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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Copyright © 2024 Al-Hassnan, AlDosary, AlHargan, AlQudairy, Almass, Alahmadi, AlShahrani, AlBakheet, Almuhaizea, Taylor, Colak and Kaya.Background: Iron–sulfur cluster assembly 2 (ISCA2) deficiency is linked to an autosomal recessive disorder known as multiple mitochondrial dysfunctions syndrome 4 (MMDS4). This disorder is characterized by leukodystrophy and neuroregression. Currently, most of the reported patients are from Saudi Arabia. All these patients carry a homozygous founder variant (NM_194279.2:c.229G>A:p.Gly77Ser) in ISCA2. Methods: We describe a patient who underwent full clinical evaluation, including metabolic, neurological, and radiological examinations. Standard genetic testing, including whole exome sequencing coupled with autozygome analysis, was undertaken, as were assessments of mitochondrial DNA (mtDNA) copy number and mtDNA sequencing on DNA extracted from blood and cultured fibroblasts. Functional workup consisted of splicing assessment of ISCA2 using RT-PCR, biochemical assessment of complex I status using dipstick assays, and mitochondrial respiration measurements using a Seahorse XFp analyzer. Results: We present the clinical and functional characterization of a novel homozygous ISCA2 missense variant (NM_194279.3:c.70A>G:p.Arg24Gly), leading to aberrant splicing in a patient presenting with neuroregression, generalized spasticity with exaggerated deep tendon reflexes and head lag, and progressive loss of acquired milestones. The novel variant was fully segregated in a wider family and was absent in a large control cohort, ethnically matching in-house exomes, local databases such as CGMdb and Saudi Human Genome Program, and ClinVar. Conclusions: Our analyses revealed that the variant is pathogenic, disrupting normal ISCA2 splicing and presumably leading to a truncated protein that disturbs metabolic pathways in patient-derived cells.
Author(s): Al-Hassnan Z, AlDosary M, AlHargan A, AlQudairy H, Almass R, Alahmadi KO, AlShahrani S, AlBakheet A, Almuhaizea MA, Taylor RW, Colak D, Kaya N
Publication type: Article
Publication status: Published
Journal: Frontiers in Psychiatry
Year: 2024
Volume: 15
Online publication date: 18/10/2024
Acceptance date: 26/08/2024
Date deposited: 03/12/2024
ISSN (electronic): 1664-0640
Publisher: Frontiers Media SA
URL: https://doi.org/10.3389/fpsyt.2024.1428175
DOI: 10.3389/fpsyt.2024.1428175
Data Access Statement: The datasets for this article are not publicly available due to concerns regarding participant/patient anonymity. Requests to access the datasets should be directed to the corresponding author.
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