Distal Myopathy Research Articles

Laing Early-onset Distal Myopathy Due to the MYH7 Mutation in an Iranian Family

Laing Early-onset Distal Myopathy Due to the MYH7 Mutation in an Iranian Family

"Boule du biceps" in dysferlinopathy.

Eymard et al.1 first described “boule du biceps” (bulging of biceps), a ball-like appearance caused by the selective atrophy of the distal half of the biceps brachii (BB) muscle, in patients with dysferliniopathy. This sign is also known as biceps lump. In our cohort of 24 patients with dysferlinopathy (22 symptomatic and 2 asymptomatic hyperCKemia), all confirmed both by the absence of dysferlin on muscle biopsy and by the presence of DYSF mutation on genetic analysis, except for 4 patients who were diagnosed only at the protein level. Among the 20 patients who were genetically confirmed, 18 were homozygotes for 3 different recurrent (c.342+1G>A, c.755C>T, and c.4431G>T) and 3 different nonrecurrent (c.1958delG, c.3944\_3948delinsG, and c.5983\_5984del) mutations, and 2 were compound heterozygotes of mutations different from those in other patients (c.2190dupA/c.3597G>A and c.4101G>A/c.6124C>T, respectively). Of note, we did not try to subclassify the clinical phenotype into Miyoshi myopathy and LGMD2B/LGMD-R2 dysferlin related as recent articles suggest that there is no essential difference in the pattern of muscle involvement, and thus, they are the same disease.2–5 The BB was carefully observed during contraction and relaxation to check for the sign. The function of the upper limb (UL) was assessed using the Medical Research Council (MRC) scale. Furthermore, the BB was observed in patients with other muscular dystrophy in our cohort (DMD/BMD 118 cases, sarcoglycanopathy 12 cases, FSHD 5 cases, LGMD2A 18 cases, and other LGMDs 5 cases). Boule du biceps was observed in 71% (17/24) of our patients with dysferlinopathy, including the 2 asymptomatic ones. The UL MRC score was 4 or higher in the 17 patients who showed boule du biceps, but was 3+ or lower in the 7 patients who lacked the sign. None of the controls showed boule du biceps. MRI of the BB of the asymptomatic patient during arm flexion showed that the distal part of the short head was partially infiltrated by fat, whereas the long head and the proximal part of the short head were spared. MRI of the symptomatic patient showed moderate fat infiltration in the long head and in the distal part of the short head, whereas the proximal part of the short head was spared (figure). The sign was absent in patients with more marked muscle weakness, suggesting that even the proximal portion of the BB may be affected in the advanced stages and thus can no longer show contraction. Five of 7 patients who did not show boule du biceps were nonambulant, indicating that this sign disappears in advanced stage of the disease. Our findings suggest that the distal portion of the short head of the BB is affected even in early stages, whereas the proximal part is spared, which gives rise to boule du biceps. This can be a valuable diagnostic clinical feature for dysferlinopathy from early stages of the disease.

Mutations in the J domain of DNAJB6 cause dominant distal myopathy

Eight patients from five families with undiagnosed dominant distal myopathy underwent clinical, neurophysiological and muscle biopsy examinations. Molecular genetic studies were performed using targeted sequencing of all known myopathy genes followed by segregation of the identified mutations in the affected families using Sanger sequencing. Two novel mutations in DNAJB6 J domain, c.149C>T (p.A50V) and c.161A>C (p.E54A), were identified as the cause of disease. The muscle involvement with p.A50V was distal calf-predominant, and the p.E54A was more proximo-distal. Histological findings were similar to those previously reported in DNAJB6 myopathy. In line with reported pathogenic mutations in the glycine/phenylalanine (G/F) domain of DNAJB6, both the novel mutations showed reduced anti-aggregation capacity by filter trap assay and TDP-43 disaggregation assays. Modeling of the protein showed close proximity of the mutated residues with the G/F domain. Myopathy-causing mutations in DNAJB6 are not only located in the G/F domain, but also in the J domain. The identified mutations in the J domain cause dominant distal and proximo-distal myopathy, confirming that mutations in DNAJB6 should be considered in distal myopathy cases.

GNE myopathy – A cross-sectional study on spatio-temporal gait characteristics

GNE myopathy is a rare, predominantly distal myopathy, involving mainly the lower limbs and presenting with gait disturbances. In this cross-sectional study gait evaluation of 23 (14 men) genetically confirmed GNE myopathy patients was done using Instrumented walkway analysis (GAITRite®) along with video gait capture. We recorded the topographical pattern of muscles involvement in lower limbs and correlated Functional Ambulation Profile-FAP and Medical Research council-MRC grading of lower limb scores with duration of illness. Early foot flat, foot drop gait with wider out-toed stance and higher perturbations with increased pressure at heel and decreased arm swing were noted. Muscle topography showed predominant weakness in ankle dorsi-flexors, flexor hallucis longus, extensor hallucis longus, hip adductors and knee flexors with stark sparing of quadriceps and relative sparing of hip- abductors, extensors, flexors and ankle plantar-flexors. Gait parameters in women were significantly more affected than men (p < 0.05) for the same duration of illness. FAP score and MRC grading of lower limb scores correlated significantly with duration of illness (p < 0.05). We observed that ankle dorsiflexors were affected earliest with sparing of quadriceps muscles in these patients.

Clinical myopathy in patients with nephropathic cystinosis.

Nephropathic cystinosis is a lysosomal storage disorder. Patient survival years after renal transplantation has revealed systemic complications including distal myopathy and dysphagia. We evaluated 20 adult patients with nephropathic cystinosis using patient-reported and clinical outcome measures. Standard motor measures, video fluoroscopy swallow studies, and tests of respiratory function were performed. We also used Rasch analysis of an initial survey to design a 16-item survey focused on upper and lower extremity function, which was completed by 31 additional patients. Distal myopathy and dysphagia were common in patients with nephropathic cystinosis. Muscle weakness ranges from mild involvement of intrinsic hand muscles to prominent distal greater than proximal weakness and contractures. In addition to further characterization of underlying dysphagia and muscle weakness, we propose a new psychometrically devised, disease specific, functional outcome measures for distal myopathy in patients with nephropathic cystinosis.

Human muscle pathology is associated with altered phosphoprotein profile of mitochondrial proteins in the skeletal muscle

Analysis of human muscle diseases highlights the role of mitochondrial dysfunction in the skeletal muscle. Our previous work revealed that diverse upstream events correlated with altered mitochondrial proteome in human muscle biopsies. However, several proteins showed relatively unchanged expression suggesting that post-translational modifications, mainly protein phosphorylation could influence their activity and regulate mitochondrial processes. We conducted mitochondrial phosphoprotein profiling, by proteomics approach, of healthy human skeletal muscle (n = 10) and three muscle diseases (n = 10 each): Dysferlinopathy, Polymyositis and Distal Myopathy with Rimmed Vacuoles. Healthy human muscle mitochondrial proteins displayed 253 phosphorylation sites (phosphosites), which contributed to metabolic and redox processes and mitochondrial organization etc. Electron transport chain complexes accounted for 84 phosphosites. Muscle pathologies displayed 33 hyperphosphorylated and 14 hypophorphorylated sites with only 5 common proteins, indicating varied phosphorylation profile across muscle pathologies. Molecular modelling revealed altered local structure in the phosphorylated sites of Voltage-Dependent Anion Channel 1 and complex V subunit ATP5B1. Molecular dynamics simulations in complex I subunits NDUFV1, NDUFS1 and NDUFV2 revealed that phosphorylation induced structural alterations thereby influencing electron transfer and potentially altering enzyme activity. We propose that altered phosphorylation at specific sites could regulate mitochondrial protein function in the skeletal muscle during physiological and pathological processes.

Distal myopathy induced arrhythmogenic right ventricular cardiomyopathy in a pedigree carrying novel DSG2 null variant

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare cardiac disease predominantly caused by variants in desmosome genes. Variants in human Desmoglein-2 (DSG2) gene can cause ARVC with incomplete penetrance. However, it remains unknown whether ARVC would penetrate by distal myopathy. MethodsWe performed targeted next-generation sequencing using a cardiomyopathy/ionchannelopathy panel in a Chinese ARVC pedigree. Plasmids of DSG2 were constructed, and pathogenicity of the DSG2 variant was investigated by real-time PCR, western blots, Immunofluorescence, and electron microscope. ResultsWe identified a novel nonsense variant in DSG2 (c.710T > A, p.Leu237Ter) and a reported pathogenic missense variant of distal myopathy in MYH7 (c. 1322C > T, p.Thr441Met) in the proband of an ARVC pedigree. The functional analyses suggested that the nonsense variant could affect the expression and cell location of DSG2, and the number and shape of desmosomes were affected as well, indicating that the variant was implicated in the pathogenesis of ARVC. We found only patients carrying the distal myopathy pathogenic variant would manifested early-onset severe ARVC phenotype, which suggested that MYH7-p.Thr441Met variant could induced the onset of ARVC in the DSG2-p.Leu237Ter variant carriers. ConclusionsOur study identified a novel null variant in DSG2 gene (c.710T > A, p.Leu237Ter) in an ARVC pedigree with incomplete penetrance. Only patients who carried a distal myopathy associated variant in MYH7 (c. 1322C > T, p.Thr441Met) would induce the onset of ARVC with early-onset and severe symptoms.

Genetic distal myopathies

Distal myopathies are a group of rare muscle disorders that are characterized by selective weakness of the distal muscles of the lower and/or upper limbs at disease onset. Predominant muscle weakness can affect distal lower legs, including calf muscles and/or foot dorsiflexors, and/or distal upper limb muscles. In a later stage of the disease sometimes proximal muscles are also involved. Age of onset varies from early-childhood to late-adulthood. Creatine kinase in serum can range from normal to highly elevated. Electromyography usually reveals a myogenic pattern often associated with spontaneous activity. Histopathological changes on muscle biopsy can vary from nonspecific myopathic changes to the presence of rimmed vacuoles or central nuclei to myofibrillar pathology. Muscle MRI can be a useful tool in the differential diagnosis of distal myopathies. The majority of distal myopathies have a genetic etiology. The underlying molecular defect in distal myopathies is heterogeneous and the number of causative genes and novel mutations in known genes are constantly increasing due to the application of recent next-generation sequencing techniques such as (whole) exome sequencing. In addition, there is a considerable overlap with neurogenic disorders, since it has been demonstrated that distal myopathies can result from defective proteins encoded by genes causative of neurogenic disorders. Moreover, also acquired neuromuscular disorders and myopathies can present with distal weakness. In this presentation, I will provide an overview on the clinical, histopathological, muscle imaging and molecular aspects of distal myopathies, as well as their differential diagnoses, focusing on the most recent developments in the field.

O.20Mutations in ACTN2 gene cause a novel form of adult-onset distal myopathy

We studied three families from the same village in northern Spain and one family from Sweden with an autosomal dominant distal myopathy with rimmed vacuolar pathology. Affected members shared a very similar clinical phenotype, a characteristic pattern of muscle involvement by MRI and common histologic features. In particular, all the patients showed an adult-onset, asymmetric muscle weakness, with atrophy of tibialis anterior and initial involvement of ankle dorsiflexion later progressing to proximal limb muscles. We identified an ACTN2 c.1459T>C (p.C487R) variant co-segregating with the disease in families 1–3. An ACTN2 c.392T>C (p.L131P) variant was identified in the affected members of family 4. In all the families enrolled, the private ACTN2 variants are fully penetrant and co-segregate with the disease. ACTN2 encodes for alpha actinin2, a protein highly expressed in the Z-disk of cardiac and skeletal sarcomeres, where it plays several structural and functional roles through a complex network of interactions with other sarcomeric proteins. Our findings demonstrate that ACTN2 mutations cause a new type of dominant late-onset and slowly progressive distal myopathy. Dominant ACTN2 mutations were previously associated with hypertrophic and dilated cardiomyopathies. At the same time as our studies, two ACTN2 mutations have been described as the cause of a congenital core myopathy patients. Additional studies are needed to improve our understanding of the genotype-phenotype correlation and to clarify the molecular mechanisms of the actinopathies.

P.246Drosophila model of myosin myopathy rescued by overexpression of a TRIM-protein family member

Myosin is a molecular motor indispensable for body movement and heart contractility. Apart from pure cardiomyopathy, mutations in MYH7 encoding slow/β-cardiac myosin heavy chain also cause skeletal muscle disease with or without cardiac involvement. Mutations within the α-helical rod domain of MYH7 are mainly associated with Laing distal myopathy. To investigate the mechanisms underlying the pathology of the recurrent causative MYH7 mutation (K1729del), we have developed a Drosophila melanogaster model of Laing distal myopathy by genomic engineering of the Drosophila Mhc locus. Homozygous MhcK1728del animals die during larval/pupal stages, and both homozygous and heterozygous larvae display reduced muscle function. Flies expressing only MhcK1728del in indirect flight and jump muscles, and heterozygous MhcK1728del animals, were flightless, with reduced movement and decreased lifespan. Sarcomeres of MhcK1728del mutant indirect flight muscles and larval body wall muscles were disrupted with clearly disorganized muscle filaments. Homozygous MhcK1728del larvae also demonstrated structural and functional impairments in heart muscle, which were not observed in heterozygous animals, indicating a dose-dependent effect of the mutated allele. The impaired jump and flight ability and the myopathy of indirect flight and leg muscles associated with MhcK1728del were fully suppressed by expression of Abba/Thin, an E3-ligase that is essential for maintaining sarcomere integrity. This model of Laing distal myopathy in Drosophila recapitulates certain morphological phenotypic features seen in Laing distal myopathy patients with the recurrent K1729del mutation. Our observations that Abba/Thin modulates these phenotypes suggest that manipulation of Abba/Thin activity levels may be beneficial in Laing distal myopathy.

P.242Phenotypic variability in a cohort of patients with TTN-related congenital myopathy

The term `titinopathies' encompasses a heterogeneous group of myopathies caused by mutations in TTN. The most common resulting clinical picture is the congenital myopathy. The limb-girdle dystrophy and distal myopathy with onset during the adulthood are other well-known phenotypes related to TTN. A severe myocardiopathy is associated in some cases. Describing the clinical, histopathological, and molecular findings in patients with TTN-related congenital myopathy followed-up in our hospital. A retrospective descriptive study was conducted. Six patients with molecular diagnosis of TTN-related congenital myopathy were included. The onset was observed during the neonatal period in more than 80% of cases. Weakness was detected during the first year of life in the remaining patient. Axial weakness was observed in all the patients. Scoliosis was detected in 50%, whereas ophthalmoparesis/ophthalmoplegia was not showed by any patient. Autonomous ambulation was not acquired in 3 out of the 6 patients and one other patient lost this ability at 4 years of age. Respiratory involvement needing nocturnal non-invasive ventilation was observed in one patient. Cardiac involvement was not detected in any case. Creatin quinase levels were within the normal range in all the cases. The muscle biopsy findings were relatively heterogeneous, mainly characterized by the fiber size variability, internal nucleus, and cores. TTN-related congenital myopathy is characterized by the presence of a marked axial weakness that can lead to an early scoliosis. Roughly 50% of patients are not able to achieve an autonomous ambulation.

E-POSTERS – EARLY ONSET MUSCLE DISEASE – CASE REPORTS: EP.120ADSSL1 distal myopathy presenting with a more rapid progressive course in patient with trisomy 21

We report a 22 year old female of mixed European and Mexican background with novel compound heterozygous ADSSL1 gene mutations (p.Gly326Asp, pat and c.1202+1G>A, mat) identified by exome sequencing with a more progressive clinical course due to her other diagnosis of trisomy 21 (T21). Her development was appropriate for T21, but she never learned to run, jump or use stairs independently. At age 8 yr, her motor skills started to regress with emergence of weakness. She used a walker by 10 yr and lost ambulation at 12 yr. Currently, she cannot weight-bear (strength 1/5 in most leg muscles; quadriceps at 1-2/5), but has more preserved upper extremity use (strength 3 to 3-/5 range). She has hip, knee contractures, end-grade elbow contractures, and coexistence of finger flexor contractures with laxity in PIP and DIP joints. Her cognitive delays are typical for T21. She developed progressive scoliosis that required T4-L4 spinal fusion at 12 yr of age. There is no cardiomyopathy and her LVSF is 36%. Nocturnal hypoventilation started at age 13 yr with use of BiPAP during sleep since 16 yr of age. Unlike previously reported cases, she had a normal CK and her muscle biopsy at 14 yr did not show rimmed vacuoles or nemaline rods but rather severe myopathic changes: fibrosis and adipose infiltration, variation in fiber size with small, atrophic fibers intermixed with hypertrophic fibers, rounded and splitting fibers, increased central nuclei and occasional degenerating/regenerating fibers. To date, ADSSL1 gene mutations, encoding an enzyme converting inosine monophosphate (IMP) to adenosine monophosphate (AMP), have been reported only in 9 Korean patients from 6 families with 8 of the 9 patients having the same compound heterozygous mutations, suggesting a founder-effect. Identification of another patient with novel mutations suggests that this form of myopathy is panethnic and likely underdiagnosed among patients presenting with signs of generalized and distal myopathy.

DISTAL MYOPATHIES: P.244SYNE1 cerebellar ataxia "plus" syndrome: characterizing the skeletal muscle and cardiopulmonary phenotype

DISTAL MYOPATHIES: P.244SYNE1 cerebellar ataxia "plus" syndrome: characterizing the skeletal muscle and cardiopulmonary phenotype

EP.24Recessive mutations in CAV3 - a new differential diagnosis of early-onset neuromuscular disorders

Dominant CAV3 mutations account for a very wide phenotypical spectrum, including limb girdle muscular dystrophy (LGMD), rippling muscle disease (RMD), distal myopathy or asymptomatic hyperCKemia. Very few recessive cases have been reported to date with mild clinical features. Here we report a 19-month-old male presenting antenatally with reduced foetal movements from 36/40 and possible polyhydramnios. Family history had been unremarkable except for a history of speech and language delay in 2 siblings. He was delivered by elective Caesarean section at 38 weeks gestation. He was hypotonic at birth and was given facial oxygen and started on intravenous antibiotics until sepsis had been excluded. He quickly established spontaneous breathing and breast feeding. He was re-admitted to hospital when he was 2 months old with bronchiolitis when he was noted to have generalized hypotonia pronounced axially, with significant head lag and scarce antigrativity movements in his legs. There was bilateral talipes but there were no other contractures. DTR were difficult to elicit. He was not dysmorphic and did not have any facial weakness or ophthalmoplegia. CK was elevated up to 7398 IU/L. Brain MRI and cardiac evaluation were normal. His muscle biopsy showed abnormal variation in fibre size, increase in internal nuclei, necrosis and regeneration with modest endomysial chronic inflammation. Molecular analysis revealed a homozygous CAV3 mutation (c.10_17delGAAGAGCA; p.Glu4Hisfs*17) in trans. Further muscle biopsy IHC studies revealed complete caveolin-3 deficiency. Subsequently the patient achieved independent sitting at the age of 8 months, crawled from 1 year and walked independently at 18 months. No rippling of muscle was noted on further examination. This report expands the genetic and clinico-pathological spectrum of CAV3-associated disease, and suggests that recessive CAV3 mutations ought to be considered in the differential diagnosis of early-onset neuromuscular disorders.

P.160The spectrum of disease-causing and normal variation in the nebulin gene

The nebulin gene (NEB) with 183 exons is one of the largest genes in human. More than 240 different disease-causing variants in NEB have been identified in some 220 families. Around 50% of nemaline myopathies (NM) are caused by mutations in NEB. Mutations in NEB also cause core-rod myopathy, distal forms of NM, distal myopathy without nemaline rods, and multiple pterygium syndrome. The majority (95%) of the disease-causing variants in NEB are recessive point mutations, mainly nonsense and splice site mutations, and small indels, causing frameshifts. The remaining 5% of mutations are large copy number variations (CNVs). In addition to the recurrent CNVs in the triplicate region and the founder mutation with world-wide occurrence, deletion of exon 55, 11 different large pathogenic duplications and deletions have been identified in NEB. Until recently, all identified mutations in NEB have been recessive. Now it is known that large in-frame deletions in NEB, leading to the expression of substantially smaller proteins, can have a dominant-negative effect, and cause dominant distal forms of NM. The genome aggregation database (gnomAD) contains exome and genome data from 141,456 unrelated individuals, excluding patients with severe pediatric disorders. The total number of different NEB variants listed in gnomAD is 10,634. Most of the variants (96%) are very rare, only present in a few heterozygotes. Intronic variants comprise 43%, missense variants 40%, synonymous variants 14%, loss-of-function variants 3%, and UTR variants 0.2% of the total variation. It is noteworthy that 12.5% of the intronic variants are in the splice regions (excluding splice donor and acceptor sites), and may affect splicing. Rare variants are the most common variant type in NEB, complicating the interpretation of pathogenicity. Therefore, the pathogenicity of especially missense and splice site variants in NEB requires verification by functional analyses at the protein and mRNA level.

O.9Dominant Collagen XII-related myopathy with a distal myopathy phenotype, amenable to treatment with allele-specific knockdown

O.9Dominant Collagen XII-related myopathy with a distal myopathy phenotype, amenable to treatment with allele-specific knockdown

EP.15Valosin-containing protein-related myopathy and Meige's syndrome: just a coincidence or not?

Valosin-containing protein (VCP) is a hexameric AAA+-type ATPase with a central role in various cellular activities. Mutations in the VCP gene have been associated with a variety of disorders, including distal myopathy with rimmed vacuoles and Parkinson's disease (PD). To date there is no report of association of VCP-related disease with Meige's syndrome. A 64-year-old man presented with a steppage gait since the age of 50 years. Clinical evaluation revealed weakness of ankle dorsiflexion and an open tibialis anterior biopsy showed a chronic myopathy with rimmed vacuoles. Subsequent genetic testing revealed a pathogenic mutation c.476G>A (p.R159H) in exon 5 of the VCP gene. The rest of the neurological evaluation was normal besides the presence of involuntary tonic spasms of orbicularis oculi and oromandibular muscles. The patient reported that these spasms of eye closure, begun at 54 years to slowly spread to involve his orimandibular muscles and the platysma within five years. He was diagnosed with Meige's syndrome and treated with Onabotulinumtoxin A injections with moderate success. While there are several reports of patients with VCP-related PD, there has been no association to date with another movement disorder. This is the first case of a patient with typical Meige's syndrome carrying a VCP gene mutation and it probably represents a novel extramuscular manifestation of VCP-related proteinopathy. The causal relation between the VCP defect and Meige's syndrome is difficult to establish and further pathological studies are necessary to validate this hypothesis. As a whole, this case adds to the increasing body of literature, identifying a possible novel presentation of VCP mutations.

P.82First clinical and neuropathological description of a myofibrillar myopathy with congenital onset based on a homozygous recessive FLNC mutation

Filamin C encoded by the FLNC gene is a large actin-cross-linking protein involved in reorganization of actin cytoskeleton in response to signaling events and displaying structural functions at the Z-lines in muscle cells. FLNC-related disorders have been associated with myofibrillar myopathies of adult onset and dominant inheritance. Here, we describe the case of a boy of a consanguineous family with a congenital onset of generalized muscular hypotonia and muscular weakness, delayed motor development without cardiac involvement. We performed molecular genetic testing, histopathologic and morphological analyses (including electron microscopy), analysis of the proteomic signature and a FLNC folding assay. Two homozygous mutations (chr7:128478771 C>G; c.1325C>G; homozygous p.Pro442Arg in exon 8) in the FLNC-rod domain were found. The pathogenicity of these mutations could be confirmed by functional analysis. The heterozygous parents are clinically healthy. Based on the mode of inheritance and clinical details, we - for the first time - identified a patient with congenital autosomal recessive myopathy due to a homozygous variant in the FLNC. The disease course started in the neonatal period as a congenital myopathy with development of a distal myopathy in childhood without cardiac involvement, so far. Thus, our combined findings extend the currently recognized clinical and genetic spectrum of filaminopathies.

P.257Analysis of 34 Korean patients of GNE mutations associated distal myopathy with rimmed vacuoles

P.257Analysis of 34 Korean patients of GNE mutations associated distal myopathy with rimmed vacuoles

Dominant collagen XII mutations cause a distal myopathy.

ObjectiveTo characterize the natural history and clinical features of myopathies caused by mono‐allelic, dominantly acting pathogenic variants in COL12A1. MethodsPatients with dominant COL12A1‐related myopathies were characterized by history and clinical examination, muscle imaging, and genetic analysis. Pathogenicity of the variants was assessed by immunostaining patient‐derived dermal fibroblast cultures for collagen XII.ResultsFour independent families with childhood‐onset weakness due to novel, dominantly acting pathogenic variants in COL12A1 were identified. Adult patients exhibited distal‐predominant weakness. Three families carried dominantly acting glycine missense variants, and one family had a heterozygous, intragenic, in‐frame deletion of exon 52 of COL12A1. All pathogenic variants resulted in increased intracellular retention of collagen XII in patient‐derived fibroblasts as well as loss of extracellular, fibrillar collagen XII deposition. Since haploinsufficiency for COL12A1 is largely clinically asymptomatic, we designed and evaluated small interfering RNAs (siRNAs) that specifically target the mutant allele containing the exon 52 deletion. Immunostaining of the patient fibroblasts treated with the siRNA showed a near complete correction of collagen XII staining patterns.InterpretationThis study characterizes a distal myopathy phenotype in adults with dominant COL12A1 pathogenic variants, further defining the phenotypic spectrum and natural history of COL12A1‐related myopathies. This work also provides proof of concept of a precision medicine treatment approach by proposing and validating allele‐specific knockdown using siRNAs specifically designed to target a patient’s dominant COL12A1 disease allele.