Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Leping, Perera, Lalith, Varghese, Sonia A., Shiloh-Malawsky, Yael, Hunter, Senyene E., Sneddon, Tam P., Powell, Cynthia M., Matera, A. Gregory, Fan, Zheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
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
_version_ 1785120114261098496
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
work_keys_str_mv AT lileping ahomozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization
AT pereralalith ahomozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization
AT varghesesoniaa ahomozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization
AT shilohmalawskyyael ahomozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization
AT huntersenyenee ahomozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization
AT sneddontamp ahomozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization
AT powellcynthiam ahomozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization
AT materaagregory ahomozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization
AT fanzheng ahomozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization
AT lileping homozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization
AT pereralalith homozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization
AT varghesesoniaa homozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization
AT shilohmalawskyyael homozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization
AT huntersenyenee homozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization
AT sneddontamp homozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization
AT powellcynthiam homozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization
AT materaagregory homozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization
AT fanzheng homozygousmissensevariantintheygboxdomaininanindividualwithseverespinalmuscularatrophyacasereportandvariantcharacterization