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Rhabdomyolysis is often due to a combination of environmental trigger(s) and genetic predisposition; however, the underlying genetic cause remains elusive in many cases. Mutations in CAV3 lead to various neuromuscular phenotypes with partial overlap, including limb girdle muscular dystrophy type 1C (LGMD1C), rippling muscle disease, distal myopathy and isolated hyperCKemia. Here we present a series of eight patients from seven families presenting with exercise intolerance and rhabdomyolysis caused by mutations in CAV3 diagnosed by next generation sequencing (NGS) (n = 6). Symptoms included myalgia (n = 7), exercise intolerance (n = 7) and episodes of rhabdomyolysis (n = 2). Percussion-induced rapid muscle contractions (PIRCs) were seen in five out of six patients examined. A previously reported heterozygous mutation in CAV3 (p.T78M) and three novel variants (p.V14I, p.F41S, p.F54V) were identified. Caveolin-3 immunolabeling in muscle was normal in 3/4 patients; however, immunoblotting showed more than 50% reduction of caveolin-3 in five patients compared with controls. This case series demonstrates that exercise intolerance, myalgia and rhabdomyolysis may be caused by CAV3 mutations and broadens the phenotypic spectrum of caveolinopathies. In our series, immunoblotting was a more sensitive method to detect reduced caveolin-3 levels than immunohistochemistry in skeletal muscle. Patients presenting with muscle pain, exercise intolerance and rhabdomyolysis should be routinely tested for PIRCs as this may be an important clinical clue for caveolinopathies, even in the absence of other "typical" features. The use of NGS may expand current knowledge concerning inherited diseases, and unexpected/atypical phenotypes may be attributed to well-known human disease genes.

missense mutations. However, very few families with a recessive mode of inheritance have also been recognized [2]. Desmin immunostaining of normal skeletal muscle shows uniform sarcoplasmic and subsarcolemmal localization, while affected muscles display cytoplasmic aggregates of misfolded filaments and disruption of the myofibrillar apparatus rather than absence of protein [2], so that individuals with desmin mutations are frequently categorized within the group of disorders known as myofibrillar myopathies. We describe a family with no history of neuromuscular or cardiac disorders with two siblings affected by autosomal recessive desminopathy manifesting as a slowly progressive, predominantly proximal muscle fatigue and weakness. The proband, a 12 year old boy, was born at term and had normal gross motor milestones, but presented poor head control when crawling, lack of facial expression and congenital ptosis. From the age of 3 he showed difficulty rising from the floor, jumping, running and going upstairs. The weakness was slowly progressive over the years and he remains independently mobile. He tires easily and benefits from short breaks. On examination he presented with shoulder, grip and hip muscle weakness, symmetrical scapular winging, mild thoracic scoliosis and mild bilateral calf hypertrophy. Muscle MRI features are shown in Fig. 1a. He shows an unusual pattern of swallowing, turning his neck to ingest food, but he has a good appetite and is generally healthy. Forced vital capacity (FVC) was 45 % of the predicted value in sitting. CK levels were raised up to 1,000 IU/L, cardiac examinations were normal. His 11 year old sister displayed a slightly less pronounced weakness, contractures of long finger flexors and shoulders and hyperextensible elbows as well as similar tiredness and swallowing habit as her brother. She has a small appetite with a weight below the 3rd centile and also presents a history of asthma and rare chest infections. Her FVC was 40 % of the predicted value Desmin is a muscle-specific intermediate filament that provides maintenance of cellular integrity and force transmission [2]. DES gene mutations cause a spectrum of adult-onset disorders, ranging from myopathies with and without cardiac involvement to cardiomyopathy without skeletal muscle involvement [3]. Distal and proximal weakness involving upper and lower limbs muscles are observed in most patients [9]. Desminopathies are usually inherited in an autosomal dominant fashion, predominantly with

In 2001, we described an autosomal dominant myopathy characterized by neuromuscular ventilatory failure in ambulant patients. Here we describe the underlying genetic basis for the disorder, and we define the neuromuscular, respiratory and radiological phenotype in a study of 31 mutation carriers followed for up to 31 years. A combination of genome-wide linkage and whole exome sequencing revealed the likely causal genetic variant in the titin (TTN) gene (g.274375T>C; p.Cys30071Arg) within a shared haplotype of 2.93 Mbp on chromosome 2. This segregated with the phenotype in 21 individuals from the original family, nine subjects in a second family with the same highly selective pattern of muscle involvement on magnetic resonance imaging and a third familial case with a similar phenotype. Comparing the mutation carriers revealed novel features not apparent in our original report. The clinical presentation included predominant distal, proximal or respiratory muscle weakness. The age of onset was highly variable, from early adulthood, and including a mild phenotype in advanced age. Muscle weakness was earlier onset and more severe in the lower extremities in nearly all patients. Seven patients also had axial muscle weakness. Respiratory function studies demonstrated a gradual deterioration over time, reflecting the progressive nature of this condition. Cardiomyopathy was not present in any of our patients despite up to 31 years of follow-up. Magnetic resonance muscle imaging was performed in 21 affected patients and revealed characteristic abnormalities with semitendinosus involvement in 20 of 21 patients studied, including 3 patients who were presymptomatic. Diagnostic muscle histopathology most frequently revealed eosinophilic inclusions (inclusion bodies) and rimmed vacuoles, but was non-specific in a minority of patients. These findings have important clinical implications. This disease should be considered in patients with adult-onset proximal or distal myopathy and early respiratory failure, even in the presence of non-specific muscle pathology. Muscle magnetic resonance imaging findings are characteristic and should be considered as an initial investigation, and if positive should prompt screening for mutations in TTN. With 363 exons, screening TTN presented a major challenge until recently. However, whole exome sequencing provides a reliable cost-effective approach, providing the gene of interest is adequately captured.