Profiling of pathogenic variants in Japanese patients with sarcoglycanopathy
Abstract Background Sarcoglycanopathies (SGPs) are limb-girdle muscular dystrophies (LGMDs) that can be classified into four types, LGMDR3, LGMDR4, LGMDR5, and LGMDR6, caused by mutations in the genes, SGCA, SGCB, SGCG, and SGCD, respectively. SGPs are relatively rare in Japan. This study aims to pr...
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BMC
2025-01-01
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| Series: | Orphanet Journal of Rare Diseases |
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| Online Access: | https://doi.org/10.1186/s13023-024-03521-2 |
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| author | Rui Shimazaki Yoshihiko Saito Tomonari Awaya Narihiro Minami Ryo Kurosawa Motoyasu Hosokawa Hiroaki Ohara Shinichiro Hayashi Akihide Takeuchi Masatoshi Hagiwara Yukiko K. Hayashi Satoru Noguchi Ichizo Nishino |
| author_facet | Rui Shimazaki Yoshihiko Saito Tomonari Awaya Narihiro Minami Ryo Kurosawa Motoyasu Hosokawa Hiroaki Ohara Shinichiro Hayashi Akihide Takeuchi Masatoshi Hagiwara Yukiko K. Hayashi Satoru Noguchi Ichizo Nishino |
| author_sort | Rui Shimazaki |
| collection | DOAJ |
| description | Abstract Background Sarcoglycanopathies (SGPs) are limb-girdle muscular dystrophies (LGMDs) that can be classified into four types, LGMDR3, LGMDR4, LGMDR5, and LGMDR6, caused by mutations in the genes, SGCA, SGCB, SGCG, and SGCD, respectively. SGPs are relatively rare in Japan. This study aims to profile the genetic variants that cause SGPs in Japanese patients. Methods Clinical course and pathological findings were retrospectively reviewed in Japanese patients with SGP. Genetic analyses were performed using a combination of targeted resequencing with a hereditary muscle disease panel, whole genome sequencing, multiplex ligation-dependent probe amplification, and long-read sequencing. The structures of transcripts with aberrant splicing were also determined by RT-PCR, RNA-seq, and in silico prediction. Results We identified biallelic variants in SGC genes in 53 families, including three families with LGMDR6, which had not been identified in Japan so far. SGCA was the most common causative gene, accounting for 56% of cases, followed by SGCG, SGCB, and SGCD, at 17%, 21%, and 6%, respectively. Missense variants in SGCA were very frequent at 78.3%, while they were relatively rare in SGCB, SGCG, and SGCD at 11.1%, 18.2%, and 16.6%, respectively. We also analyzed the haplotypes of alleles carrying three variants found in multiple cases: c.229C > T in SGCA, c.325C > T in SGCB, and exon 6 deletion in SGCG; two distinct haplotypes were found for c.229C > T in SGCA, while each of the latter two variants was on single haplotypes. Conclusions We present genetic profiles of Japanese patients with SGPs. Haplotype analysis indicated common ancestors of frequent variants. Our findings will support genetic diagnosis and gene therapy. |
| format | Article |
| id | doaj-art-521a6c01a7d744119c73f3176fdc42e1 |
| institution | Kabale University |
| issn | 1750-1172 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Orphanet Journal of Rare Diseases |
| spelling | doaj-art-521a6c01a7d744119c73f3176fdc42e12025-01-05T12:45:57ZengBMCOrphanet Journal of Rare Diseases1750-11722025-01-0120111510.1186/s13023-024-03521-2Profiling of pathogenic variants in Japanese patients with sarcoglycanopathyRui Shimazaki0Yoshihiko Saito1Tomonari Awaya2Narihiro Minami3Ryo Kurosawa4Motoyasu Hosokawa5Hiroaki Ohara6Shinichiro Hayashi7Akihide Takeuchi8Masatoshi Hagiwara9Yukiko K. Hayashi10Satoru Noguchi11Ichizo Nishino12Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and PsychiatryDepartment of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and PsychiatryDepartment of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto UniversityDepartment of Genome Medicine Development, Medical Genome Center, National Center of Neurology and PsychiatryDepartment of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto UniversityDepartment of Developmental Biology and Functional Genomics, Ehime University Graduate School of MedicineDepartment of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto UniversityDepartment of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and PsychiatryDepartment of Developmental Biology and Functional Genomics, Ehime University Graduate School of MedicineDepartment of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto UniversityDepartment of Pathophysiology, Tokyo Medical UniversityDepartment of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and PsychiatryDepartment of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and PsychiatryAbstract Background Sarcoglycanopathies (SGPs) are limb-girdle muscular dystrophies (LGMDs) that can be classified into four types, LGMDR3, LGMDR4, LGMDR5, and LGMDR6, caused by mutations in the genes, SGCA, SGCB, SGCG, and SGCD, respectively. SGPs are relatively rare in Japan. This study aims to profile the genetic variants that cause SGPs in Japanese patients. Methods Clinical course and pathological findings were retrospectively reviewed in Japanese patients with SGP. Genetic analyses were performed using a combination of targeted resequencing with a hereditary muscle disease panel, whole genome sequencing, multiplex ligation-dependent probe amplification, and long-read sequencing. The structures of transcripts with aberrant splicing were also determined by RT-PCR, RNA-seq, and in silico prediction. Results We identified biallelic variants in SGC genes in 53 families, including three families with LGMDR6, which had not been identified in Japan so far. SGCA was the most common causative gene, accounting for 56% of cases, followed by SGCG, SGCB, and SGCD, at 17%, 21%, and 6%, respectively. Missense variants in SGCA were very frequent at 78.3%, while they were relatively rare in SGCB, SGCG, and SGCD at 11.1%, 18.2%, and 16.6%, respectively. We also analyzed the haplotypes of alleles carrying three variants found in multiple cases: c.229C > T in SGCA, c.325C > T in SGCB, and exon 6 deletion in SGCG; two distinct haplotypes were found for c.229C > T in SGCA, while each of the latter two variants was on single haplotypes. Conclusions We present genetic profiles of Japanese patients with SGPs. Haplotype analysis indicated common ancestors of frequent variants. Our findings will support genetic diagnosis and gene therapy.https://doi.org/10.1186/s13023-024-03521-2SarcoglycanopathiesHaplotypingJapanGenetic ProfileRNA-SeqLimb-Girdle muscular dystrophies |
| spellingShingle | Rui Shimazaki Yoshihiko Saito Tomonari Awaya Narihiro Minami Ryo Kurosawa Motoyasu Hosokawa Hiroaki Ohara Shinichiro Hayashi Akihide Takeuchi Masatoshi Hagiwara Yukiko K. Hayashi Satoru Noguchi Ichizo Nishino Profiling of pathogenic variants in Japanese patients with sarcoglycanopathy Orphanet Journal of Rare Diseases Sarcoglycanopathies Haplotyping Japan Genetic Profile RNA-Seq Limb-Girdle muscular dystrophies |
| title | Profiling of pathogenic variants in Japanese patients with sarcoglycanopathy |
| title_full | Profiling of pathogenic variants in Japanese patients with sarcoglycanopathy |
| title_fullStr | Profiling of pathogenic variants in Japanese patients with sarcoglycanopathy |
| title_full_unstemmed | Profiling of pathogenic variants in Japanese patients with sarcoglycanopathy |
| title_short | Profiling of pathogenic variants in Japanese patients with sarcoglycanopathy |
| title_sort | profiling of pathogenic variants in japanese patients with sarcoglycanopathy |
| topic | Sarcoglycanopathies Haplotyping Japan Genetic Profile RNA-Seq Limb-Girdle muscular dystrophies |
| url | https://doi.org/10.1186/s13023-024-03521-2 |
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