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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Autores principales:	Evelina Siavrienė, Gunda Petraitytė, Birutė Burnytė, Aušra Morkūnienė, Violeta Mikštienė, Tautvydas Rančelis, Algirdas Utkus, Vaidutis Kučinskas, Eglė Preikšaitienė
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	CAPN3 LGMDR1 cDNA assay Splicing variant Compound heterozygosity Diseases of the musculoskeletal system RC925-935
Acceso en línea:	https://doaj.org/article/9fa109b82e7f4d818b1ad473453435d8
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spelling	oai:doaj.org-article:9fa109b82e7f4d818b1ad473453435d82021-12-05T12:18:21ZCompound heterozygous c.598_612del and c.1746-20C > G CAPN3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case report10.1186/s12891-021-04920-31471-2474https://doaj.org/article/9fa109b82e7f4d818b1ad473453435d82021-12-01T00:00:00Zhttps://doi.org/10.1186/s12891-021-04920-3https://doaj.org/toc/1471-2474Abstract 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.Evelina SiavrienėGunda PetraitytėBirutė BurnytėAušra MorkūnienėVioleta MikštienėTautvydas RančelisAlgirdas UtkusVaidutis KučinskasEglė PreikšaitienėBMCarticleCAPN3LGMDR1cDNA assaySplicing variantCompound heterozygosityDiseases of the musculoskeletal systemRC925-935ENBMC Musculoskeletal Disorders, Vol 22, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	CAPN3 LGMDR1 cDNA assay Splicing variant Compound heterozygosity Diseases of the musculoskeletal system RC925-935
spellingShingle	CAPN3 LGMDR1 cDNA assay Splicing variant Compound heterozygosity Diseases of the musculoskeletal system RC925-935 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
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.
format	article
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
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_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_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_sort	compound heterozygous c.598_612del and c.1746-20c > g capn3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case report
publisher	BMC
publishDate	2021
url	https://doaj.org/article/9fa109b82e7f4d818b1ad473453435d8
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Compound heterozygous c.598_612del and c.1746-20C > G CAPN3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case report

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