Molecular Genetic Diagnosis of a Bethlem Myopathy Family with an Autosomal-Dominant COL6A1 Mutation,as Evidenced by Exome Sequencing

BackgroundWe describe herein the application of whole exome sequencing (WES) for the molecular genetic diagnosis of a large Korean family with dominantly inherited myopathy.ConclusionsThis is the first report of identification of COL6A1-mediated Bethlem myopathy in Korea, and indicates the utility of WES for the diagnosis of muscular dystrophy.     

Whole Exome Sequencing and Heterologous Cellular Electrophysiology Studies Elucidate a Novel Loss-of-Function Mutation in the CACNA1A-Encoded Neuronal P/Q-Type Calcium Channel in a Child With Congenital Hypotonia and Developmental Delay

BackgroundA 4-year-old boy born at 37 weeks' gestation with intrauterine growth retardation presented with developmental delay with pronounced language and gross motor delay, axial hypotonia, and dynamic hypertonia of the extremities. Investigations including the Minnesota Newborn Screen, thyroid stimulating hormone/thyroxin, and inborn errors of metabolism screening were negative. Cerebral magnetic resonance imaging and spectroscopy were normal. Genetic testing was negative for coagulopathy, Smith-Lemli-Opitz, fragile X, and Prader-Willi/Angelman syndromes. Whole genome array analysis was unremarkable.MethodsWhole exome sequencing was performed through a commercial testing laboratory to elucidate the underlying etiology for the child's presentation. A de novo mutation was hypothesized. In attempt to establish pathogenicity of our candidate variant, cellular electrophysiologic functional analysis of the putative de novo mutation was performed using patch-clamp technology.ResultsWhole exome sequencing revealed a p.P1353L variant in the CACNA1A gene, which encodes for the α1-subunit of the brain-specific P/Q-type calcium channel (Ca_V2.1). This presynaptic high-voltage-gated channel couples neuronal excitation to the vesicular release of neurotransmitter and is implicated in several neurologic disorders. DNA Sanger sequencing confirmed that the de novo mutation was absent in both parents and present in the child only. Electrophysiologic analysis of P1353L-CACNA1A demonstrated near complete loss of function, with a 95% reduction in peak current density.ConclusionsWhole exome sequencing coupled with cellular electrophysiologic functional analysis of a de novo CACNA1A missense mutation has elucidated the probable underlying pathophysiologic mechanism responsible for the child's phenotype. Genetic testing of CACNA1A in patients with congenital hypotonia and developmental delay may be warranted.     

Correction to: Whole Exome Sequencing Identifies Two Novel Mutations in the Reticulon 4–Interacting Protein 1 Gene in a Chinese Family with Autosomal Recessive Optic Neuropathies

The original version of this article unfortunately contained mistakes in the affiliation section.     

Segawa disease with a novel heterozygous mutation in exon 5 of the GCH-1 gene (E183K)

We report a novel missense mutation in the GCH-1 gene resulting in Segawa disease. The patient, a 6-year-old girl, presented with dystonia. Her CSF biopterin and neopterin levels were reduced, suggesting Segawa disease. L-dopa administration led to clinical improvement. Genetic analysis revealed a missense mutation in exon 5 of the GCH-1 gene (E183K). Although dystonia or other movement disorders were not identified in her family, this may be explained by the low penetrance of Segawa disease.     

A Double Mutation of the Ryanodine Receptor Type 1 Gene in a Malignant Hyperthermia Family with Multiminicore Myopathy

Background and purpose

At least 100 Ryanodine receptor type 1 (RYR1) mutations associated with malignant hyperthermia (MH) and central core disease (CCD) have been identified, but 2 RYR1 mutations accompanying multiminicore myopathy in an MH and/or CCD family have been reported only rarely.

Methods

Fifty-three members of a large MH family were investigated with clinical, histopathologic, RYR1 mutation, and haplotyping studies. Blood creatine kinase (CK) and myoglobin levels were also measured where possible.

Results

Sequencing of the entire RYR1 coding region identified a double RYR1 mutation (R2435H and A4295V) in MH/CCD regions 2 and 3. Haplotyping analysis revealed that the two missense heterozygous mutations (c.7304G>A and c.12891C>T) were always present on a common haplotype allele, and were closely cosegregated with histological multiminicores and elevated serum CK. All the subjects with the double mutation showed elevated serum CK and myoglobin, and the obtained muscle biopsy samples showed multiminicore lesions, but only two family members presented a late-onset, slowly progressive myopathy.

Conclusions

We found multiminicore myopathy with clinical and histological variability in a large MH family with an unusual double RYR1 mutation, including a typical CCD-causing known mutant. These results suggest that multiminicore lesions are associated with the presence of more than two mutations in the RYR1 gene.