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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10571918/ https://www.ncbi.nlm.nih.gov/pubmed/37841286 http://dx.doi.org/10.3389/fncel.2023.1259380 |
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author | Li, Leping Perera, Lalith Varghese, Sonia A. Shiloh-Malawsky, Yael Hunter, Senyene E. Sneddon, Tam P. Powell, Cynthia M. Matera, A. Gregory Fan, Zheng |
author_facet | Li, Leping Perera, Lalith Varghese, Sonia A. Shiloh-Malawsky, Yael Hunter, Senyene E. Sneddon, Tam P. Powell, Cynthia M. Matera, A. Gregory Fan, Zheng |
author_sort | Li, Leping |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-10571918 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-105719182023-10-14 A homozygous missense variant in the YG box domain in an individual with severe spinal muscular atrophy: a case report and variant characterization Li, Leping Perera, Lalith Varghese, Sonia A. Shiloh-Malawsky, Yael Hunter, Senyene E. Sneddon, Tam P. Powell, Cynthia M. Matera, A. Gregory Fan, Zheng Front Cell Neurosci Cellular Neuroscience 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. Frontiers Media S.A. 2023-09-26 /pmc/articles/PMC10571918/ /pubmed/37841286 http://dx.doi.org/10.3389/fncel.2023.1259380 Text en Copyright © 2023 Li, Perera, Varghese, Shiloh-Malawsky, Hunter, Sneddon, Powell, Matera and Fan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cellular Neuroscience Li, Leping Perera, Lalith Varghese, Sonia A. Shiloh-Malawsky, Yael Hunter, Senyene E. Sneddon, Tam P. Powell, Cynthia M. Matera, A. Gregory Fan, Zheng A homozygous missense variant in the YG box domain in an individual with severe spinal muscular atrophy: a case report and variant characterization |
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 | Cellular Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10571918/ https://www.ncbi.nlm.nih.gov/pubmed/37841286 http://dx.doi.org/10.3389/fncel.2023.1259380 |
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