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. 2019 Jan 20;132(2):127-134.
doi: 10.1097/CM9.0000000000000001.

A novel phenotype with splicing mutation identified in a Chinese family with desminopathy

Peng Fan  1 , Chao-Xia Lu  2 , Xue-Qi Dong  3 , Di Zhu  3 , Kun-Qi Yang  1 , Ke-Qiang Liu  2 , Di Zhang  3 , Ying Zhang  1 , Xu Meng  1 , Hui-Qiong Tan  3 , Li-Tian Yu  3 , Ke-Fei Dou  1 , Ya-Xin Liu  3 , Xue Zhang  2 , Xian-Liang Zhou  1
Affiliations

A novel phenotype with splicing mutation identified in a Chinese family with desminopathy

Peng Fan et al. Chin Med J (Engl). .

Abstract

Background: Desminopathy, a hereditary myofibrillar myopathy, mainly results from the desmin gene (DES) mutations. Desminopathy involves various phenotypes, mainly including different cardiomyopathies, skeletal myopathy, and arrhythmia. Combined with genotype, it helps us precisely diagnose and treat for desminopathy.

Methods: Sanger sequencing was used to characterize DES variation, and then a minigene assay was used to verify the effect of splice-site mutation on pre-mRNA splicing. Phenotypes were analyzed based on clinical characteristics associated with desminopathy.

Results: A splicing mutation (c.735+1G>T) in DES was detected in the proband. A minigene assay revealed skipping of the whole exon 3 and transcription of abnormal pre-mRNA lacking 32 codons. Another affected family member who carried the identical mutation, was identified with a novel phenotype of desminopathy, non-compaction of ventricular myocardium. There were 2 different phenotypes varied in cardiomyopathy and skeletal myopathy among the 2 patients, but no significant correlation between genotype and phenotype was identified.

Conclusions: We reported a novel phenotype with a splicing mutation in DES, enlarging the spectrum of phenotype in desminopathy. Molecular studies of desminopathy should promote our understanding of its pathogenesis and provide a precise molecular diagnosis of this disorder, facilitating clinical prevention and treatment at an early stage.

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Figures

Figure 1
Figure 1
Electrocardiograph shows the aggravation of arrhythmia in the proband. (A) Complete left bundle branch block. (B) Third-degree atrioventricular. (C) Ventricular pacing after implanted a pacemaker.
Figure 2
Figure 2
A splicing mutation in DES in a Chinese family with desminopathy. (A) Pedigree of this family. The black arrow indicated proband. (B) Sanger sequencing chromatogram shows a heterozygous c.735+1G>T splicing mutation in DES. DES: desmin gene.
Figure 3
Figure 3
Imaging features of the patients. (A and B) Echocardiography and computed tomography show enlargement of left atrium (LA) and right atrium (RA) in the proband. (C) The black arrow indicated non-compaction of ventricular myocardium (individual VI 8) by magnetic resonance imaging.
Figure 4
Figure 4
Splicing skipping was identified by a minigene assay. (A) Schematic diagram of the abnormal splicing process. (B) Reverse-transcription polymerase chain reaction (RT-PCR) products were separated by electrophoresis. (C) Sanger sequencing of RT-PCR products identified exon 3 skipping in the mutant type.
See this image and copyright information in PMC

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Supplementary concepts