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Objectives Diagnostic process of mitochondrial disorders (MD) is challenging because of the clinical variability and genetic heterogeneity of these conditions. Next-Generation Sequencing (NGS) technology offers a high-throughput platform for nuclear MD. Methods We included 59 of 72 patients that undergone WES and targeted exome sequencing panel suspected to have potential PMDs. Patients who were included in the analysis considering the possible PMD were reviewed retrospectively and scored according to the Mitochondrial Disease Criteria Scale. Results Sixty-one percent of the patients were diagnosed with whole-exome sequencing (WES) (36/59) and 15% with targeted exome sequencing (TES) (9/59). Patients with MD-related gene defects were included in the mito group, patients without MD-related gene defects were included in the nonmito group, and patients in whom no etiological cause could be identified were included in the unknown etiology group. In 11 out of 36 patients diagnosed with WES, a TES panel was applied prior to WES. In 47 probands in 39 genes (SURF1, SDHAF1, MTO1, FBXL4, SLC25A12, GLRX5, C19oRF12, NDUFAF6, DARS2, BOLA3, SLC19A3, SCO1, HIBCH, PDHA1, PDHAX, PC, ETFA, TRMU, TUFM, NDUFS6, WWOX, UBCD TREX1, ATL1, VAC14, GFAP, PLA2G6, TPRKB, ATP8A2, PEX13, IGHMBP2, LAMB2, LPIN1, GFPT1, CLN5, DOLK) (20 mito group, 19 nonmito group) 59 variants (31 mito group, 18 nonmito group) were detected. Seven novel variants in the mito group (SLC25A12, GLRX5, DARS2, SCO1, PC, ETFA, NDUFS6), nine novel variants in the nonmito group (IVD, GCDH, COG4, VAC14, GFAP, PLA2G6, ATP8A2, PEX13, LPIN1) were detected. Conclusions We explored the feasibility of identifying pathogenic alleles using WES and TES in MD. Our results show that WES is the primary method of choice in the diagnosis of MD until at least all genes responsible for PMD are found and are highly effective in facilitating the diagnosis process.

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Background. The recently described FBXL4-related encephalomyopathic mitochondrial DNA depletion syndrome 13 (MTDPS13) manifests with severe encephalopathy, early-onset lactic acidosis, hypotonia, developmental delay and feeding difficulty. Less than 100 cases with FBXL4-related MTDPS13 and 47 pathogenic mutations in the FBXL4 gene have been identified thus far. Here, we describe a patient diagnosed with MTDPS13 with two novel variants of the FBXL4 gene. Case. A 51-day-old male was admitted with the complaint of bloody stool. His physical examination revealed facial dysmorphic features, developmental delay and truncal hypotonia with lack of head control. Laboratory investigations showed anemia, neutropenia, metabolic acidosis with hyperlactatemia, elevated fumaric acid, 2-ketoglutaric acid in urine and elevated alanine level in plasma which were consistent with mitochondrial dysfunction. Brain magnetic resonance imaging (MRI) showed large ventricles, thin corpus callosum and poor myelination. Drug-resistant epilepsy developed during the clinical follow-up. Ketogenic diet was initiated for intractable epilepsy; which was then interrupted due to severe metabolic acidosis. Compound heterozygous pathogenic variants were detected in the FBXL4 gene [p.Gly258* (c.772G > T, Exon 5)/p.Trp354Ser (c.1061G > C, Exon 6)] with whole-exome sequencing. Conclusion. We detected two novel variants of the FBXL4 gene. To the best of our knowledge, this is the first case in the literature that presented with gastrointestinal bleeding as an encephalomyopathic form of mitochondrial DNA depletion syndromes and for whom ketogenic diet was initiated due to intractable epilepsy, which was not reported in previous cases.