Variants located in intron 6 of SMN1 lead to misdiagnosis in genetic detection and screening for SMA
Accurate genetic diagnosis is necessary for guiding the treatment of spinal muscular atrophy (SMA). An updated consensus for the diagnosis and management of SMA was published in 2018. However, clinicians should remain alert to some pitfalls of genetic testing that can occur when following a routine...
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Elsevier
2024-03-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844024040465 |
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| author | Yujin Qu Jinli Bai Hui Jiao Hong Qi Wenchen Huang Shijia OuYang Xiaoyin Peng Yuwei Jin Hong Wang Fang Song |
| author_facet | Yujin Qu Jinli Bai Hui Jiao Hong Qi Wenchen Huang Shijia OuYang Xiaoyin Peng Yuwei Jin Hong Wang Fang Song |
| author_sort | Yujin Qu |
| collection | DOAJ |
| description | Accurate genetic diagnosis is necessary for guiding the treatment of spinal muscular atrophy (SMA). An updated consensus for the diagnosis and management of SMA was published in 2018. However, clinicians should remain alert to some pitfalls of genetic testing that can occur when following a routine diagnosis. In this study, we report the diagnosis of three unrelated individuals who were initially misdiagnosed as carrying a homozygous deletion of SMN1 exon 7. MLPA (P060 and P021) and qPCR were used to detect the copy number of SMN. SMN1 variants were identified by SMN1 clone and next-generation sequencing (NGS). Transcription of SMN1 variants was detected using qRT-PCR and ex vivo splicing analysis. Among the three individuals, one was identified as a patient with SMA carrying a heterozygous deletion and a pathogenic variant (c.835-17_835-14delCTTT) of SMN1, one was a healthy carrier only carrying a heterozygous deletion of SMN1 exon 7, and the third was a patient with nemaline myopathy 2 carrying a heterozygous deletion of SMN1 exon 7. The misdiagnosis of these individuals was attributed to the presence of the c.835-17_835-14delCTTT or c.835-17C > G variants in SMN1 intron 6, which affect the amplification of SMN1 exon 7 during MLPA-P060 and qPCR testing. However, MLPA-P021 and NGS analyses were unaffected by these variants. These results support that additional detection methods should be employed in cases where the SMN1 copy number is ambiguous to minimize the misdiagnosis of SMA. |
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| last_indexed | 2024-04-24T13:48:34Z |
| publishDate | 2024-03-01 |
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| spelling | doaj.art-b844da04ae9f4896a4351e47954502f12024-04-04T05:06:38ZengElsevierHeliyon2405-84402024-03-01106e28015Variants located in intron 6 of SMN1 lead to misdiagnosis in genetic detection and screening for SMAYujin Qu0Jinli Bai1Hui Jiao2Hong Qi3Wenchen Huang4Shijia OuYang5Xiaoyin Peng6Yuwei Jin7Hong Wang8Fang Song9Department of Medical Genetics, Capital Institute of Pediatrics, Beijing, ChinaDepartment of Medical Genetics, Capital Institute of Pediatrics, Beijing, ChinaDepartment of Neurology, Children’s Hospital Affiliated to Capital Institute of Pediatrics, Beijing, ChinaPrenatal Diagnosis Center, Beijing Haidian District Maternal and Child Health Care Hospital, Beijing, ChinaDepartment of Medical Genetics, Capital Institute of Pediatrics, Beijing, ChinaDepartment of Medical Genetics, Capital Institute of Pediatrics, Beijing, ChinaDepartment of Neurology, Children’s Hospital Affiliated to Capital Institute of Pediatrics, Beijing, ChinaDepartment of Medical Genetics, Capital Institute of Pediatrics, Beijing, ChinaDepartment of Medical Genetics, Capital Institute of Pediatrics, Beijing, ChinaDepartment of Medical Genetics, Capital Institute of Pediatrics, Beijing, China; Corresponding author. Department of Medical Genetics, Capital Institute of Pediatrics, Room 521, Research Building, No. 2 Ya Bao Road, Chao Yang District, Beijing, 100020, China.Accurate genetic diagnosis is necessary for guiding the treatment of spinal muscular atrophy (SMA). An updated consensus for the diagnosis and management of SMA was published in 2018. However, clinicians should remain alert to some pitfalls of genetic testing that can occur when following a routine diagnosis. In this study, we report the diagnosis of three unrelated individuals who were initially misdiagnosed as carrying a homozygous deletion of SMN1 exon 7. MLPA (P060 and P021) and qPCR were used to detect the copy number of SMN. SMN1 variants were identified by SMN1 clone and next-generation sequencing (NGS). Transcription of SMN1 variants was detected using qRT-PCR and ex vivo splicing analysis. Among the three individuals, one was identified as a patient with SMA carrying a heterozygous deletion and a pathogenic variant (c.835-17_835-14delCTTT) of SMN1, one was a healthy carrier only carrying a heterozygous deletion of SMN1 exon 7, and the third was a patient with nemaline myopathy 2 carrying a heterozygous deletion of SMN1 exon 7. The misdiagnosis of these individuals was attributed to the presence of the c.835-17_835-14delCTTT or c.835-17C > G variants in SMN1 intron 6, which affect the amplification of SMN1 exon 7 during MLPA-P060 and qPCR testing. However, MLPA-P021 and NGS analyses were unaffected by these variants. These results support that additional detection methods should be employed in cases where the SMN1 copy number is ambiguous to minimize the misdiagnosis of SMA.http://www.sciencedirect.com/science/article/pii/S2405844024040465Spinal muscular atrophyMisdiagnosisVariantGenetic diagnosisCarrier screening |
| spellingShingle | Yujin Qu Jinli Bai Hui Jiao Hong Qi Wenchen Huang Shijia OuYang Xiaoyin Peng Yuwei Jin Hong Wang Fang Song Variants located in intron 6 of SMN1 lead to misdiagnosis in genetic detection and screening for SMA Heliyon Spinal muscular atrophy Misdiagnosis Variant Genetic diagnosis Carrier screening |
| title | Variants located in intron 6 of SMN1 lead to misdiagnosis in genetic detection and screening for SMA |
| title_full | Variants located in intron 6 of SMN1 lead to misdiagnosis in genetic detection and screening for SMA |
| title_fullStr | Variants located in intron 6 of SMN1 lead to misdiagnosis in genetic detection and screening for SMA |
| title_full_unstemmed | Variants located in intron 6 of SMN1 lead to misdiagnosis in genetic detection and screening for SMA |
| title_short | Variants located in intron 6 of SMN1 lead to misdiagnosis in genetic detection and screening for SMA |
| title_sort | variants located in intron 6 of smn1 lead to misdiagnosis in genetic detection and screening for sma |
| topic | Spinal muscular atrophy Misdiagnosis Variant Genetic diagnosis Carrier screening |
| url | http://www.sciencedirect.com/science/article/pii/S2405844024040465 |
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