A homozygous missense variant in the YG box domain in an individual with severe spinal muscular atrophy: a case report and variant characterization.

Autor:	Li L; Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, NC, United States., Perera L; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, Durham, NC, United States., Varghese SA; Division of Pediatric Neurology, Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States., Shiloh-Malawsky Y; Division of Pediatric Neurology, Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States., Hunter SE; Division of Pediatric Neurology, Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States., Sneddon TP; Department of Pathology and Lab Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States., Powell CM; Division of Genetics and Metabolism, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States., Matera AG; Integrative Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States., Fan Z; Division of Pediatric Neurology, Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in cellular neuroscience [Front Cell Neurosci] 2023 Sep 26; Vol. 17, pp. 1259380. Date of Electronic Publication: 2023 Sep 26 (Print Publication: 2023).
DOI:	10.3389/fncel.2023.1259380
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. (Copyright © 2023 Li, Perera, Varghese, Shiloh-Malawsky, Hunter, Sneddon, Powell, Matera and Fan.)
Databáze:	MEDLINE
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