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

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...

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Autores principales: Jalali-Sefid-Dashti, Mahjoubeh, Nel, Melissa, Heckmann, Jeannine M., Gamieldien, Junaid
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992709/
https://www.ncbi.nlm.nih.gov/pubmed/29879922
http://dx.doi.org/10.1186/s12881-018-0613-x
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author Jalali-Sefid-Dashti, Mahjoubeh
Nel, Melissa
Heckmann, Jeannine M.
Gamieldien, Junaid
author_facet Jalali-Sefid-Dashti, Mahjoubeh
Nel, Melissa
Heckmann, Jeannine M.
Gamieldien, Junaid
author_sort Jalali-Sefid-Dashti, Mahjoubeh
collection PubMed
description 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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spelling pubmed-59927092018-06-21 Exome sequencing identifies novel dysferlin mutation in a family with pauci-symptomatic heterozygous carriers Jalali-Sefid-Dashti, Mahjoubeh Nel, Melissa Heckmann, Jeannine M. Gamieldien, Junaid BMC Med Genet Research Article 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. BioMed Central 2018-06-07 /pmc/articles/PMC5992709/ /pubmed/29879922 http://dx.doi.org/10.1186/s12881-018-0613-x Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Jalali-Sefid-Dashti, Mahjoubeh
Nel, Melissa
Heckmann, Jeannine M.
Gamieldien, Junaid
Exome sequencing identifies novel dysferlin mutation in a family with pauci-symptomatic heterozygous carriers
title Exome sequencing identifies novel dysferlin mutation in a family with pauci-symptomatic heterozygous carriers
title_full Exome sequencing identifies novel dysferlin mutation in a family with pauci-symptomatic heterozygous carriers
title_fullStr Exome sequencing identifies novel dysferlin mutation in a family with pauci-symptomatic heterozygous carriers
title_full_unstemmed Exome sequencing identifies novel dysferlin mutation in a family with pauci-symptomatic heterozygous carriers
title_short Exome sequencing identifies novel dysferlin mutation in a family with pauci-symptomatic heterozygous carriers
title_sort exome sequencing identifies novel dysferlin mutation in a family with pauci-symptomatic heterozygous carriers
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992709/
https://www.ncbi.nlm.nih.gov/pubmed/29879922
http://dx.doi.org/10.1186/s12881-018-0613-x
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