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Page 194 Watson et al. J Transl Genet Genom 2020;4:188-202 I http://dx.doi.org/10.20517/jtgg.2020.31

Novel % (n) of solved cases NS 70% (19/27 var) 61% (30/49 pts) 67% (40/60 var) 51% (50/99 var) NS 98% (44/45 pts) 17 variants, 27 genes NS (12.5% novel genes)

MD % (n) of solved cases 73% (58/80) 23 mtDNA | 35 nDNA 25% (4/16) 75% Def MD 25% HS-MD 0% I/LS-MD 86% (42/49) 70% (46/67 pts) 20% LS-MD 97% HS-MD 62% (26/42) 100% (45/45) 100% (32/32)

Yield: overall mtDNA % (n) [of solved] nDNA % (n) [of solved] 68% (80/117) 20% (23/117) [29% (23/80)] 49% (57/117) [71% (57/80)] 57% (16/28) 0% (0/28) [0% (0/16)] 57% (16/28) [100% (16/16)] 35% (49/142) 7% (10/142) [20% (10/49)] 25% (35/142) [71% (35/49)] 59% (67/113) (36% LS, 90% 5% (6/113) [9% (6/67)] 54% (61/113) [91% (61/67)] 38% (42/109) (57% HS, 35% 38% (42/109) [all solved] 43% (45/104) 43% (45/104) [all solved] 60% (32/53) 60% (32/53

Nuclear genes Unfiltered Unfiltered Unfiltered Unfiltered HS) VP (custom) LS) 238 genes N/A Unfiltered Unfiltered N/A Unfiltered N/A

Sequencing approach mtDNA (n; %) nDNA (n; %) 2 step NGS: NGS whole mtDNA (B ± U.M) (all) WES (94/117; 80%) WES + mtDNA Off-target (all) WES (all) mtDNA, WES, CGH LR-PCR mtDNA (all) WES (all) WES (after routine) WES (all) 2 step: VP ± WES WES (all) WES (after mtDNA) WES (all) WES (after mtDNA) WES (all) B: Blood; Bioc: biochemical; Clin: clinical; CGH: comparative genomic hybridization; Def: definite; HS-MD: high suspicion MD; IS-MD:

sequencing Nil Targeted mtDNA NS Routine (NS) mtDNA analysis CGH mtDNA analysis mtDNA analysis CGH
Prior Single n genes NS N/A N/A N/A
Table 2. Diagnostic yield from WES studies in mitochondrial disease

Disease characteristics MD 74% (clin/ bioc) NM 26% Def MD 14% HS-MD 57% I/LS-MD 29% All MD Bioc RCD HS-MD 35% IS-MD 27% LS-MD 37% HS-MD 39% IS-MD 40% LS-MD 21% All MD Bioc RCD All MD Bioc MRCD

Paed predom Onset < 18 yo 77% Paed all Onset < 7 yo NN/I predom Paed all Onset < 15 yo 46% < 1 mo Paed all 42% NN Paed Young adult All < 27 yo NS Paed all 96% < 15 yo 66% < 1 yo
Age

Patients n 117 28 142 113 109 104 53

Theunissen et al. [15] Puusepp et al. [20] Kohda et al. [21] Pronicka et al. [17] Wortmann et al. [19] Ohtake et al. [16] Taylor et al. [18] sequencing; yo: years old

Authors 2018 2018 2016 2016 2015 2014 2014