Compound heterozygous c.598_612del and c.1746-20C > G CAPN3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case report
Abstract Background Autosomal recessive limb–girdle muscular dystrophy-1 (LGMDR1), also known as calpainopathy, is a genetically heterogeneous disorder characterised by progression of muscle weakness. Homozygous or compound heterozygous variants in the CAPN3 gene are known genetic causes of this con...
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| Format: | Article |
| Language: | English |
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BMC
2021-12-01
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| Series: | BMC Musculoskeletal Disorders |
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| Online Access: | https://doi.org/10.1186/s12891-021-04920-3 |
| _version_ | 1818721615485075456 |
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| author | Evelina Siavrienė Gunda Petraitytė Birutė Burnytė Aušra Morkūnienė Violeta Mikštienė Tautvydas Rančelis Algirdas Utkus Vaidutis Kučinskas Eglė Preikšaitienė |
| author_facet | Evelina Siavrienė Gunda Petraitytė Birutė Burnytė Aušra Morkūnienė Violeta Mikštienė Tautvydas Rančelis Algirdas Utkus Vaidutis Kučinskas Eglė Preikšaitienė |
| author_sort | Evelina Siavrienė |
| collection | DOAJ |
| description | Abstract Background Autosomal recessive limb–girdle muscular dystrophy-1 (LGMDR1), also known as calpainopathy, is a genetically heterogeneous disorder characterised by progression of muscle weakness. Homozygous or compound heterozygous variants in the CAPN3 gene are known genetic causes of this condition. The aim of this study was to confirm the molecular consequences of the CAPN3 variant NG_008660.1(NM_000070.3):c.1746-20C > G of an individual with suspected LGMDR1 by extensive complementary DNA (cDNA) analysis. Case presentation In the present study, we report on a male with proximal muscular weakness in his lower limbs. Compound heterozygous NM_000070.3:c.598_612del and NG_008660.1(NM_000070.3):c.1746-20C > G genotype was detected on the CAPN3 gene by targeted next-generation sequencing (NGS). To confirm the pathogenicity of the variant c.1746-20C > G, we conducted genetic analysis based on Sanger sequencing of the proband’s cDNA sample. The results revealed that this splicing variant disrupts the original 3′ splice site on intron 13, thus leading to the skipping of the DNA fragment involving exon 14 and possibly exon 15. However, the lack of exon 15 in the CAPN3 isoforms present in a blood sample was explained by cell-specific alternative splicing rather than an aberrant splicing mechanism. In silico the c.1746-20C > G splicing variant consequently resulted in frameshift and formation of a premature termination codon (NP_000061.1:p.(Glu582Aspfs*62)). Conclusions Based on the results of our study and the literature we reviewed, both c.598_612del and c.1746-20C > G variants are pathogenic and together cause LGMDR1. Therefore, extensive mRNA and/or cDNA analysis of splicing variants is critical to understand the pathogenesis of the disease. |
| first_indexed | 2024-12-17T20:41:33Z |
| format | Article |
| id | doaj.art-9fa109b82e7f4d818b1ad473453435d8 |
| institution | Directory Open Access Journal |
| issn | 1471-2474 |
| language | English |
| last_indexed | 2024-12-17T20:41:33Z |
| publishDate | 2021-12-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Musculoskeletal Disorders |
| spelling | doaj.art-9fa109b82e7f4d818b1ad473453435d82022-12-21T21:33:18ZengBMCBMC Musculoskeletal Disorders1471-24742021-12-012211810.1186/s12891-021-04920-3Compound heterozygous c.598_612del and c.1746-20C > G CAPN3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case reportEvelina Siavrienė0Gunda Petraitytė1Birutė Burnytė2Aušra Morkūnienė3Violeta Mikštienė4Tautvydas Rančelis5Algirdas Utkus6Vaidutis Kučinskas7Eglė Preikšaitienė8Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius UniversityDepartment of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius UniversityDepartment of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius UniversityDepartment of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius UniversityBiobank of Lithuanian Population and Rare Disorders, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius UniversityDepartment of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius UniversityDepartment of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius UniversityDepartment of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius UniversityDepartment of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius UniversityAbstract Background Autosomal recessive limb–girdle muscular dystrophy-1 (LGMDR1), also known as calpainopathy, is a genetically heterogeneous disorder characterised by progression of muscle weakness. Homozygous or compound heterozygous variants in the CAPN3 gene are known genetic causes of this condition. The aim of this study was to confirm the molecular consequences of the CAPN3 variant NG_008660.1(NM_000070.3):c.1746-20C > G of an individual with suspected LGMDR1 by extensive complementary DNA (cDNA) analysis. Case presentation In the present study, we report on a male with proximal muscular weakness in his lower limbs. Compound heterozygous NM_000070.3:c.598_612del and NG_008660.1(NM_000070.3):c.1746-20C > G genotype was detected on the CAPN3 gene by targeted next-generation sequencing (NGS). To confirm the pathogenicity of the variant c.1746-20C > G, we conducted genetic analysis based on Sanger sequencing of the proband’s cDNA sample. The results revealed that this splicing variant disrupts the original 3′ splice site on intron 13, thus leading to the skipping of the DNA fragment involving exon 14 and possibly exon 15. However, the lack of exon 15 in the CAPN3 isoforms present in a blood sample was explained by cell-specific alternative splicing rather than an aberrant splicing mechanism. In silico the c.1746-20C > G splicing variant consequently resulted in frameshift and formation of a premature termination codon (NP_000061.1:p.(Glu582Aspfs*62)). Conclusions Based on the results of our study and the literature we reviewed, both c.598_612del and c.1746-20C > G variants are pathogenic and together cause LGMDR1. Therefore, extensive mRNA and/or cDNA analysis of splicing variants is critical to understand the pathogenesis of the disease.https://doi.org/10.1186/s12891-021-04920-3CAPN3LGMDR1cDNA assaySplicing variantCompound heterozygosity |
| spellingShingle | Evelina Siavrienė Gunda Petraitytė Birutė Burnytė Aušra Morkūnienė Violeta Mikštienė Tautvydas Rančelis Algirdas Utkus Vaidutis Kučinskas Eglė Preikšaitienė Compound heterozygous c.598_612del and c.1746-20C > G CAPN3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case report BMC Musculoskeletal Disorders CAPN3 LGMDR1 cDNA assay Splicing variant Compound heterozygosity |
| title | Compound heterozygous c.598_612del and c.1746-20C > G CAPN3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case report |
| title_full | Compound heterozygous c.598_612del and c.1746-20C > G CAPN3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case report |
| title_fullStr | Compound heterozygous c.598_612del and c.1746-20C > G CAPN3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case report |
| title_full_unstemmed | Compound heterozygous c.598_612del and c.1746-20C > G CAPN3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case report |
| title_short | Compound heterozygous c.598_612del and c.1746-20C > G CAPN3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case report |
| title_sort | compound heterozygous c 598 612del and c 1746 20c g capn3 genotype cause autosomal recessive limb girdle muscular dystrophy 1 a case report |
| topic | CAPN3 LGMDR1 cDNA assay Splicing variant Compound heterozygosity |
| url | https://doi.org/10.1186/s12891-021-04920-3 |
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