J Clin Neurol.  2015 Apr;11(2):183-187. 10.3988/jcn.2015.11.2.183.

Molecular Genetic Diagnosis of a Bethlem Myopathy Family with an Autosomal-Dominant COL6A1 Mutation, as Evidenced by Exome Sequencing

• Park HJ
• Choi YC
• Kim SM
• Kim SH
• Hong YB
• Yoon BR
• Chung KW
• Choi BO

• KMID: 2242664
• DOI: http://doi.org/10.3988/jcn.2015.11.2.183

Abstract

BACKGROUND
We describe herein the application of whole exome sequencing (WES) for the molecular genetic diagnosis of a large Korean family with dominantly inherited myopathy.
CASE REPORT
The affected individuals presented with slowly progressive proximal weakness and ankle contracture. They were initially diagnosed with limb-girdle muscular dystrophy (LGMD) based on clinical and pathologic features. However, WES and subsequent capillary sequencing identified a pathogenic splicing-site mutation (c.1056+1G>A) in COL6A1, which was previously reported to be an underlying cause of Bethlem myopathy. After identification of the genetic cause of the disease, careful neurologic examination revealed subtle contracture of the interphalangeal joint in the affected members, which is a characteristic sign of Bethlem myopathy. Therefore, we revised the original diagnosis from LGMD to Bethlem myopathy.
CONCLUSIONS
This is the first report of identification of COL6A1-mediated Bethlem myopathy in Korea, and indicates the utility of WES for the diagnosis of muscular dystrophy.

Keyword

Bethlem myopathy; collagen type VI alpha 1 (COL6A1); whole exome sequencing

MeSH Terms

Ankle
Capillaries
Contracture
Diagnosis*
Exome*
Humans
Joints
Korea
Molecular Biology*
Muscular Diseases*
Muscular Dystrophies
Muscular Dystrophies, Limb-Girdle
Neurologic Examination

Figure

• 

  Fig. 1 A: Pedigree of an autosomal-dominant Bethlem myopathy family. Asterisks (*) indicate individuals whose DNA was used for exome sequencing. Genotypes of COL6A1 (c.1056+1G>A) are indicated under each subject (arrow, proband; square, male; circle, female; filled, affected; not filled, unaffected; diagonal bar across symbol, deceased). B: Sequencing chromatograms of the c.1056+1G>A splicing-site mutation in COL6A1. Arrow indicates the polymorphic site. The COL6A1 mutations detected by exome sequencing were confirmed by capillary sequencing. The heterozygous c.1056+1G>A mutation was completely cosegregated with the affected individuals within this family, and was not found in a sample of 200 healthy controls.

• 

  Fig. 2 Histopathologic observations of biceps brachii muscle samples taken from the proband (III-4). A: Hematoxylin and eosin staining revealed variations in muscle fiber size and some fibers with internal nuclei (×200). B: Modified Gomori trichrome staining revealed a few ragged red fibers (×200). C: Staining with nicotinamide adenine dinucleotide tetrazolium reductase revealed architectural changes of disorganized intermyofibrillar networks, such as lobulated fibers (×400). D: Adenosine triphosphatase (pH 9.4) staining demonstrated a 69% predominance of type I fibers (×100).

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