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Molecular Genetics & Genomic Medicine Aug 2019Due to inconsistencies with reported myofibrillar myopathy (MFM), including autosomal dominant inheritance, late onset and a slowly progressive course, the severe,...
BACKGROUND
Due to inconsistencies with reported myofibrillar myopathy (MFM), including autosomal dominant inheritance, late onset and a slowly progressive course, the severe, recessively inherited form of CRYAB (alpha-B crystallin) gene-related infantile MFM has been suggested. Here, we report an infant in a Chinese family with fatal neonatal-onset hypertonic MFM with a novel CRYAB homozygous variant (c.3G > A (p.Met1?)).
METHODS
Muscle biopsy indicated that muscle fibers showed a uniformly small diameter, cell atrophy, and visible focal muscle fiber degeneration and necrosis consistent with myogenic myopathy. We performed the whole exome sequencing of pathogenic genes and identified it as MFM.
RESULTS
The proband presented with profound muscle stiffness, progressive respiratory distress and a concurrent abnormal increase in myocardial enzymogram, and the patient died in the 17th month of life. Muscle biopsy and electron microscopy results were consistent with ultramicroscopic myogenic damage and pathological changes. Mutation analysis of the proband identified a novel rare homozygous mutation in the initiation codon of the CRYAB gene, which was inherited from currently asymptomatic, heterozygous carrier parents, and his heterozygous biological brother is unaffected.
CONCLUSIONS
This article reports one infant with CRYAB-related neonatal onset MFM with a novel homozygous variant in CRYAB. To our knowledge, this is the first reported case of infantile alpha-Bcrystallinopathy in the Chinese population.
Topics: Asian People; Biopsy; Cardiomyopathies; Cataract; Codon, Initiator; DNA Mutational Analysis; Fatal Outcome; Homozygote; Humans; Infant; Male; Muscles; Muscular Diseases; Mutation; Exome Sequencing; alpha-Crystallin B Chain
PubMed: 31215171
DOI: 10.1002/mgg3.825 -
European Journal of Human Genetics :... Aug 2019We establish autosomal recessive DES variants p.(Leu190Pro) and a deep intronic splice variant causing inclusion of a frameshift-inducing artificial exon/intronic...
We establish autosomal recessive DES variants p.(Leu190Pro) and a deep intronic splice variant causing inclusion of a frameshift-inducing artificial exon/intronic fragment, as the likely cause of myopathy with cardiac involvement in female siblings. Both sisters presented in their twenties with slowly progressive limb girdle weakness, severe systolic dysfunction, and progressive, severe respiratory weakness. Desmin is an intermediate filament protein typically associated with autosomal dominant myofibrillar myopathy with cardiac involvement. However a few rare cases of autosomal recessive desminopathy are reported. In this family, a paternal missense p.(Leu190Pro) variant was viewed unlikely to be causative of autosomal dominant desminopathy, as the father and brothers carrying this variant were clinically unaffected. Clinical fit with a DES-related myopathy encouraged closer scrutiny of all DES variants, identifying a maternal deep intronic variant within intron-7, predicted to create a cryptic splice site, which segregated with disease. RNA sequencing and studies of muscle cDNA confirmed the deep intronic variant caused aberrant splicing of an artificial exon/intronic fragment into maternal DES mRNA transcripts, encoding a premature termination codon, and potently activating nonsense-mediate decay (92% paternal DES transcripts, 8% maternal). Western blot showed 60-75% reduction in desmin levels, likely comprised only of missense p.(Leu190Pro) desmin. Biopsy showed fibre size variation with increased central nuclei. Electron microscopy showed extensive myofibrillar disarray, duplication of the basal lamina, but no inclusions or aggregates. This study expands the phenotypic spectrum of recessive DES cardio/myopathy, and emphasizes the continuing importance of muscle biopsy for functional genomics pursuit of 'tricky' variants in neuromuscular conditions.
Topics: Adult; Base Sequence; Cardiomyopathies; Desmin; Exons; Family Health; Female; Genes, Recessive; Genetic Predisposition to Disease; Humans; Introns; Male; Muscular Dystrophies; Mutation, Missense; Myopathies, Structural, Congenital; Pedigree; RNA Splicing; Siblings
PubMed: 31024060
DOI: 10.1038/s41431-019-0393-6