Whole exome sequencing revealed a mutation in COL6A1 associated with ullrich congenital muscular dystrophy

Collagen type VI-related disorders consist of Ullrich congenital muscular dystrophies (UCMD) and Bethlem myopathy, in which these entities are at two opposite extremes of the phenotype continuum. Clinical characteristics include proximal joint contracture, distal joint hyperlaxity, generalized muscle weakness, normal cognitive function, and pulmonary insufficiency. Affected individuals have trouble standing up and walking independently. Mutations in 3 genes (COL6A1, COL6A2, and COL6A3) are associated with decreasing collagen-VI production and disrupting the microfibrillar network between skeletal muscles. In the present study, using whole-exome sequencing (WES), a pathogenic variant in the COL6A1 gene (NM_001848, c.868G>C, p.G290R) was detected in a Vietnamese family with UCMD patients. Segregation analysis by Sanger sequencing confirmed that this mutation was inherited in an autosomal dominant pattern. This study expands the breadth of congenital muscular dystrophies research landcape and underscores the efficiency of WES in investigating the etiology of this group of heterogeneous diseases. Insight about the underlying genetic causes could contribute to develop a well-timed treatment regimen and help patients make an informed decision about reproductive health.

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Diagnostic utility of exome sequencing for inherited peripheral neuropathies

Neuromuscular Diseases ◽

10.17650/2222-8721-2020-10-4-12-26 ◽

2020 ◽

Vol 10 (4) ◽

pp. 12-26

Author(s):

O. A. Shchagina ◽

O. P. Ryzhkova ◽

A. L. Chukhrova ◽

T. V. Milovidova ◽

P. Gundorova ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Neuromuscular Disorders ◽

Congenital Muscular Dystrophy ◽

Gene Mutations ◽

Research Centre ◽

Congenital Myasthenic Syndrome ◽

Hereditary Motor ◽

Pathogenic Variants ◽

Whole Exome

Introduction. Hereditary motor and sensory neuropathies, a highly genetic heterogeneous group of disorders, have a phenotype caused by peripheral nerve damage.Purpose of the study – to assess the extent of genetic heterogeneity of hereditary motor and sensory neuropathies in Russian patients and to evaluate the diagnostic effectiveness of using full-exome research methods to find the genetic cause of hereditary motor and sensory neuropathies.Materials and methods. The material for the study was DNA samples from 51 patients and their family members referred for whole exome sequencing to the DNA-diagnostics laboratory of Research Centre for Medical Genetics in 2017–2019. Methods: whole exome sequencing, Sanger sequencing, restriction fragment length polymorphism.Results. Whole exome sequencing in combination with segregation analysis of the pathogenic variants in families allowed to determine the cause of the disease in 41 % of cases. In another 16 % of cases, candidate genetic variants as a possible cause of the disease were revealed, but additional studies are needed to confirm it. The most frequently mutated gene was MFN2 caused neuropathy in 6 unrelated families. MPZ gene mutations were detected in two families, AARS gene mutations were revealed in another two families, and mutations in GJB1, HINT1, INF2, LRSAM1, LITAF, MME, NEFL, WWOX were detected once. Among the causal variants, mutations in B4GALNT1 caused spastic paraplegia, in COL6A1 led to Bethlem’s congenital muscular dystrophy, and in SYT2 caused congenital myasthenic syndrome indicating difficulties in differential diagnosis of inherited neuromuscular disorders. A PMP22 duplication was detected in 2 families prior to whole exome sequencing.Conclusion. Whole exome sequencing is very important for finding the molecular cause of hereditary motor and sensory neuropathies. In most cases, additional methods should be used to clarify the pathogenicity of variants detected by whole exome sequencing. However, it is necessary to remember that the most common cause of the disease is a large duplication of the region 17p11.2.

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