Inclusion Criteria:
* • Patient age at time of consent is \<21 years.
* Clinically confirmed genetic muscle disease\* with either:
* a pathogenic or likely pathogenic variant in a disease-causing gene11, or
* a variant of uncertain significance that is considered by the investigators to be potentially causative of the patient's neuromuscular phenotype\*\*.
* The identified variant is theoretically amenable to at least one of the following RNA-targeted therapeutic strategies12 described below and based on published guidelines \*\*\*:
* ASO-mediated splice modulation through forced exon inclusion or pseudoexon exclusion
* ASO-mediated allele-specific knockdown
* Variant population frequency ≤1:100,000 based on reference databases (e.g., gnomAD).
* The clinical phenotype is sufficiently severe and/or progressive to warrant consideration of future investigational therapeutic approaches, as determined by consensus of the trial team, taking into account factors such as:
* Ambulatory status
* Respiratory involvement
* Dysphagia
* Functional independence
* Expected disease progression
* Frequency of hospitalization and/or ICU admission
* Disease course is not expected to progress to death or end-stage pathology within a timeframe that would preclude meaningful longitudinal observation or potential future interventional study planning (anticipated ≥4 years).
* For patients with Duchenne muscular dystrophy, glucocorticoid dosing (adjusted for weight) is stable for the preceding 3 months prior to start date.
* Willingness to participate in all study-related observational assessments and to adhere to standard-of-care clinical management.
* Parent or caregiver is fluent in English to ensure valid administration of standardized outcome measures and informed consent procedures.
* Genetic muscle disease is defined as a genetically determined condition in which the primary phenotype arises from skeletal muscle pathology. Disorders may have extra-muscular manifestations (e.g., neurocognitive features in Duchenne muscular dystrophy), but skeletal muscle dysfunction must be the primary driver of impairment. Eligible diagnoses include congenital muscular dystrophies, congenital myopathies, dystrophinopathies, limb-girdle muscular dystrophies, and skeletal muscle channelopathies. Confirmation of the variant of interest must be obtained through DNA sequencing performed in a CLIA-certified laboratory.
* For subjects with variants of uncertain significance by standard American College of Medical Genetics (ACMG) criteria, orthogonal pathogenicity data will be required. This is expected in cases of deep intronic variants, where clinical genetic reports may not account for RNA sequencing data obtained from external labs.
* ASO-amenable variants will be defined based on the variant type and mechanism of disease. For subjects with deep intronic pathogenic variants, evidence of a pseudoexon or abnormal exclusion of an exon by RNA sequencing data will be required for study participation. For subjects with dominant, gain of function variants, evidence from literature for toxic gain of function as a mechanism of disease will be required and evidence from literature that haploinsufficiency is not a disease mechanism will also be required.
Exclusion Criteria:
* • Availability of an effective (expected to halt all disease progression) disease-modifying therapy for the patient's condition at the time of enrollment.
* Pathogenic or suspected causative variant with population frequency \>1:100,000 based on standard reference databases.
* Variants with mechanisms not compatible with the therapeutic strategies under evaluation, including:
* Splice-site variants within 10 bp of canonical donor or acceptor sites
* Dominant variants acting through haploinsufficiency
* Recessively acting missense variants
* Whole-gene deletions
* Mitochondrially encoded variants
* Current enrollment in, or planned enrollment in, another interventional clinical trial.
* Pregnancy or intention to become pregnant during the anticipated study period.
* Inability of the subject or family to comply with study procedures.
* Chronic thrombocytopenia (platelet count \<75,000/uL that is not transient) or coagulation disorders (International normalized ratio (INR)\>1.3, activated partial thromboplastin time \>40 seconds, or symptomatic von Willebrand disease)
* Comorbid conditions that would interfere with the performance or interpretation of key outcome measures, including but not limited to:
* Severe intellectual disability
* Severe systemic non-neuromuscular disease (e.g., advanced liver disease) or central nervous system injury (e.g., anoxic brain injury)
* Active malignancy undergoing treatment
