Exome sequencing identifies novel dysferlin mutation in a family with pauci-symptomatic heterozygous carriers
| Autor: | Melissa Nel, Junaid Gamieldien, Jeannine M. Heckmann, Mahjoubeh Jalali-Sefid-Dashti |
|---|---|
| Přispěvatelé: | Department of Medicine, Faculty of Health Sciences |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adult Male Dysferlinopathy Heterozygote lcsh:Internal medicine Adolescent lcsh:QH426-470 Offspring Biology Compound heterozygosity Dysferlin 03 medical and health sciences symbols.namesake Young Adult 0302 clinical medicine Exome Sequencing Pauci-symptomatic carriers Genetics medicine Humans Exome Sibling lcsh:RC31-1245 Genetics (clinical) Exome sequencing Sanger sequencing Siblings Homozygote Cramps Neuromuscular Diseases Myalgia Middle Aged medicine.disease Prognosis Pedigree lcsh:Genetics 030104 developmental biology Muscular Dystrophies Limb-Girdle Mutation symbols biology.protein Female 030217 neurology & neurosurgery Follow-Up Studies |
| Zdroj: | BMC Medical Genetics BMC Medical Genetics, Vol 19, Iss 1, Pp 1-6 (2018) |
| Popis: | Background We investigated a South African family of admixed ancestry in which the first generation (G1) developed insidious progressive distal to proximal weakness in their twenties, while their offspring (G2) experienced severe unexpected symptoms of myalgia and cramps since adolescence. Our aim was to identify deleterious mutations that segregate with the affected individuals in this family. Methods Exome sequencing was performed on five cases, which included three affected G1 siblings and two pauci-symptomatic G2 offspring. As controls we included an unaffected G1 sibling and a spouse of one of the G1 affected individuals. Homozygous or potentially compound heterozygous variants that were predicted to be functional and segregated with the affected G1 siblings, were further evaluated. Additionally, we considered variants in all genes segregating exclusively with the affected (G1) and pauci-symptomatic (G2) individuals to address the possibility of a pseudo-autosomal dominant inheritance pattern in this family. Results All affected G1 individuals were homozygous for a novel truncating p.Tyr1433Ter DYSF (dysferlin) mutation, with their asymptomatic sibling and both pauci-symptomatic G2 offspring carrying only a single mutant allele. Sanger sequencing confirmed segregation of the variant. No additional potentially contributing variant was found in the DYSF or any other relevant gene in the pauci-symptomatic carriers. Conclusion Our finding of a truncating dysferlin mutation confirmed dysferlinopathy in this family and we propose that the single mutant allele is the primary contributor to the neuromuscular symptoms seen in the second-generation pauci-symptomatic carriers. |
| Databáze: | OpenAIRE |
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