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ORIGINAL RESEARCH article
Front. Psychiatry
Sec. Intellectual Disabilities
Volume 15 - 2024 |
doi: 10.3389/fpsyt.2024.1428175
This article is part of the Research Topic Rare Genetic Disorders Associated with Intellectual Disability View all articles
A novel missense mutation in ISCA2 causes aberrant splicing and leads to Multiple Mitochondrial Dysfunctions Syndrome 4
Provisionally accepted- 1 King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
- 2 Newcastle University, Newcastle upon Tyne, North East England, United Kingdom
Background: ISCA2 deficiency has been linked to an autosomal recessive disorder known as multiple mitochondrial dysfunctions syndrome 4 (MMDS4). The disorder is characterized by leukodystrophy and neuroregression. Currently, most of the reported patients who carry a homozygous founder (NM_194279.2:c.229G>A:p.Gly77Ser) variant are from Saudi Arabia.We described a patient who was subjected to a full clinical evaluation, including metabolic, neurological, and radiological examination. 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, a biochemical assessment of complex I status using dipstick assays, and mitochondrial respiration measurements using a Seahorse XFp analyzer.We present the clinical and functional characterization of a novel and homozygous ISCA2 missense variant (NM_194279.3:c.70A>G:p.Arg24Gly), a change 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 the 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 in ClinVar.Our analyses reveal that the variant is pathogenic disrupting normal ISCA2 splicing and presumably leading to a truncated protein that result in disturbance of metabolic pathways in patient-derived cells.
Keywords: ISCA2 founder variant, Novel splicing variant, mtDNA, depletion, Leukodystrophy, Neuroregression
Received: 05 May 2024; Accepted: 26 Aug 2024.
Copyright: © 2024 Al-Hassnan, Aldosary, Alhargan, AlQudairy, Almass, Alahmadi, Alshahrani, Albakheet, Al-Muhaizea, Taylor, Colak and KAYA. 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) or licensor 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.
* Correspondence:
NAMIK KAYA, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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