The clinical utility of molecular genetic testing strategies for the diagnosis of mitochondrial disorders. R. Bai, D. Arjona, J. Higgs, J. Scuffins, J. Juusola, P. Vitazka, J. Neidich, K. Retterer, K. Parsons, N. Smaoui, E. Haverfield, S. Suchy, G. Richard GeneDx Inc, Gaithersburg, MD.

   Mitochondrial disorders (MtD) are genetically and clinically heterogeneous, making the choice of genetic tests for patients with suspected MtD a challenge. This study compared clinical utility of different genetic tests for MtD: whole mitochondrial genome analysis for mtDNA mutations (WMG), a nuclear NGS panel of 140 genes common in MtD (CompNuc), and whole exome sequencing (WES) to screen most nuclear genes. Patients undergoing these tests were classified into clinical groups according to MtD diagnostic criteria (NEUROLOGY 2006;67:1823). DNA samples from 635 unrelated patients were tested by WMG (121 definite, 173 probable, 285 possible, 56 unclassified); 669 by CompNuc (102 definite, 106 probable, 403 possible, 58 unclassified), and 200 by WES (26 definite, 37 probable, and 137 possible; 152 cases included both parental samples or trios). Of 635 WMG cases, 42 (6.6%) were diagnostic for definitive mutations and 29 (4.7%) for variants segregating with disease in the family, with a yield of 11.2% (71/635). The positive rate by group for definite/probable, possible, and unclassified MtD patients were 20.3% (60/294), 3.2% (9/285) and 3.6% (2/56), respectively. Of 669 CompNuc cases, diagnostic results were identified in 119 (17.8%), with a positive rate of 39.9% (83/208) for definite/probable, 7.7% (31/403) for possible, and 8.6% (5/58) for unclassified MtD patients. Of 200 patients tested by WES, 61 had a mutation identified, with a positive rate of ~30% for definite/probable MtD (19/63) as well as 30% for possible MtD (42/137). Trios yielded 49 positive results (32.2%), more successful than singleton testing (12; 25%). In 20 (32.8%) positive WES cases, mutations were found in a CompNuc gene, the remainder in genes causing a disorder with clinical overlap with a MtD. 52 patients negative for CompNuc had additional reflex testing to WES. Diagnostic mutations were identified in 15 (29%) of these, all in non-MtD genes. The technical reliability of CompNuc was higher than WES. WES missed 7% of the reportable variants identified by CompNuc, all in pseudogene/low coverage regions. For patients highly suspected of a mitochondrial disorder, combined mitochondrial genome sequencing and a comprehensive MtD nuclear gene panel may detect mutations in ~ 60% of patients, the most successful strategy. For patients without strong evidence of MtD, concurrent WES with mitochondrial genome sequencing is preferable, identifying an underlying cause in ~1/3 of cases.

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