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BMC Medical Genetics

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Open Access 01-12-2018 | Research article

Exome sequencing identifies novel dysferlin mutation in a family with pauci-symptomatic heterozygous carriers

Authors: Mahjoubeh Jalali-Sefid-Dashti, Melissa Nel, Jeannine M. Heckmann, Junaid Gamieldien

Published in: BMC Medical Genetics | Issue 1/2018

Abstract

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.

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Title: Exome sequencing identifies novel dysferlin mutation in a family with pauci-symptomatic heterozygous carriers
Authors: Mahjoubeh Jalali-Sefid-Dashti
Melissa Nel
Jeannine M. Heckmann
Junaid Gamieldien
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2018
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/s12881-018-0613-x

At a glance: The STEP trials

Springer Medicine

Exome sequencing identifies novel dysferlin mutation in a family with pauci-symptomatic heterozygous carriers

Abstract

Background

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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