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

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Molecular Genetic Diagnosis of a Bethlem Myopathy Family with an Autosomal-Dominant COL6A1 Mutation, As Evidenced by Exome Sequencing CASE REPORT Print ISSN 1738-6586 / On-line ISSN 2005-5013 J Clin Neurol 2014 Open Access Molecular Genetic Diagnosis of a Bethlem Myopathy Family with an Autosomal-Dominant COL6A1 Mutation, as Evidenced by Exome Sequencing Hyung Jun Park,a* Young-Chul Choi,b* Seung Min Kim,b Se Hoon Kim,c Young Bin Hong,d Bo Ram Yoon,e Ki Wha Chung,e Byung-Ok Choid aDepartment of Neurology, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul, Korea bDepartments of Neurology and cPathology, Yonsei University College of Medicine, Seoul, Korea dDepartment of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea eDepartment of Biological Science, Kongju National University, Gongju, Korea Received May 16, 2013 Revised September 3, 2013 BackgroundzzWe describe herein the application of whole exome sequencing (WES) for the Accepted September 6, 2013 molecular genetic diagnosis of a large Korean family with dominantly inherited myopathy. Correspondence Case ReportzzThe affected individuals presented with slowly progressive proximal weakness Byung-Ok Choi, MD and ankle contracture. They were initially diagnosed with limb-girdle muscular dystrophy Department of Neurology, (LGMD) based on clinical and pathologic features. However, WES and subsequent capillary se- Samsung Medical Center, quencing identified a pathogenic splicing-site mutation (c.1056+1G>A) in COL6A1, which was Sungkyunkwan University previously reported to be an underlying cause of Bethlem myopathy. After identification of the School of Medicine, genetic cause of the disease, careful neurologic examination revealed subtle contracture of the 81 Irwon-ro Gangnam-gu, interphalangeal joint in the affected members, which is a characteristic sign of Bethlem myopa- Seoul 135-710, Korea thy. Therefore, we revised the original diagnosis from LGMD to Bethlem myopathy. Tel +82-2-3410-1296 Fax +82-2-3410-0052 ConclusionszzThis is the first report of identification of COL6A1-mediated Bethlem myopathy E-mail [email protected] in Korea, and indicates the utility of WES for the diagnosis of muscular dystrophy. Ki Wha Chung, PhD J Clin Neurol 2014 Department of Biological Science, Kongju National University, Key WordszzBethlem myopathy, collagen type VI alpha 1 (COL6A1), whole exome sequencing. 56 Gongjudaehak-ro, Gongju 314-701, Korea Tel +82-41-850-8506 Fax +82-41-850-0957 E-mail [email protected] *Hyung Jun Park and Young-Chul Choi contributed equally to this work. Introduction uation, muscle pathology, muscle immunoanalysis, and muta- tional analysis is typically used for the diagnosis of muscular Muscular dystrophy is a clinically and genetically heteroge- dystrophy.1,2 However, this serial approach often fails to iden- neous inherited disorder characterized by progressive muscle tify causative mutations due to high phenotypic and pathologic weakness and wasting. A step-by-step approach with assess- variability, small pedigrees, and the limited power of tradi- ment of medical history, clinical examination, laboratory eval- tional linkage analyses.3 Recent advances in next-generation cc This is an Open Access article distributed under the terms of the Cre- sequencing has made it possible to selectively sequence only ative Commons Attribution Non-Commercial License (http://creative- the protein-coding exons of the genome, a process termed commons.org/licenses/by-nc/3.0) which permits unrestricted non-com- ‘whole exome sequencing’ (WES). The application of WES mercial use, distribution, and reproduction in any medium, provided the ori- ginal work is properly cited. not only saves time but is also cost-effective for the identifi- Copyright © 2014 Korean Neurological Association 1 Bethlem Myopathy with COL6A1 Mutation cation of causative genes in Mendelian diseases.4 Therefore, muscles of her upper and lower limbs were more severely WES is being increasingly adopted for the identification of involved than the distal muscles, and her ankle joints were causative genes in muscular dystrophy research.5-8 affected by contracture. In addition, she appeared to exhibit Herein we report a mutation in the gene encoding collagen mild facial weakness and absent tendon reflexes in the upper type VI α1 (COL6A1) in a large Korean family with autoso- and lower limbs. However, sensory examination revealed no mal-dominant Bethlem myopathy that was detected using abnormalities. Laboratory studies revealed a serum creatine WES. kinase level of 66 IU/L (normal, <135 IU/L), and her vital ca- pacity was 3,120 mL. Electrocardiography and echocardiog- Case Report raphy findings were normal. Nerve conduction studies and needle electromyography revealed active generalized myop- Eighteen members of a large Korean family with dominantly athy. A muscle biopsy sample obtained from the left biceps inherited myopathy (7 affected and 11 unaffected) were en- brachii revealed nonspecific muscular dystrophic changes. rolled (Fig. 1A). Written informed consent to participate was Hematoxylin and eosin staining revealed variation in muscle obtained from all participants and from the parents of partici- fiber size (Fig. 2A), and modified Gomori trichrome staining pants younger than 18 years, according to a protocol approved revealed a few ragged red fibers (Fig. 2B). Architectural by the Institutional Review Board for Ewha Womans Univer- changes of disorganized intermyofibrillar networks, such as sity Mokdong Hospital, Seoul, Korea. lobulated fibers, were accentuated in staining with nicotin- amide adenine dinucleotide tetrazolium reductase (Fig. 2C). Patients In addition, adenosine triphosphatase (pH 9.4) staining dem- The proband, a 38-year-old woman (III-4), presented with onstrated a 69% predominance of type I fibers (Fig. 2D). progressive proximal weakness and ankle contractures (Sup- Electron microscopy revealed many mitochondria, and im- plementary Table 1). Her initial development after birth was munohistochemical analyses of the muscle specimens re- reportedly normal, but she did not begin walking until she vealed normal staining patterns for the C-terminal of dystro- was 16 months old. She recalled that she had always been phin, rod domain of dystrophin, N-terminal of dystrophin, weaker than her peers. Her motor function remained relative- dysferlin, α-sarcoglycan, β-sarcoglycan, γ-sarcoglycan, ly stable until her mid-20s. However, she experienced slowly δ-sarcoglycan, α-dystroglycan, and caveolin. progressive muscle weakness after the delivery of her first The other affected members of the family had similar clin- child at an age of 27 years. Her neck flexors [Medical Re- ical presentations (Supplementary Table 1). They experi- search Council (MRC) grade 3] appeared to be more dam- enced very slow progressive muscle weakness and lived aged than her neck extensor (MRC grade 4+). The proximal without significant disability until old age. Subject II-2 re- I 1 2 II * 1 2 3 4 5 6 7 G/A G/A G/G Fig. 1. A: Pedigree of an autosomal- dominant Bethlem myopathy family. As- III terisks (*) indicate individuals whose 1 2 3 4 5 6 7 8 9 10 11 DNA was used for exome sequencing. G/G G/A G/A G/G G/G Genotypes of COL6A1 (c.1056+1G>A) * * * are indicated under each subject (arrow, IV proband; square, male; circle, female; 1 2 3 4 5 6 7 8 9 10 11 12 13 14 filled, affected; not filled, unaffected; di- A G/G G/G G/G G/G G/G G/A G/A G/A G/G G/G agonal bar across symbol, deceased). B: Sequencing chromatograms of the Wild allele Mutated allele (c.1056+1G>A) c.1056+1G>A splicing-site mutation in Exon 14 Intron Exon 14 Intron COL6A1. Arrow indicates the polymor- phic site. The COL6A1 mutations detect- ed by exome sequencing were confirmed by capillary sequencing. The heterozy- gous c.1056+1G>A mutation was com- pletely cosegregated with the affected individuals within this family, and was not B found in a sample of 200 healthy controls. 2 J Clin Neurol 2014 Park HJ et al. A B 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 Go- mori trichrome staining revealed a few ragged red fibers( ×200). C: Staining with nicotinamide adenine dinucleotide tetra- zolium reductase revealed architectural changes of disorganized intermyofibril- lar networks, such as lobulated fibers (×400). D: Adenosine triphosphatase (pH 9.4) staining demonstrated a 69% pre- C D dominance of type I fibers (×100). quired aid for ambulation after the age of 50 years, while sub- functionally significant cosegregated variants (Supplementary ject II-3 (61 years old) was able to walk independently. The Table 3). Subsequent capillary sequencing analysis of control ankle joints were affected by contracture in all seven affected samples and other family members who were not included in patients, while the elbow joints were involved only in subject the exome sequencing excluded most variants as the underly- II-2. Based on the clinical and pathologic features, the family ing cause of myopathy. However, a c.1056+1G>A splicing-site was initially diagnosed with autosomal-dominant limb-girdle mutation in COL6A1 completely cosegregated with affected muscular dystrophy. status within the family (Fig. 1B), and was not found in 200 After identification of the causative gene, all affected mem- healthy controls. This mutation has been reported to be the bers underwent a second neurologic examination. This iden- underlying cause of Bethlem myopathy.10-13 Thus, we deter- tified contracture of the interphalangeal joint–which is a char- mined that the c.1056+ 1G>A mutation in COL6A1 was the acteristic sign of Bethlem myopathy–in five family members underlying cause of the disease in this family. (II-2, II-3, III-4, III-6, and IV-7). These contractures were very subtle and were not found on routine neurologic examination; Discussion they were only apparent when the wrist and fingers were ex- tended passively. Whole exome sequencing of five members from a single family identified a splice donor site mutation at c.1056+1G>A Genetic analysis of COL6A1.
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