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Mitochondrial “dysmorphology” in variant classification

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Abstract

Mitochondrial disorders are challenging to diagnose. Exome sequencing has greatly enhanced the diagnostic precision of these disorders although interpreting variants of uncertain significance (VUS) remains a formidable obstacle. Whether specific mitochondrial morphological changes can aid in the classification of these variants is unknown. Here, we describe two families (four patients), each with a VUS in a gene known to affect the morphology of mitochondria through a specific role in the fission–fusion balance. In the first, the missense variant in MFF, encoding a fission factor, was associated with impaired fission giving rise to a characteristically over-tubular appearance of mitochondria. In the second, the missense variant in DNAJA3, which has no listed OMIM phenotype, was associated with fragmented appearance of mitochondria consistent with its published deficiency states. In both instances, the highly specific phenotypes allowed us to upgrade the classification of the variants. Our results suggest that, in select cases, mitochondrial “dysmorphology” can be helpful in interpreting variants to reach a molecular diagnosis.

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Acknowledgements

We would like to thank the study families for their enthusiastic participation. We acknowledge the technical help by the Sequencing, Genotyping and Bioinformatics Core Facilities at KFSHRC.

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Correspondence to Fowzan S. Alkuraya.

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439_2021_2378_MOESM1_ESM.pptx

Supplementary file1 Fig. S1 A and B Cell viability of patients (family 1-IV:2 and family 2-IV:3, respectively), is significantly affected compared to controls (experimental and biological triplicates, and unpaired t-test used for statistically analysis). Fig. S2 Mitochondria network analysis tool (MiNA) applied for analysis of MFF-defective cells (family 2-IV:3) compared to controls shows long tangled patient mitochondria, with statistically significant difference in footprint. Fig. S3 Immunoblot results for A MFF protein in (family 2-IV:3) and B DNAJA3 protein in (family 1-IV:2) show no significant difference in the protein level extracted from the affected fibroblasts compared to the control (representative of biological triplicates). (PPTX 937 KB)

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Shamseldin, H.E., Alhashem, A., Tabarki, B. et al. Mitochondrial “dysmorphology” in variant classification. Hum Genet 141, 55–64 (2022). https://doi.org/10.1007/s00439-021-02378-w

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  • DOI: https://doi.org/10.1007/s00439-021-02378-w

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