The utility of next-generation sequencing technologies in diagnosis of Mendelian mitochondrial diseases and reflections on clinical spectrum

Author:

Kose Melis12,Isik Esra2,Aykut Ayça3,Durmaz Asude3,Kose Engin4,Ersoy Melike5,Diniz Gulden6,Adebali Ogun7,Ünalp Aycan8,Yilmaz Ünsal8,Karaoğlu Pakize8,Edizer Selvinaz9,Tekin Hande Gazeteci10,Özdemir Taha Reşid11,Atik Tahir2,Onay Hüseyin3,Özkınay Ferda2

Affiliation:

1. Department of Pediatrics , Division of Inborn Errors of Metabolism, İzmir Katip Çelebi University , Izmir , Turkey

2. Department of Pediatrics , Division of Genetics, Ege University , Izmir , Turkey

3. Department of Medical Genetics , Ege University , Izmir , Turkey

4. Department of Pediatrics , Division of Inborn Errors of Metabolism, Ankara University , Ankara , Turkey

5. Department of Pediatrics , Division of Inborn Errors of Metabolism, Health Sciences University, Bakırkoy Sadi Konuk Research and Training Hospital , Istanbul , Turkey

6. Department of Pathology , İzmir Democrasy University , Izmir , Turkey

7. Adebali Lab, Molecular Biology, Genetics and Bioengineering Program , Faculty of Engineering and Natural Sciences, Sabanci University , Istanbul , Turkey

8. Department of Pediatric Neurology , Health Sciences University Dr. Behçet Uz Children Research and Training Hospital , Izmir , Turkey

9. Department of Pediatrics , Division of Pediatric Neurology, Kanuni Sultan Suleyman University , Istanbul , Turkey

10. Department of Pediatrics , Division of Pediatric Neurology, Çiğli Training and Research Hospital , Izmir , Turkey

11. Department of Medical Genetics , Health Sciences University Tepecik Training and Research Hospital , Izmir , Turkey

Abstract

Abstract 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.

Publisher

Walter de Gruyter GmbH

Subject

Endocrinology,Endocrinology, Diabetes and Metabolism,Pediatrics, Perinatology and Child Health

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