First Identification of Rare Exonic and Deep Intronic Splice-Altering Variants in Patients With Beta-Sarcoglycanopathy
BackgroundThe precise genetic diagnosis of a sarcoglycanopathy or dystrophinopathy is sometimes extremely challenging, as pathogenic non-coding variants and/or complex structural variants do exist in DMD or sarcoglycan genes. This study aimed to determine the genetic diagnosis of three patients from...
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| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Pediatrics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fped.2022.900280/full |
| _version_ | 1811333450199728128 |
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| author | Zhiying Xie Chengyue Sun Chang Liu Xujun Chu Qiang Gang Meng Yu Yiming Zheng Lingchao Meng Fan Li Dongliang Xia Li Wang Ying Li Jianwen Deng He Lv Zhaoxia Wang Wei Zhang Yun Yuan |
| author_facet | Zhiying Xie Chengyue Sun Chang Liu Xujun Chu Qiang Gang Meng Yu Yiming Zheng Lingchao Meng Fan Li Dongliang Xia Li Wang Ying Li Jianwen Deng He Lv Zhaoxia Wang Wei Zhang Yun Yuan |
| author_sort | Zhiying Xie |
| collection | DOAJ |
| description | BackgroundThe precise genetic diagnosis of a sarcoglycanopathy or dystrophinopathy is sometimes extremely challenging, as pathogenic non-coding variants and/or complex structural variants do exist in DMD or sarcoglycan genes. This study aimed to determine the genetic diagnosis of three patients from two unrelated families with a suspected sarcoglycanopathy or dystrophinopathy based on their clinical, radiological, and pathological features, for whom routine genomic detection approaches failed to yield a definite genetic diagnosis.MethodsMuscle-derived reverse transcription-polymerase chain reaction analysis and/or TA cloning of DMD, SGCA, SGCB, SGCD, and SGCG mRNA were performed to identify aberrant transcripts. Genomic Sanger sequencing around the aberrant transcripts was performed to detect possible splice-altering variants. Bioinformatic and segregation studies of the detected genomic variants were performed in both families.ResultsIn patients F1-II1 and F1-II2, we identified two novel pathogenic compound heterozygous variants in SGCB. One is a deep intronic splice-altering variant (DISV), c.243 + 1558C > T in intron 2 causing the activation of an 87-base pair (bp) pseudoexon, and the other one is a non-canonical splicing site variant, c.243 + 6T > A leading to the partial intron inclusion of 10-bp sequence. A novel DISV, c.243 + 1576C > G causing a 106-bp pseudoexon activation, and a nonsense variant in SGCB were identified in compound heterozygous state in patient F2-II1. Unexpectedly, the predicted nonsense variant, c.334C > T in exon 3, created a new donor splice site in exon 3 that was stronger than the natural one, resulting in a 97-bp deletion of exon 3 (r.333_429del).ConclusionThis is the first identification of rare exonic and DISVs in the SGCB gene. |
| first_indexed | 2024-04-13T16:53:02Z |
| format | Article |
| id | doaj.art-6b7a5cb39dfa4c6d816f5201dfa7942b |
| institution | Directory Open Access Journal |
| issn | 2296-2360 |
| language | English |
| last_indexed | 2024-04-13T16:53:02Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pediatrics |
| spelling | doaj.art-6b7a5cb39dfa4c6d816f5201dfa7942b2022-12-22T02:38:53ZengFrontiers Media S.A.Frontiers in Pediatrics2296-23602022-06-011010.3389/fped.2022.900280900280First Identification of Rare Exonic and Deep Intronic Splice-Altering Variants in Patients With Beta-SarcoglycanopathyZhiying Xie0Chengyue Sun1Chang Liu2Xujun Chu3Qiang Gang4Meng Yu5Yiming Zheng6Lingchao Meng7Fan Li8Dongliang Xia9Li Wang10Ying Li11Jianwen Deng12He Lv13Zhaoxia Wang14Wei Zhang15Yun Yuan16Department of Neurology, Peking University First Hospital, Beijing, ChinaDepartment of Neurology, Peking University People’s Hospital, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaScience and Technology, Running Gene Inc., Beijing, ChinaScience and Technology, Running Gene Inc., Beijing, ChinaBeijing Anzhen Hospital, Capital Medical University, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaBackgroundThe precise genetic diagnosis of a sarcoglycanopathy or dystrophinopathy is sometimes extremely challenging, as pathogenic non-coding variants and/or complex structural variants do exist in DMD or sarcoglycan genes. This study aimed to determine the genetic diagnosis of three patients from two unrelated families with a suspected sarcoglycanopathy or dystrophinopathy based on their clinical, radiological, and pathological features, for whom routine genomic detection approaches failed to yield a definite genetic diagnosis.MethodsMuscle-derived reverse transcription-polymerase chain reaction analysis and/or TA cloning of DMD, SGCA, SGCB, SGCD, and SGCG mRNA were performed to identify aberrant transcripts. Genomic Sanger sequencing around the aberrant transcripts was performed to detect possible splice-altering variants. Bioinformatic and segregation studies of the detected genomic variants were performed in both families.ResultsIn patients F1-II1 and F1-II2, we identified two novel pathogenic compound heterozygous variants in SGCB. One is a deep intronic splice-altering variant (DISV), c.243 + 1558C > T in intron 2 causing the activation of an 87-base pair (bp) pseudoexon, and the other one is a non-canonical splicing site variant, c.243 + 6T > A leading to the partial intron inclusion of 10-bp sequence. A novel DISV, c.243 + 1576C > G causing a 106-bp pseudoexon activation, and a nonsense variant in SGCB were identified in compound heterozygous state in patient F2-II1. Unexpectedly, the predicted nonsense variant, c.334C > T in exon 3, created a new donor splice site in exon 3 that was stronger than the natural one, resulting in a 97-bp deletion of exon 3 (r.333_429del).ConclusionThis is the first identification of rare exonic and DISVs in the SGCB gene.https://www.frontiersin.org/articles/10.3389/fped.2022.900280/fullSGCBaberrant splicingintronsplice-altering variantsdiagnosis |
| spellingShingle | Zhiying Xie Chengyue Sun Chang Liu Xujun Chu Qiang Gang Meng Yu Yiming Zheng Lingchao Meng Fan Li Dongliang Xia Li Wang Ying Li Jianwen Deng He Lv Zhaoxia Wang Wei Zhang Yun Yuan First Identification of Rare Exonic and Deep Intronic Splice-Altering Variants in Patients With Beta-Sarcoglycanopathy Frontiers in Pediatrics SGCB aberrant splicing intron splice-altering variants diagnosis |
| title | First Identification of Rare Exonic and Deep Intronic Splice-Altering Variants in Patients With Beta-Sarcoglycanopathy |
| title_full | First Identification of Rare Exonic and Deep Intronic Splice-Altering Variants in Patients With Beta-Sarcoglycanopathy |
| title_fullStr | First Identification of Rare Exonic and Deep Intronic Splice-Altering Variants in Patients With Beta-Sarcoglycanopathy |
| title_full_unstemmed | First Identification of Rare Exonic and Deep Intronic Splice-Altering Variants in Patients With Beta-Sarcoglycanopathy |
| title_short | First Identification of Rare Exonic and Deep Intronic Splice-Altering Variants in Patients With Beta-Sarcoglycanopathy |
| title_sort | first identification of rare exonic and deep intronic splice altering variants in patients with beta sarcoglycanopathy |
| topic | SGCB aberrant splicing intron splice-altering variants diagnosis |
| url | https://www.frontiersin.org/articles/10.3389/fped.2022.900280/full |
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