A homozygous missense variant in the YG box domain in an individual with severe spinal muscular atrophy: a case report and variant characterization
The vast majority of severe (Type 0) spinal muscular atrophy (SMA) cases are caused by homozygous deletions of survival motor neuron 1 (SMN1). We report a case in which the patient has two copies of SMN1 but clinically presents as Type 0 SMA. The patient is an African American male carrying a homozy...
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| Format: | Article |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2023.1259380/full |
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| author | Leping Li Lalith Perera Sonia A. Varghese Yael Shiloh-Malawsky Senyene E. Hunter Tam P. Sneddon Cynthia M. Powell A. Gregory Matera Zheng Fan |
| author_facet | Leping Li Lalith Perera Sonia A. Varghese Yael Shiloh-Malawsky Senyene E. Hunter Tam P. Sneddon Cynthia M. Powell A. Gregory Matera Zheng Fan |
| author_sort | Leping Li |
| collection | DOAJ |
| description | The vast majority of severe (Type 0) spinal muscular atrophy (SMA) cases are caused by homozygous deletions of survival motor neuron 1 (SMN1). We report a case in which the patient has two copies of SMN1 but clinically presents as Type 0 SMA. The patient is an African American male carrying a homozygous maternally inherited missense variant (c.796T>C) in a cis-oriented SMN1 duplication on one chromosome and an SMN1 deletion on the other chromosome (genotype: 2*+0). Initial extensive genetic workups including exome sequencing were negative. Deletion analysis used in the initial testing for SMA also failed to detect SMA as the patient has two copies of SMN1. Because of high clinical suspicion, SMA diagnosis was finally confirmed based on full-length SMN1 sequencing. The patient was initially treated with risdiplam and later gene therapy with onasemnogene abeparvovec at 5 months without complications. The patient’s muscular weakness has stabilized with mild improvement. The patient is now 28 months old and remains stable and diffusely weak, with stable respiratory ventilatory support. This case highlights challenges in the diagnosis of SMA with a non-deletion genotype and provides a clinical example demonstrating that disruption of functional SMN protein polymerization through an amino acid change in the YG-box domain represents a little known but important pathogenic mechanism for SMA. Clinicians need to be mindful about the limitations of the current diagnostic approach for SMA in detecting non-deletion genotypes. |
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| language | English |
| last_indexed | 2024-04-24T23:58:38Z |
| publishDate | 2023-09-01 |
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| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-bd5ba1db86b34213987350d7bbf7dbd12024-03-14T10:51:11ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022023-09-011710.3389/fncel.2023.12593801259380A homozygous missense variant in the YG box domain in an individual with severe spinal muscular atrophy: a case report and variant characterizationLeping Li0Lalith Perera1Sonia A. Varghese2Yael Shiloh-Malawsky3Senyene E. Hunter4Tam P. Sneddon5Cynthia M. Powell6A. Gregory Matera7Zheng Fan8Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, NC, United StatesGenome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, Durham, NC, United StatesDivision of Pediatric Neurology, Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDivision of Pediatric Neurology, Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDivision of Pediatric Neurology, Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDepartment of Pathology and Lab Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDivision of Genetics and Metabolism, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesIntegrative Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDivision of Pediatric Neurology, Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesThe vast majority of severe (Type 0) spinal muscular atrophy (SMA) cases are caused by homozygous deletions of survival motor neuron 1 (SMN1). We report a case in which the patient has two copies of SMN1 but clinically presents as Type 0 SMA. The patient is an African American male carrying a homozygous maternally inherited missense variant (c.796T>C) in a cis-oriented SMN1 duplication on one chromosome and an SMN1 deletion on the other chromosome (genotype: 2*+0). Initial extensive genetic workups including exome sequencing were negative. Deletion analysis used in the initial testing for SMA also failed to detect SMA as the patient has two copies of SMN1. Because of high clinical suspicion, SMA diagnosis was finally confirmed based on full-length SMN1 sequencing. The patient was initially treated with risdiplam and later gene therapy with onasemnogene abeparvovec at 5 months without complications. The patient’s muscular weakness has stabilized with mild improvement. The patient is now 28 months old and remains stable and diffusely weak, with stable respiratory ventilatory support. This case highlights challenges in the diagnosis of SMA with a non-deletion genotype and provides a clinical example demonstrating that disruption of functional SMN protein polymerization through an amino acid change in the YG-box domain represents a little known but important pathogenic mechanism for SMA. Clinicians need to be mindful about the limitations of the current diagnostic approach for SMA in detecting non-deletion genotypes.https://www.frontiersin.org/articles/10.3389/fncel.2023.1259380/fullspinal muscular atrophy (SMA)c.796T>C variantg.27134T>G polymorphismAfrican Americannon-deletionmodeling |
| spellingShingle | Leping Li Lalith Perera Sonia A. Varghese Yael Shiloh-Malawsky Senyene E. Hunter Tam P. Sneddon Cynthia M. Powell A. Gregory Matera Zheng Fan A homozygous missense variant in the YG box domain in an individual with severe spinal muscular atrophy: a case report and variant characterization Frontiers in Cellular Neuroscience spinal muscular atrophy (SMA) c.796T>C variant g.27134T>G polymorphism African American non-deletion modeling |
| title | A homozygous missense variant in the YG box domain in an individual with severe spinal muscular atrophy: a case report and variant characterization |
| title_full | A homozygous missense variant in the YG box domain in an individual with severe spinal muscular atrophy: a case report and variant characterization |
| title_fullStr | A homozygous missense variant in the YG box domain in an individual with severe spinal muscular atrophy: a case report and variant characterization |
| title_full_unstemmed | A homozygous missense variant in the YG box domain in an individual with severe spinal muscular atrophy: a case report and variant characterization |
| title_short | A homozygous missense variant in the YG box domain in an individual with severe spinal muscular atrophy: a case report and variant characterization |
| title_sort | homozygous missense variant in the yg box domain in an individual with severe spinal muscular atrophy a case report and variant characterization |
| topic | spinal muscular atrophy (SMA) c.796T>C variant g.27134T>G polymorphism African American non-deletion modeling |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2023.1259380/full |
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