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Watson et al. J Transl Genet Genom 2020;4:188-202 I http://dx.doi.org/10.20517/jtgg.2020.31 Page 193

Novel % (n) of solved cases 62% (8/13 var) 40% (4/10 nDNA var) NS 17% (1/6 new diagnoses) 48% (10/21 var) NS 23% (3/13 pts) 62% (8/13 var)

MD % (n) of solved cases 63% (5/8 pts) 62% (8/13 var) N/A (only analysed MD genes) 84% (21/25) 50% (3/6 new diagnoses) 31% (4/13 pts) 100% (7/7 pts) 100% (13/13) 71% (5/7 pts)

Yield: overall mtDNA % (n) [of solved] nDNA % (n) [of solved] 6% (8/127); 75% (6/8) of WES 0% (0/127) 6% (8/127) [all solved] 29% (23/80) 19% (15/80) [65% (15/23)] 10% (8/80) [35% (8/23)] 20% (25/125): 15% panel; 5% 20% (25/125) 19/125 panel; 6/10 WES 23% (23/102); 17/18 control, 6/84 new 12% (12/102) [52% (12/23)] 11% (11/102) [48% (11/23)] 9% (13/148) 9% (13/148) [all solved] 16% (7/44) 16% (7/44) [all solved] 31% (13/42) 2% (1/42) [8

Nuclear genes 136 genes (3 custom panels) 281 genes (custom) 132 genes WES (custom) N/A 1598 genes (MitoExome, expanded) 447 genes N/A (custom) 211 genes N/A (custom) 1034 genes (MitoExome) 908 genes new N/A

Sequencing approach mtDNA (n; %) nDNA (n; %) mtDNA, nDNA panel ± WES NGS mtDNA (M) (all) Panel (68%) WES (6%) 2 step NGS NGS mtDNA screen (all) Panel: targeted (all) 2 step: panel ± WES Panel (all); WES (8%) mtDNA + exome panel MitoExome mtDNA (all) MitoExome panel (all) Targeted exome panel Panel: targeted (all) Targeted exome panel Panel: targeted (all) mtDNA + exome panel MitoExome mtDNA (all) MitoExome panel (all) Targeted NGS pan

sequencing Nil NS mtDNA analysis Single n genes Varied mtDNA Single n genes Varied mtDNA Single n genes mtDNA, POLG, ≤ 10 n genes NS seq
Table 1. Diagnostic yield from NGS panel studies in mitochondrial disease
Prior N/A N/A N/A 10/26 mtDNA N/A neonatal/infant; NS: not stated; Paed: paediatric; + control: positive control; predom: predominant; pts: patients; var: variants; WES: whole exome sequencing; yo: years old

Disease characteristics All MD Bioc RCD All MD Clin/bioc/ histology All MD Clin/bioc Def/HS 80% IS/LS 20% + control 18% Mixed Def/HS-MD 36% bioc RCD All MD Bioc (M/Fib) All MD Clin/Bioc RCD Mixed: Def, HS and LS-MD 2 + control

Age Onset < 20 yo Adult predom Paed predom Range: 0-64 Mean: 27 yo Paed predom 83% < 18 yo Onset < 1 yo
Paed all Most < 1 yo 70% adult 30% paed 62% < 1yo Mixed Range 0-83 Mixed Mean 11.4 Range 2-30 Paed All NN/I Paed all 88% effectiveness, and can be readily re-investigated [19] .

Patients (n) 127 80 125 102 148 44 42 26

Schoonen et al. [22] Plutino et al. [72] Legati et al. [23] Lieber et al. [73] Neveling et al. [53] Calvo et al. [74] Vasta et al. [71]

Authors 2019 2018 2016 2013 DaRe et al. [61] 2013 2013 2012 2012