Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy

Julien Couthouis, Alya R. Raphael, Carly Siskind, Andrew R. Findlay, Jason D. Buenrostro, William J. Greenleaf, Hannes Vogel, John W. Day, Kevin M. Flanigan, Aaron D. Gitler

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Limb-girdle muscular dystrophy primarily affects the muscles of the hips and shoulders (the "limb-girdle" muscles), although it is a heterogeneous disorder that can present with varying symptoms. There is currently no cure. We sought to identify the genetic basis of limb-girdle muscular dystrophy type 1 in an American family of Northern European descent using exome sequencing. Exome sequencing was performed on DNA samples from two affected siblings and one unaffected sibling and resulted in the identification of eleven candidate mutations that co-segregated with the disease. Notably, this list included a previously reported mutation in DNAJB6, p.Phe89Ile, which was recently identified as a cause of limb-girdle muscular dystrophy type 1D. Additional family members were Sanger sequenced and the mutation in DNAJB6 was only found in affected individuals. Subsequent haplotype analysis indicated that this DNAJB6 p.Phe89Ile mutation likely arose independently of the previously reported mutation. Since other published mutations are located close by in the G/F domain of DNAJB6, this suggests that the area may represent a mutational hotspot. Exome sequencing provided an unbiased and effective method for identifying the genetic etiology of limb-girdle muscular dystrophy type 1 in a previously genetically uncharacterized family. This work further confirms the causative role of DNAJB6 mutations in limb-girdle muscular dystrophy type 1D.

Original languageEnglish
Pages (from-to)431-435
Number of pages5
JournalNeuromuscular Disorders
Volume24
Issue number5
DOIs
StatePublished - May 2014
Externally publishedYes

Keywords

  • DNAJB6
  • Exome sequencing
  • Limb-girdle muscular dystrophy

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    Couthouis, J., Raphael, A. R., Siskind, C., Findlay, A. R., Buenrostro, J. D., Greenleaf, W. J., Vogel, H., Day, J. W., Flanigan, K. M., & Gitler, A. D. (2014). Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy. Neuromuscular Disorders, 24(5), 431-435. https://doi.org/10.1016/j.nmd.2014.01.014