on muscle biopsy include actin accumulations, nemaline and intranuclear bodies, fiber-type disproportion, cores, caps, dystrophic features, and zebra bodies. Disorders associated with ACTA1 pathogenic variants can have autosomal dominant (90%) or recessive (10%) inheritance. Based on differences in molecular mechanism (dominant negative vs. recessive loss of function) and inheritance pattern, alpha- actinopathy was split into dominant and recessive curations.	Alpha-actinopathy (AD)	MONDO:0100084
	Congenital myopathy 2C, severe infantile, autosomal dominant (AD, 620278)		Alpha-actinopathy (AR)	MONDO:0100084
	Myopathy, scapulohumeroperoneal (AD, 616852)
	Congenital myopathy 2B, severe infantile, autosomal recessive (AR, 620265)
BIN1	Centronuclear myopathy 2 (AR, 255200)	BIN1-associated autosomal recessive centronuclear myopathy is characterized by mild, proximal, slowly progressive muscle weakness with onset ranging from birth to childhood. BIN1 has also been reported in relation to autosomal dominant centronuclear myopathy. Due to the proposed difference in mechanism (dominant negative) AD disease was evaluated in a separate curation.	Centronuclear myopathy (AR)	MONDO:0009709
BIN1	Centronuclear myopathy 2 (AR, 255200)		Centronuclear myopathy (AD)	MONDO:0009709
CCDC78	Centronuclear myopathy 4 (AD, 614807)		Centronuclear myopathy (AD)	MONDO:0018947
CFL2	Nemaline myopathy 7, autosomal recessive (AR, 610687)		Nemaline myopathy (AR)	MONDO:0012538
COL6A1	Bethlem myopathy 1 (AD/AR, 158810)	Collagen VI protein's basic structural unit is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains, encoded by COL6A1, COL6A2 and COL6A3 to form the triple helical structural element common to collagens. Mutations in Collagen VI have historically been reported in relation to two different conditions: Bethlem myopathy and Ulrich congenital muscular dystrophy. Genetic analysis in patients with each of these disorders revealed both dominant and recessive defects in one of the COL6A1, COL6A2, or COL6A3 genes that affect the final Collagen VI protein. On the basis of clinical and genetic findings, Ullrich CMD and Bethlem myopathy were regarded as being positioned at the flanking ends of a continuous spectrum of disease, rather than as distinct clinical entities. Both dominant and recessive variants are found in patients across the clinical disease spectrum, however distinct variants are associated with dominant and recessive inheritance. Dominant inheritance occurs with dominant negative mutations in the collagen VI triple helical regions, including glycine substitution and exon skip mutations. In contrast, recessive inheritance occurs with loss of function variants. For these reasons, these forms have been curated separately.	Collagen 6-related myopathy (AR)	MONDO:0100225
COL6A1	Ullrich congenital muscular dystrophy 1A (AD/AR, 254090)		Collagen 6-related myopathy (AD)	MONDO:0100225
COL6A2	Bethlem myopathy 1B (AD/AR, 620725)	See the description for COL6A1 above.	Collagen 6-related myopathy (AR)	MONDO:0100225
	Ullrich congenital muscular dystrophy 1B (AD/AR, 620727)		Collagen 6-related myopathy (AD)	MONDO:0100225
	Myosclerosis, congenital (AR, 255600)		Collagen 6-related myopathy (AD)	MONDO:0100225
COL6A3	Bethlem myopathy 1C (AD/AR, 620726)	See the description for COL6A1 above.	Collagen 6-related myopathy (AR)	MONDO:0100225
	Ullrich congenital muscular dystrophy 1C (AD/AR, 620728)	See the description for COL6A1 above.	Collagen 6-related myopathy (AD)	MONDO:0100225
	Dystonia 27 (AR, 616411)	Considered a separate disease based on phenotypic differences and apparent disease mechanism (all variants reported in the terminal VWF domains).	Dystonia (AR)	MONDO:0014627
DNM2	Centronuclear Myopathy 1 (AD, 160150)	Considered a separate disease based on phenotypic features and gain of function disease mechanism.	Centronuclear myopathy (AD)	MONDO:0008048
	Charcot-Marie-Tooth disease, axonal type 2 M (AD, 606482)	Not within the scope of the Congenital Myopathies GCEP
	Charcot-Marie-Tooth disease, dominant intermediate B (AD, 606482)
	Lethal congenital contracture syndrome 5 (AR, 615368)
HACD1	Congenital myopathy 11 (AR, 619967)		Congenital myopathy (AR)	MONDO:0019952
KBTBD13	Nemaline myopathy 6, autosomal dominant (AD, 609273)		Nemaline myopathy (AD)	MONDO:0012237
KLHL40	Nemaline myopathy 8, autosomal recessive (AR, 615348)		Nemaline myopathy (AR)	MONDO:0014138
KLHL41	Nemaline myopathy 9 (AR, 615731)		Nemaline myopathy (AR)	MONDO:0014326
LAMA2	Muscular dystrophy, congenital, merosin deficient or partially deficient (AR, 607855)	LAMA2 variants have been reported in relation to autosomal recessive congenital muscular dystrophy and a less severe, adult onset form of muscular dystrophy. Both disease forms are within one phenotypic spectrum and are caused by loss of function variants leading to variable degrees of reduction of the alpha chain of the laminin 2 protein in a recessive fashion. Therefore, the conditions have been lumped into one disease entity.	LAMA2-related muscular dystrophy (AR)	MONDO:0100228
LAMA2	Muscular dystrophy, limb-girdle, autosomal recessive 23 (AR, 618138)		LAMA2-related muscular dystrophy (AR)	MONDO:0100228
LMOD3	Nemaline Myopathy 10 (AR, 616165)		Nemaline myopathy (AR)	MONDO:0014513
MAP3K20	Centronuclear myopathy 6 with fiber-type disproportion (AR, 617760)	Considered a separate disease based on phenotypic differences.	Centronuclear myopathy with fiber-type disproportion (AR)	MONDO:0054695
MAP3K20	Split-foot malformation with mesoaxial polydactyly (AR, 616890)	Not within the scope of the Congenital Myopathies GCEP
MEGF10	Congenital myopathy 10A, severe variant (AR, 614399)	MEGF10 has been associated with autosomal recessive myopathy, historically known as early-onset myopathy-areflexia-respiratory distress-dysphagia, and has also been implicated in a form of multiminicore myopathy with generally reduced phenotypic severity and later age of onset. Both disease entities are considered part of the MEGF10-related myopathy spectrum.	MEGF10-related myopathy (AR)	MONDO:0013731
MEGF10	Congenital myopathy 10B, mild variant (AR, 620249)		MEGF10-related myopathy (AR)	MONDO:0013731
MTM1	Myopathy, centronuclear, X-linked (XL, 310400)		X-linked myotubular myopathy (XL)	MONDO:0010683
MYH2	Congenital myopathy 6 with ophthalmoplegia (AD, 605637)	MYH2 has been reported in relation to autosomal recessive and autosomal dominant proximal myopathy and ophthalmoplegia. Due to the proposed difference in mechanism (dominant negative for AD and loss of function for AR), these entities were considered in separate curations.	Proximal myopathy and ophthalmoplegia (AD)	MONDO:0011577
MYH2	Congenital myopathy 6 with ophthalmoplegia (AR, 605637)		Proximal myopathy and ophthalmoplegia (AR)	MONDO:0011577
MYH7	Congenital myopathy 7A, myosin storage, autosomal dominant (AD, 608358)	Represent a clinical spectrum of overlapping myopathies with predominantly autosomal dominant inheritance.	MYH7-related skeletal myopathy (AD)	MONDO:0008050
	Laing distal myopathy (AD, 160500)
	Scapuloperoneal syndrome, myopathic type (AD, 181430)
	Cardiomyopathy, dilated, 1S (AD, 613426)	Not within the scope of the Congenital Myopathies GCEP
	Cardiomyopathy, hypertrophic, 1 (AD, 192600)
	Left ventricular noncompaction 5 (AD, 613426)
MYL1	Congenital myopathy 14 (AR, 618414)		Congenital myopathy (AR)	MONDO:0019952
MYO18B	Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism (AR, 616549)		Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome (AR)	MONDO:0014689
MYPN	Congenital myopathy 24 (AR, 617336)		MYPN-related myopathy (AR)	MONDO:0015023
	Cardiomyopathy, dilated, 1KK (AD, 615248)	Not within the scope of the Congenital Myopathies GCEP
	Cardiomyopathy, familial restrictive, 4 (AD, 615248)
	Cardiomyopathy, hypertrophic, 22 (AD, 615248)
NEB	Nemaline Myopathy 2 (AR, 256030)	Distal nebulin myopathy was considered with the spectrum of disease of Nemaline myopathy 2, with a consistent mechanism of autosomal recessive loss of function.	Nemaline myopathy (AR)	MONDO:0009725
	Autosomal dominant nebulin-related myopathy (AD)	Certain variants in NEB have been associated with autosomal dominant nebulin-related myopathy, which was considered to have a different disease mechanism compared to autosomal recessive NEB-related nemaline myopathy.	Nemaline myopathy (AD)	MONDO:0002921
	Arthrogryposis Multiplex Congenita 6 (AR, 619334)	Not within the scope of the Congenital Myopathies GCEP
ORAI1	Myopathy, tubular aggregate, 2 (AD, 615883)	Distinct phenotypes, inheritance, and molecular mechanisms distinguish this autosomal dominant gain of function myopathy from the autosomal recessive loss of function immunodeficiency.	Tubular aggregate myopathy (AD)	MONDO:0008051
ORAI1	Immunodeficiency 9 (AR, 612782)	Not within the scope of the Congenital Myopathies GCEP
PYROXD1	Myopathy, myofibrillar, 8 (AR, 617258)		Myofibrillar myopathy (AR)	MONDO:0014993
RYR1	Congenital myopathy 1A, autosomal dominant, with susceptibility to malignant hyperthermia (AD, 117000)	Spectrum of disease resulting from loss of function and hypomorphic variants (AR) or dominant negative variants (AD). Individuals may have a variety of histological features including central cores, minicores, central nuclei, type 1 fiber uniformity or disproportion.	RYR1-related myopathy (AR)	MONDO:0100150
	Congenital myopathy 1B, autosomal recessive (AR, 255320)		RYR1-related myopathy (AD)	MONDO:0100150
	Malignant hyperthermia susceptibility 1 (AD, 145600)	Not within the scope of the Congenital Myopathies GCEP
	King-Denborough syndrome (AD, 619542)	Not within the scope of the Congenital Myopathies GCEP
RYR3	Congenital myopathy 20 (AR, 620310)		Congenital myopathy (AR)	MONDO:0019952
SCN4A	Myasthenic syndrome, congenital, 16 (AR, 614198)	Autosomal recessive fetal hypokinesia and congenital myopathy SCN4A-related congenital myasthenic syndrome. All disease forms were curated under a single disease entity.	SCN4A-related myopathy (AR)	MONDO:0100121
	Congenital myopathy 22A, classic (AR, 620351)
	Congenital myopathy 22B, severe fetal (AR, 620369)
	Hyperkalemic periodic paralysis, type 2 (AD, 170500)	Not within the scope of the Congenital Myopathies GCEP
	Hypokalemic periodic paralysis, type 2 (AD, 613345)
	Myotonia congenita, atypical, acetazolamide-responsive (AD, 608390)
	Paramyotonia congenita (AD, 168300)
SELENON	Congenital myopathy 3 with rigid spine (AR, 602771)		SELENON-related myopathy (AR)	MONDO:0100100
SPEG	Centronuclear myopathy 5 (AR, 615959)		Centronuclear myopathy (AR)	MONDO:0014418
STAC3	Congenital myopathy 13 (AR, 255995)		Bailey-Bloch congenital myopathy (AR)	MONDO:0009722
STIM1	Myopathy, tubular aggregate, 1 (AD, 160565)	Stormorken syndrome was considered within the spectrum of tubular aggregate myopathy.	Tubular aggregate myopathy (AD)	MONDO:0008051
	Stormorken syndrome (AD, 185070)		Tubular aggregate myopathy (AD)	MONDO:0008051
	Immunodeficiency 10 (AR, 612783)	Not within the scope of the Congenital Myopathies GCEP
TNNT1	Nemaline myopathy 5A, autosomal recessive, severe infantile (AR, 605355)	Due to differences in inheritance pattern, molecular mechanism (potential gain of function compared to loss of function), and phenotypic variability, AD and AR nemaline myopathy associated with TNNT1 were considered separately.	Nemaline myopathy (AR)	MONDO:0011539
	Nemaline myopathy 5B, autosomal recessive, childhood-onset (AR, 620386)		Nemaline myopathy (AD)	MONDO:0018958
	Nemaline myopathy 5C, autosomal dominant (AD, 620389)		Nemaline myopathy (AD)	MONDO:0018958
TNNT3	Nemaline myopathy (AR)	Autosomal recessive nemaline myopathy was considered a distinct disease entity from autosomal dominant arthrogryposis due to reported differences in molecular mechanism (loss of function for nemaline myopathy) and phenotypic spectrum.	Nemaline myopathy (AR)	MONDO:0018958
TNNT3	Arthrogryposis, distal, type 2B2 (AD, 618435)	Not within the scope of the Congenital Myopathies GCEP
TPM2	Nemaline myopathy 4, autosomal dominant (AD, 609285)	Represent a clinical spectrum of overlapping myopathies, however the arthrogryposis phenotype is significantly different and considered separately.	TPM2-related myopathy (AD)	MONDO:0100196
	CAP myopathy 2 (AD, 609285)		TPM2-related myopathy (AD)	MONDO:0100196
	Arthrogryposis, distal, type 2B4 (AD, 108120)	Not within the scope of the Congenital Myopathies GCEP
	Arthrogryposis, distal, type 1A (AD, 108120)	Not within the scope of the Congenital Myopathies GCEP
TPM3	Congenital myopathy 4A, autosomal dominant (AD, 255310)	Autosomal dominant and autosomal recessive disease forms were considered to represent a clinical spectrum of overlapping myopathies.	TPM3-related myopathy (AD)	MONDO:0100108
TPM3	Congenital myopathy 4B, autosomal recessive (AR, 609284)		TPM3-related myopathy (AR)	MONDO:0100108
TTN	Myopathy, myofibrillar, 9, with early respiratory failure (AD, 603689)	Considered a separate disease based on distinct molecular mechanism (heterozygous missense variants in the A-band region) and clinical presentation of autosomal dominant hereditary proximal myopathy with prominent respiratory failure.	Myopathy, myofibrillar, 9, with early respiratory failure (AD)	MONDO:0011362
	Tibial muscular dystrophy, tardive (AD, 600334)	Considered a separate disease based on distinct molecular mechanism (heterozygous missense and truncating variants in the M-line region) and clinical presentation of autosomal dominant later onset, slowly progressive disease typically confined to the tibialis anterior muscle.	Tibial muscular dystrophy (AD)	MONDO:0010870
	Congenital myopathy 5 with cardiomyopathy (AR, 611705)	Considered a group of related entities with shared molecular mechanisms and inheritance pattern, despite variability in associated phenotypes (including age of onset, progression, and pattern and severity of muscle involvement).	TTN-related myopathy (AR)	MONDO:0100175
	Muscular dystrophy, limb-girdle, autosomal recessive 10 (AR, 608807)		TTN-related myopathy (AR)	MONDO:0100175
	Cardiomyopathy, dilated, 1G (604145)	Not within the scope of the Congenital Myopathies GCEP
	Cardiomyopathy, familial hypertrophic, 9 (AD, 613765)	Not within the scope of the Congenital Myopathies GCEP

Overall, the CongenMyopathy-GCEP curated 37 genes for 50 gene-disease relationships, which resulted in 35 (70%) Definitive, eight (16%) Moderate, six (12%) Limited, and one (2%) Disputed disease relationship classifications (Figure 1, Table 2). Those classified as Definitive were scored 12–18 points. Twelve classifications, including well-established disease genes such as ACTA1, NEB, and MTM1, reached the maximum score of 18 (Figure 2). Genetic evidence reflecting numerous reports from the literature of causative variants reached the maximum of 12 points in 28 (80%) of the Definitive classifications and 56% of all classifications. All genes with 12 points of genetic evidence were classified as having Definitive evidence for the respective diseases. Additional experimental evidence was available for all Definitive classifications. The experimental evidence reached the maximum score of 6 points in 14 (40%) of the Definitive classifications and 28% of all classifications, including KLHL41, which was classified as having Moderate evidence for nemaline myopathy due to having 2.8 points for genetic evidence at the time of curation. There were no gene-disease relationships classified as Strong, due to the absence of curated genes with a total of ≥12 points without replication over time, which is the only criteria that distinguishes Strong from Definitive classification.

Figure 1.

Overview of gene-disease validity classifications for genes that have been implicated in congenital myopathies. Distribution of gene-disease classifications with percentage of gene-disease relationships at each clinical validity classification. A total of 50 gene-disease relationships were assessed.

Figure 2.

Genetic and experimental evidence scores for congenital myopathies gene-disease validity classifications. Genetic and experimental scores are depicted by the black and gray bars, respectively. Total points for each classification are as follows: Limited (0.1–6 points), Moderate (7–11 points), Definitive (12–18 points). The Strong classification is not depicted as no gene-disease relationships that were reviewed by the CongenMyopathy-GCEP were classified in this category. Classifications modified for insufficient genetic evidence (L-Limited, D-Disputed) or GCEP internal genetic evidence data (M-Moderate) are indicated. Curations performed for the same gene and mode of inheritance with different diseases: TTN-AD: TTN to AD tibial muscular dystrophy, TTN-AD2: TTN to AD hereditary proximal myopathy with early respiratory failure, COL6A3-AR: COL6A3 to AR collagen 6-relayed myopathy, COL6A3-AR2: COL6A3 to AR dystonia.

Table 2.

Clinical validity classifications for genes implicated in congenital myopathies.

Gene	Disease (Inheritance)	Mondo ID	Classification (points)
ACTA1	Alpha-actinopathy (AD)	MONDO:0100084	Definitive (18)
ACTA1	Alpha-actinopathy (AR)	MONDO:0100084	Definitive (14.5)
BIN1	Centronuclear myopathy (AR)	MONDO:0009709	Definitive (17.2)
BIN1	Centronuclear myopathy (AD)	MONDO:0009709	Limited (5.85)
CCDC78	Centronuclear myopathy (AD)	MONDO:0018947	Limited (7)*
CFL2	Nemaline myopathy (AR)	MONDO:0012538	Definitive (12.1)
COL6A1	Collagen 6-related myopathy (AR)	MONDO:0100225	Definitive (18)
COL6A1	Collagen 6-related myopathy (AD)	MONDO:0100225	Definitive (18)
COL6A2	Collagen 6-related myopathy (AR)	MONDO:0100225	Definitive (17)
COL6A2	Collagen 6-related myopathy (AD)	MONDO:0100225	Definitive (15.75)
COL6A3	Collagen 6-related myopathy (AR)	MONDO:0100225	Definitive (15)
COL6A3	Collagen 6-related myopathy (AD)	MONDO:0100225	Definitive (18)
COL6A3	Dystonia (AR)	MONDO:0014627	Limited (2.75)
DNM2	Centronuclear myopathy (AD)	MONDO:0008048	Definitive (18)
HACD1	Congenital myopathy (AR)	MONDO:0019952	Definitive (15.6)
KBTBD13	Nemaline myopathy (AD)	MONDO:0012237	Moderate (10.45)
KLHL40	Nemaline myopathy (AR)	MONDO:0014138	Definitive (18)
KLHL41	Nemaline myopathy (AR)	MONDO:0014326	Moderate (8.8)
LAMA2	LAMA2-related muscular dystrophy (AR)	MONDO:0100228	Definitive (18)
LMOD3	Nemaline myopathy (AR)	MONDO:0014513	Definitive (17.5)
MAP3K20	Centronuclear myopathy with fiber-type disproportion (AR)	MONDO:0054695	Moderate (6.5)
MEGF10	MEGF10-related myopathy (AR)	MONDO:0013731	Definitive (16)
MTM1	Myotubular myopathy (XL)	MONDO:0010683	Definitive (18)
MYH2	Proximal myopathy and ophthalmoplegia (AR)	MONDO:0011577	Definitive (13.5)
MYH2	Proximal myopathy and ophthalmoplegia (AD)	MONDO:0011577	Moderate (8)
MYH7	MYH7-related skeletal myopathy (AD)	MONDO:0008050	Definitive (16.5)
MYL1	Congenital myopathy (AR)	MONDO:0019952	Limited (4)
MYO18B	Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome (AR)	MONDO:0014689	Moderate (8.65)
MYPN	MYPN-related myopathy (AR)	MONDO:0015023	Definitive (14.5)
NEB	Nemaline myopathy (AR)	MONDO:0009725	Definitive (18)
NEB	AD nebulin-related myopathy (AD)	MONDO:0002921	Moderate (5.5)**
ORAI1	Tubular aggregate myopathy (AD)	MONDO:0008051	Definitive (12)
PYROXD1	Myofibrillar myopathy (AR)	MONDO:0014993	Definitive (14.9)
RYR1	RYR1-related myopathy (AR)	MONDO:0100150	Definitive (18)
RYR1	RYR1-related myopathy (AD)	MONDO:0100150	Definitive (16)
RYR3	Congenital myopathy (AR)	MONDO:0019952	Disputed (2)
SCN4A	SCN4A-related myopathy (AR)	MONDO:0100121	Definitive (13.5)
SELENON	SELENON-related myopathy (AR)	MONDO:0100100	Definitive (15.5)
SPEG	Centronuclear myopathy (AR)	MONDO:0014418	Definitive (16.5)
STAC3	Bailey-Bloch congenital myopathy (AR)	MONDO:0009722	Definitive (17)
STIM1	Tubular aggregate myopathy (AD)	MONDO:0008051	Definitive (17)
TNNT1	Nemaline myopathy (AR)	MONDO:0011539	Definitive (18)
TNNT1	Nemaline myopathy (AD)	MONDO:0018958	Limited (4.75)
TNNT3	Nemaline myopathy (AR)	MONDO:0018958	Limited (4)
TPM2	TPM2-related myopathy (AD)	MONDO:0100196	Definitive (15)
TPM3	TPM3-related myopathy (AD)	MONDO:0100108	Definitive (13.5)
TPM3	TPM3-related myopathy (AR)	MONDO:0100108	Definitive (13)
TTN	TTN-related myopathy (AR)	MONDO:0100175	Definitive (18)
TTN	Myopathy, myofibrillar, 9, with early respiratory failure (AD)	MONDO:0011362	Moderate (7.6)
TTN	Tibial muscular dystrophy (AD)	MONDO:0010870	Moderate (7.1)

AD: Autosomal dominant; AR: Autosomal recessive. *Classification of CCDC78 was modified from Moderate to Limited due to the genetic evidence not meeting Moderate classification requirement of minimum 3 probands. **Classification of the validity of NEB-AD nebulin-related myopathy was modified from Limited to Moderate based on internal genetic evidence provided by GCEP group members.

Non-Definitive classifications earned 2–10.45 points and lacked evidence in genetic and/or experimental categories (Figure 2). Gene-disease relationships that reached a higher classification had a higher number of probands that reached a higher genetic evidence score. KBTBD13, KLHL41, MAP3K20, MYH2, MYO18B, NEB-related AD nebulin-related myopathy, TTN-related AD myofibrillar myopathy with early respiratory failure, and TTN-related AD tibial muscular dystrophy were classified as having Moderate evidence for gene-disease association. Current evidence of a relationship with congenital myopathies was considered as Limited for CCDC78 for centronuclear myopathy and MYL1 with congenital myopathy. CCDC78 had a total score of 7 points, which would have been sufficient for Moderate disease relationship classification; however, only 2 probands with CCDC78 variants were available to be scored as genetic evidence. Due to the requirement for a minimum of 3 probands for Moderate classification, the relationship of CCDC78 with centronuclear myopathy remained as Limited at this time. Four genes that have been implicated in multiple diseases were also considered to have Limited evidence for a relationship with congenital myopathies: BIN1 association with AD centronuclear myopathy, TNNT3 association with AR nemaline myopathy (relationship with AD distal arthrogryposis was not considered), TNNT1 with AD nemaline myopathy, and COL6A3 with AR dystonia. Gene-disease relationships with Limited validity had two or fewer probands reported at this time.

Finally, RYR3 was classified as having a Disputed disease relationship. RYR3 was reported once in relation to AR congenital myopathy in a single affected individual in 2018.¹¹ The two unique reported missense variants have been the only variants asserted to be associated with disease and the impact of these variants on protein function is currently unclear. Some functional evidence supporting this gene-disease relationship exists, including protein expression data,¹⁶ functional alteration data from Ryr3 knockout mice,^17,18 and RYR3-depleted zebrafish.¹⁹ Although the relevant experimental evidence is supportive of a gene-disease relationship, because the single report implicating RYR3 in AR congenital myopathy in humans was considered as being insufficient to be scored as genetic evidence at this time, the relationship of RYR3 to congenital myopathies was classified as Disputed.

To assess how gene-disease relationship classifications may impact variant classifications in congenital myopathy genes, we analyzed the variant classifications that have been submitted to ClinVar for each gene. In ClinVar, variants in genes with non-Definitive roles with submitted classifications for congenital myopathy-related conditions were predominantly variants of uncertain significance (VUS). In genes with non-Definitive classification, only 5.7% (57/992) of variants other than those classified as benign/likely benign were classified as pathogenic or likely pathogenic (P/LP), whereas 94.3% were classified as VUS (1471/1564), with 99.3% (299/301) of such variants classified as VUS in genes with Limited classification and 91.7% (610/665) classified as VUS in genes with Moderate classification. On the other hand, in genes with a Definitive role in disease, 22.6% (3789/16769) of variants other than benign/likely benign were classified as P/LP and 77.4% were classified as VUS (Figure 3). Three genes curated by the CongenMyopathy-GCEP (CCDC78, RYR3, and TNNT3) did not have any P/LP ClinVar submissions related to congenital myopathies that met criteria for analysis, all variants in these genes were classified as VUS by the submitters.

Figure 3.

Classifications in ClinVar for variants in congenital myopathy genes. Percentage of variants with pathogenic or likely pathogenic (P/LP) and variant of uncertain significance (VUS) classifications in ClinVar for congenital myopathy-related conditions are presented for genes classified by the CongenMyopathy-GCEP. The total number of variants P/LP and VUS variants assessed for each gene are presented on the right side of each bar.

Discussion

A substantial proportion of genes reported in patients with congenital myopathies have been associated with a wide phenotypic spectrum and overlapping features, which poses a challenge in the molecular diagnosis of patients. Although genetic testing provides the opportunity to make a molecular diagnosis for genetically heterogenous conditions, its utility is often limited by inconsistency and uncertainty in the validity of a gene's role in disease and the clinical significance of genetic variants.

Of the 50 gene-disease relationships that were curated by the CongenMyopathy-GCEP, 70% had Definitive level of evidence for a causal role in one or more types of congenital myopathies. Gene-disease validity classifications have been published by other ClinGen GCEPs investigating various genetic disorders.^20–31 The proportion of curated genes classified as having Definitive evidence for disease relationship ranges from 5% (Brugada syndrome) to 75% (intellectual disability/autism).^23,30 Many factors may contribute to the relative proportion of genes with non-Definitive classification in different disease groups, including the ambiguity and complexity of disease phenotypes or presence of reliable functional studies and animal models.

Curation of distinct phenotypes and inheritance patterns is important to enable a better prediction of the possible disease presentation and inheritance patterns when novel variants are identified in these genes. Eleven of the 37 genes curated were determined to be associated with more than one distinct congenital myopathy subtype due to differences in molecular mechanism, phenotype, and/or inheritance pattern (Table 1). For example, RYR1 was evaluated separately for AD and AR inheritance, based on the difference in pathogenic mechanisms (dominant negative for AD versus loss of function for AR), and phenotypic variability, most notably the overlap of the AD phenotype with malignant hyperthermia susceptibility. On the other hand, TNNT1 was evaluated separately for the classically observed association of loss of function variants with AR nemaline myopathy and the distinctive phenotypic features not being present in the more recently defined association of potential gain of function variants with AD nemaline myopathy.²⁷ The strength of a gene's associations with different diseases was variable. For example, the causal role of COL6A3 in collagen 6-related myopathy was classified as Definitive, while its relationship with dystonia was considered as having only Limited level of evidence. The gene curated by the CongenMyopathy-GCEP related to the highest number of disease entities was TTN. Multiple diseases, including cardiomyopathies, muscular dystrophies, and myopathies have been associated with TTN variants in the literature. In particular, the TTN-associated neuromuscular disorders encompass a range of distinct clinical presentations with wide variation in severity, age of onset, progression, and pattern of muscle involvement, as well as differences in inheritance patterns and suspected molecular mechanisms. Because of these differences, the curation of this gene was separated into three distinct gene-disease pairs to allow individual evaluation of the unique disease entities (Table 1). The size of the TTN gene and the encoded protein, as well as the number of diverse isoforms complicate functional studies on this gene. As a result, none of the TTN curations reached the maximum number of points for experimental evidence. For example, although over twelve TTN missense variants have been associated with AD myofibrillar myopathy with early respiratory failure^32–37 to date, including three recurrent variants identified in multiple affected individuals, lack of sufficient experimental evidence supporting the effect of the variants on protein function led to this gene-disease relationship being classified as having Moderate evidence. Conversely, a broad spectrum of congenital myopathy phenotypes was associated with four of the genes classified as having Definitive evidence (ACTA1, COL6A1, COL6A2, and COL6A3). For these genes, disease names that encompass the continuum of histological and clinical phenotypes were selected, rather than the existing disease names that are commonly used for referring to the distinct clinical or pathological presentations. Thus, ACTA1 was curated for the broad disease entity of alpha-Actinopathy, which includes overlapping congenital and adult-onset myopathies characterized by muscle weakness, hypotonia, myopathic facies, respiratory dysfunction, and rarely, cardiac involvement. Inter- and intra-familial phenotypic variability observed for individual variants suggested that these entities are part of the same clinical spectrum. While nemaline myopathy is the most common presentation, several other histopathologically distinct myopathies have been reported in association with ACTA1 variants. Specific skeletal muscle structural lesions visible on muscle biopsy include actin accumulations, nemaline and intranuclear bodies, fiber-type disproportion, cores, caps, dystrophic features, and zebra bodies.³⁸ Approximately 200 unique variants have been reported to date in ACTA1, resulting in both dominant (∼90%) and recessive disease (∼10%).³⁸

Of note, 30% (15 of 50) of gene-disease associations have Moderate, Limited, or Disputed classification. Six gene-disease relationships were classified as having Limited evidence. All Limited classifications, except for CCDC78, are for relatively recent disease gene discoveries and although more genetic and/or experimental evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the proposed gene-disease relationships.

A Moderate classification typically indicates that there is emerging but insufficient evidence for the validity of gene-disease relationship at the time of curation to classify as Strong, although it is likely to reach Strong/Definitive in time.³⁹ Moderate classifications will be re-evaluated every two years to maintain current gene-disease validity classifications and may become Strong and Definitive classification over time as evidence accrues.³⁹ Updates to gene-disease validity classifications will be published on the ClinGen CongenMyopathy-GCEP website. Whether the genes with Limited level of evidence will have further data supporting a higher disease validity classification in the future depends on the availability of additional case and experimental studies. To improve understanding of gene- and variant-disease relationships, we encourage publication of additional studies particularly for the genes with non-Definitive relationships. The importance of available case reports is exemplified by two genes, HACD1 and MYO18B, which were reclassified from having Limited to Moderate or Definitive evidence, respectively, based on recently published studies during the CongenMyopathy-GCEP's four-year working period. Two additional genes with Moderate classification, KBTBD13 and KLHL41, each have strong experimental evidence (5.5–6 points) and could be reclassified to having higher validity if additional cases are reported in the future. Data have shown that many genes in the Limited category, particularly those that remain Limited for more than five years, do not accumulate evidence in the future to move to a higher classification.³⁹ However, the assembly of additional supportive case series for such rare genetic conditions typically takes considerable time, so that additional publications for these genes may still emerge in the future, allowing for the classification to be adjusted to a higher level of evidence.

Interpretation of a variant's clinical significance is dependent on the understanding of the gene's relationship with disease. This study presents the evaluation of the first 37 genes that have been curated by our group. Our gene curation efforts continue addressing new genes that are implicated in congenital myopathies and will be ongoing as new gene-disease relationships are published in the future. We will continue to share our curations and classifications on the publicly available ClinGen website as they get completed. In our analysis, genes with a non-Definitive role in congenital myopathies had a higher proportion of variants classified as VUS compared to genes with Definitive roles. Evidence-based curation of genes is essential to guide appropriate classification and reporting of variants and is expected to improve variant interpretations to assist in patient care. Through systematic assessment of gene-disease relationships in combination with evidence supporting individual variant classifications, the CongenMyopathy-GCEP aims to facilitate accurate molecular diagnoses of patients with congenital myopathies.

Supplemental Material

sj-docx-1-jnd-10.1177_22143602251339369 - Supplemental material for Clinical validity of congenital myopathy genes determined by the ClinGen Congenital Myopathies Expert Panel

Supplemental material, sj-docx-1-jnd-10.1177_22143602251339369 for Clinical validity of congenital myopathy genes determined by the ClinGen Congenital Myopathies Expert Panel by Justyne E Ross, May Flowers, Shannon McNulty, Mayher Patel, Hui Yang, Brooke Palus, Marwa Abdelmoneim Elnagheeb, Lucy Eng, Emma Owens, Alan H Beggs, Enrico Bertini, Adele D'Amico, Sandra Donkervoort, James Dowling, Fabiana Fattori, Ana Ferreiro, Casie A Genetti, Hernan Gonorazky, Monkol Lek, Amanda Lindy, Livija Medne, Francesco Muntoni, Sander Pajusalu, Katarina Pelin, John Rendu, Anna Sarkozy, Matteo Vatta, Tom Winder, Grace Yoon, Carsten G Bönnemann and Ozge Ceyhan-Birsoy in Journal of Neuromuscular Diseases

Supplemental Material

sj-docx-2-jnd-10.1177_22143602251339369 - Supplemental material for Clinical validity of congenital myopathy genes determined by the ClinGen Congenital Myopathies Expert Panel

Supplemental material, sj-docx-2-jnd-10.1177_22143602251339369 for Clinical validity of congenital myopathy genes determined by the ClinGen Congenital Myopathies Expert Panel by Justyne E Ross, May Flowers, Shannon McNulty, Mayher Patel, Hui Yang, Brooke Palus, Marwa Abdelmoneim Elnagheeb, Lucy Eng, Emma Owens, Alan H Beggs, Enrico Bertini, Adele D'Amico, Sandra Donkervoort, James Dowling, Fabiana Fattori, Ana Ferreiro, Casie A Genetti, Hernan Gonorazky, Monkol Lek, Amanda Lindy, Livija Medne, Francesco Muntoni, Sander Pajusalu, Katarina Pelin, John Rendu, Anna Sarkozy, Matteo Vatta, Tom Winder, Grace Yoon, Carsten G Bönnemann and Ozge Ceyhan-Birsoy in Journal of Neuromuscular Diseases

Footnotes

ORCID iDs

Justyne E Ross

Shannon McNulty

Lucy Eng https://orcid.org/0009-0007-6180-2639

Alan H Beggs

Enrico Bertini

Casie A Genetti

Livija Medne

Francesco Muntoni

Katarina Pelin

Matteo Vatta

Grace Yoon

Funding

This publication was supported by the National Human Genome Research Institute of the National Institutes of Health through the following grants: U24NS120858, U41HG009650, U24HG009650, and U24HG006834. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Declaration of conflicting interests

M.V. receives salary from Labcorp Genetics Inc. (formerly Invitae Corp.); E.B. received reimbursements for Advisory Board by Biogen, PTC, Novartis, Roche, and Pfizer; A.H.B. has received compensation or honoraria from Audentes Therapeutics, F. Hoffman-LaRoche AG, GLG Inc, Guidepoint Global LLC, and Kate Therapeutics Inc; and holds equity in Kinea Bio and Kate Therapeutics Inc; A.S.L. is employed by, and maintains stock ownership or options with, GeneDx, LLC.

Data availability

All curation summaries and relevant references are available at https://search.clinicalgenome.org/kb/affiliate/10031.

Supplemental material

Supplemental material for this article is available online.

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