Background
Methods
Patients
ID patient | Sex | Date of birth (year) | Neonatal onset | 3-MGA in urine | Basal ganglia involvement | Death | MDC score | Muscle biopsy | Period from onset to WES (year) |
---|---|---|---|---|---|---|---|---|---|
1 | F | 2009 | + | + | 5 | 5 | |||
2 | F | 2013 | + | + | 4 | Autopsy | 0 | ||
3 | M | 2012 | + | 5 | + | 2 | |||
4 | F | 2007 | 4 | + | 0 | ||||
5 | F | 2013 | + | + | + | 5 | 0 | ||
6 | F | 2011 | 4 | 0 | |||||
7 | M | 2006 | + | 5 | + | 7 | |||
8 | M | 2008 | + | 2 | 0 | ||||
9 | M | 2011 | + | 6 | + | 2 | |||
10 | M | 2004 | + | 5 | + | 7 | |||
11 | M | 2005 | 2 | 2 | |||||
12 | M | 2005 | + | 3 | Autopsy | 7 | |||
13 | M | 2014 | + | + | + | 4 | Autopsy | 0 | |
14 | F | 2006 | + | 3 | + Autopsy | 7 | |||
15 | F | 2008 | + | + | 4 | + | 5 | ||
16 | M | 2012 | + | 3 | 0 | ||||
17 | F | 1992 | + | 3 | + | 21 | |||
18 | F | 2003 | + | 3 | + | 7 | |||
19 | M | 2009 | 5 | + | 3 | ||||
20 | M | 2009 | 4 | 2 | |||||
21 | F | 2006 | + | 6 | + | 8 | |||
22 | M | 2010 | + | + | 8 | + | 2 | ||
23 | M | 2011 | + | + | 4 | + | 3 | ||
24 | F | 2008 | + | 6 | + | 4 | |||
25 | M | 2010 | + | + | 7 | + | 3 | ||
26 | M | 2011 | + | + | 8 | + | 2 | ||
27 | M | 2008 | + | + | + | 5 | 6 | ||
28 | M | 2004 | + | + | + | 3 | + | 11 | |
29 | F | 2007 | + | 5 | + | 7 | |||
30 | F | 2002 | + | + | 2 | + | 13 | ||
31 | F | 2005 | + | 6 | + | 9 | |||
32 | M | 2002 | + | + | 5 | Autopsy | 3 | ||
33 | F | 2006 | 3 | 2 | |||||
34 | M | 2006 | + | 6 | + | 4 | |||
35 | M | 2012 | + | 6 | + | 2 | |||
36 | M | 2006 | + | + | 5 | + | 6 | ||
37 | M | 2003 | + | + | + | 7 | + | 12 | |
38 | M | 1985 | 3 | + | 12 | ||||
39 | M | 1996 | 3 | + | 11 | ||||
40 | M | 2010 | + | + | + | 5 | Autopsy | 4 | |
41 | F | 2011 | + | 4 | + | 3 | |||
42 | F | 2013 | 2 | 0 | |||||
43 | M | 1967 | + | 2 | 10 | ||||
44 | F | 1956 | 4 | 3 | |||||
45 | F | 1995 | 2 | + | 11 | ||||
46 | M | 2009 | 3 | + | 4 | ||||
47 | M | 2013 | 2 | 0 | |||||
48 | F | 2007 | 2 | 4 | |||||
49 | M | 2012 | + | + | 6 | Autopsy | 2 | ||
50 | M | 2009 | + | + | 2 | Autopsy | 5 | ||
51 | M | 2003 | + | + | + | 5 | + | 12 | |
52 | F | 2011 | + | 5 | 3 | ||||
53 | M | 2007 | 6 | + | 7 | ||||
54 | M | 1990 | + | 6 | + | 25 | |||
55 | F | 1981 | 4 | + | 21 | ||||
56 | F | 2012 | 4 | 0 | |||||
57 | M | 2010 | + | 6 | + | 0 | |||
58 | M | 2012 | + | 6 | + | 0 | |||
59 | F | 2010 | + | 6 | + | 4 | |||
60 | M | 2003 | + | + | + | 6 | + | 10 | |
61 | M | 1989 | + | 8 | + | 23 | |||
62 | M | 1997 | + | + | 6 | + | 18 | ||
63 | F | 1989 | 4 | + | 16 | ||||
64 | F | 2012 | + | + | 6 | + | 2 | ||
65 | M | 1991 | + | + | 4 | + | 23 | ||
66 | F | 2012 | + | 5 | + | 2 | |||
67 | F | 2014 | + | + | 4 | 0 | |||
68 | M | 2012 | + | 4 | + | 0 | |||
69 | M | 2013 | 3 | 0 | |||||
70 | F | 2004 | + | 5 | + | 11 | |||
71 | M | 2001 | + | + | 5 | + | 14 | ||
72 | M | 2011 | + | + | 4 | Autopsy | 3 | ||
73 | F | 2002 | + | 3 | + | 11 | |||
74 | F | 1989 | 4 | + | 12 | ||||
75 | M | 2008 | + | + | 5 | + | 6 | ||
76 | F | 2003 | + | 4 | + | 6 | |||
77 | F | 2011 | + | + | + | 6 | + | 3 | |
78 | M | 1994 | + | 3 | 17 | ||||
79 | M | 2004 | 3 | + | 6 | ||||
80 | F | 2012 | + | + | 2 | 0 | |||
81 | F | 1990 | + | + | 4 | + Autopsy | 21 | ||
82 | F | 2000 | + | 3 | 2 | ||||
83 | F | 2003 | + | + | 4 | + | 12 | ||
84 | M | 2010 | + | 3 | + | 4 | |||
85 | F | 2013 | + | + | 3 | 0 | |||
86 | M | 2008 | + | 2 | 5 | ||||
87 | M | 2010 | 3 | 0 | |||||
88 | M | 1997 | 2 | 0 | |||||
89 | F | 2004 | + | + | + | 4 | + | 11 | |
90 | M | 2002 | + | 4 | + | 13 | |||
91 | M | 2009 | + | 6 | + | 5 | |||
92 | M | 1995 | + | 2 | 5 | ||||
93 | M | 2011 | + | + | 3 | Autopsy | 3 | ||
94 | F | 2010 | + | + | 4 | 3 | |||
95 | F | 2011 | + | 4 | + | 3 | |||
96 | M | 2011 | + | 2 | 2 | ||||
97 | M | 2005 | + | ND | 4 | + | 10 | ||
98 | F | 2012 | + | + | + | 2 | Autopsy | 2 | |
99 | F | 1974 | 2 | 0 | |||||
100 | M | 2009 | + | 3 | + | 5 | |||
101 | M | 2012 | + | 4 | 0 | ||||
102 | F | 2006 | + | 3 | 0 | ||||
103 | F | 2008 | + | + | + | 3 | Autopsy | 4 | |
104 | F | 1988 | + | 4 | + | 18 | |||
105 | F | 2014 | + | + | 5 | 0 | |||
106 | M | 2011 | + | 3 | + | 2 | |||
107 | M | 2006 | 4 | + | 8 | ||||
108 | M | 2012 | + | 3 | + | 2 | |||
109 | M | 1997 | + | + | 4 | Autopsy | 18 | ||
110 | M | 2010 | 2 | + | 4 | ||||
111 | F | 2014 | + | + | 4 | 0 | |||
112 | F | 2010 | + | + | 3 | Autopsy | 4 | ||
113 | M | 2013 | + | 4 | + | 0 |
Whole-exome sequencing
Results
Gene | Chromosome:RefSeq | Variant 1 | Variant 2 | Zygosity status | Mode | ID patient | ||||
---|---|---|---|---|---|---|---|---|---|---|
Type | Status | Origin | Type | Status | Origin | |||||
Mitochondrial disease gene | ||||||||||
ACAD9
| chr3:NM_014049.4 | c.514G>A/p.Gly172Arg | Novel | mat | c.803C>T/p.Ser268Phe | Novel | pat | comphtz | AR | 15 |
ACAD9
| chr3:NM_014049.4 | c.1552C>T/p.Arg518Cys | Known | mat | c.1553G>A/p.Arg518His | Known | pat | comphtz | AR | 23 |
ACAD9
| chr3:NM_014049.4 | c.728C>G/p.Thr243Arg | Novel | ND | c.1552C>T/p.Arg518Cys | Known | mat | comphtz | AR | 53 |
ADCK3
| chr1:NM_020247.4 | c.827A>G/p.Lys276Arg | Novel | mat | c.1702delG/p.Gly568Argfs | Novel | pat | comp htz | AR | 61 |
AIFM1
| chrX:NM_004208.3 | c.1474T>C/p.Tyr492His | Novel | mat | – | – | hemi | XLR | 25 | |
CLPB
| chr11:NM_030813.4 | c.2045T>A/p.Ile682Asn | Known | pat | c.1937_1938insG/p.645Gly_646Cysfs | Known | mat | comphtz | AR | 5 |
CLPB
| chr11:NM_030813.4 | c.1249C>T/p.Arg417a
| Known | pat | c.748C>T/p.Arg250a
| Known | mat | comphtz | AR | 27 |
CLPB
| chr11:NM_030813.4 | c.1249C>T/p.Arg417a
| Known | pat | c.1222A>G/p.Arg408Gly | Known | mat | comphtz | AR | 67 |
COX10
| chr17:NM_001303.3 | c.1030A>G/p.Met344Val | Novel | pat | c.1270dupC/p.Leu424Profs | Novel | mat | comphtz | AR | 9 |
COX10
| chr17:NM_001303 | c.674C>T/p.Pro225Leu | Known | mat | c.674C>T/p.Pro225Leu | Known | pat | hom | AR | 36 |
DLD
| chr7:NM_000108.4 | c.1123G>A/p.Glu375Lys | Known | mat | c.1123G>A/p.Glu375Lys | Known | pat | hom | AR | 31 |
EARS2
| chr16:NM_001083614.1 | c.164G>A/p.Arg55His | Known | mat | c.325G>C/p.Gly109Arg | Novel | pat | comphtz | AR | 7 |
EARS2
| chr16:NM_001083614.1 | c.164G>A/p.Arg55His | Known | pat | c.1256C>T/p.Pro419Leu | Novel | mat | comphtz | AR | 70 |
FBXL4
| chr6:NM_012160.4 | c.858+1G>T/p.? | Novel | pat | c.585+5G>C/p.? | Novel | mat | comphtz | AR | 3 |
FBXL4
| chr6:NM_012160.4 | c.1303C>T/p.Arg435a
| Known | ND | c.64C>T/p.Arg22a
| Novel | mat | comphtz | AR | 52 |
FBXL4
| chr6:NM_012160.4 | c.64C>T/p.Arg22a
| Novel | mat | c.64C>T/p.Arg22a
| Novel | pat | hom | AR | 55 |
MTATP6
| chrM:NC_012920.1 | m.9185T>C/p.Leo220Pro | Known | mat | – | – | hompl | M | 32 | |
MTFMT
| chr15:NM_139242.3 | c.994C>T/p.Arg332a
| Known | ND | c.626C>T/p.Ser209Leu | Known | ND | comphtz | AR | 91 |
MTND1
| chrM:NC_012920.1 | m.3902_3908invACCTTGC/p.? | Known | de novo | – | – | hetpl | M | 22 | |
MTND1
| chrM:NC_012920.1 | m.3688G>A/p.Ala128Thr | Known | ND | – | – | hompl | M | 64 | |
MTND3
| chrM:NC_012920.1 | m.10254G>A/p.Asp66Asn | Known | de novo | – | – | hetpl | M | 57 | |
MTND5
| chrM:NC_012920.1 | m.12706T>C/p.Phe124Leu | Known | de novo | – | – | hetpl | M | 34 | |
MTND5
| chrM:NC_012920.1 | m.13513G>A/p.Asp393Asn | Known | de novo | – | – | hetpl | M | 35 | |
NAXE
| chr1:NM_144772.2 | c.653A>T/p.Asp218Val | Known | mat | c.743_744delC/p.247Ala_248Thrfs | Known | pat | comphtz | AR | 12 |
NDUFS6
| chr5:NM_004553.4 | c.313_315delAAAG/p.104Lys_106Thrfs | Novel | pat | c.334_359del26ins13/p.Glu112 fs | Novel | mat | comphtz | AR | 1 |
NDUFS7
| chr19:NM_024407.4 | c.376C>T/p.Leu126Phe | Novel | ND | c.504G>C/p.Arg168Ser | Novel | ND | het | AR | 75 |
NDUFV1
| chr11:NM_007103.3 | c.733G>A/p.Val245Met | Novel | pat | c.383G>T/p.Arg128Leu | Novel | mat | comphtz | AR | 10 |
OPA1
| chr3:NM_015560.2 | c.1146A>G/p.Ile382Met | Known | mat | – | – | htz | AD | 33 | |
PARS2
| chr1:NM_152268.3 | c.1091C>G/p.Pro364Arg | Novel | mat | c.239T>C/p.Ile80Thr | Novel | pat | comphtz | AR | 60 |
PC
| chr11:NM_000920.3 | c.808C>T/p.Arg270Trp | Known | pat | c.2381_2383delTGG/p.Val794del | Novel | mat | comphtz | AR | 29 |
PC
| chr11:NM_000920.3 | c.1487G>A/p.Arg496Gln | Novel | ND | c.584C>T/p.Ala195Val | Novel | ND | comphtz | AR | 71 |
PDHA1
| chr X:NM_000284.3 | c.262C>T/p.Arg88Cys | Known | mat | – | – | hemi | XLD | 19 | |
PDHA1
| chrX:NM_000284.3 | c.856_859dupACTT/p. Arg288Leufs | Novel | de novo | – | – | htz | XLD | 56 | |
PDHA1
| chrX:NM_000284.3 | c.933_935del/p.Arg311del l | Known | de novo | – | – | htz | XLD | 66 | |
PDHA1
| chrX:NM_000284.3 | c.291G>A/p.? | Novel | de novo | – | – | hemi, mosaic | XLD | 68 | |
POLG
| chr15:NM_001126131.1 | c.2639C>A/p.Ala880Asp | Novel | pat | c.2243G>C/p.Trp748Ser | Known | mat | comphtz | AR | 113 |
RARS2
| chr6:NM_020320.3 | c.1026G>A/p.Met342Ile | Novel | mat | c.622C>T/p.Gln208a
| Novel | pat | comphtz | AR | 41 |
RRM2B
| chr8:NM_015713.4 | c.414_415delCA/p.Tyr138a
| Novel | mat | c.414_415delCA/p.Tyr138a
| Novel | ND | hom | AR | 21 |
RRM2B
| chr8:NM_015713.4 | c.686G>T/p.Gly229Val | Known | mat | c.686G>T/p.Gly229Val | Known | pat | hom | AR | 51 |
SCO2
| chr22:NM_005138.2 | c.418G>A/p.Glu140Lys | Known | ND | c.418G>A/p.Glu140Lys | Known | ND | hom | AR | 54 |
SERAC1
| chr6:NM_032861.3 | c.1822_1828+10delinsACCAACAGG | Known | ND | c.1822_1828+10delinsACCAACAGG | Known | ND | hom | AR | 37 |
SLC19A3
| chr2:NM_025243.3 | c.68G>T/p.Gly23Val | Known | Pending | c.68G>T/p.Gly23Val | Known | Pending | hom | AR | 58 |
SLC19A3
| chr2:NM_025243.3 | c.74dupT/p.Ser26Leufs | Known | ND | c.74dupT/p.Ser26Leufs | Known | ND | hom | AR | 109 |
SLC25A12
| chr2:NM_003705.4 | c.1335C>A/p.Asn445Lys | Novel | mat | c.1335C>A/p.Asn445Lys | Novel | pat | hom | AR | 24 |
TAZ
| chrX:NM_000116.3 | c.684_685insC/p.227Phe_228Profs | Novel | ND | – | – | hemi | XLR | 28 | |
TMEM126B
a
| chr11:NM_018480.4 | c.635G>T/p.Gly212Val | Known | mat | c.635G>T/p.Gly212Val | Known | pat | hom | AR | 59 |
VARS2
| chr6:NM_001167734.1.5 | c.1100C>T/p.Thr367Ile | Known | Pending | c.1490G>A/p.Arg497His | Novel | Pending | comphtz | AR | 97 |
Non mitochondrial disease gene | ||||||||||
ADAR
| chr1:NM_001111.4 | c.3202+1G>A/p.? | Novel | ND | c.577C>G/p.Pro193Ala | Known | ND | comphtz | AR | 18 |
CACNA1A
| chr19:NM_001127221.1 | c.1997C>T/p.Thr666Met | Known | mat | – | – | htz | AD | 39 | |
CDKL5
| chrX:NM_003159.2 | c.1942C>T/p.Gln648a
| Novel | mat | – | – | hemi | XLD | 65 | |
CLN3
| chr16:NM_001042432.1 | c.954_962+18del27/p.Leu313_Trp321del | Known | pat | c.461-280_677+382del966 | Known | Pending | comphtz | AR | 88 |
CPS1
| chr2:NM_001875.4 | c.1837-8A>G/p.? | Known | mat | c.3691G>C/p.Ala1231Pro | Novel | Paternal | comphtz | AR | 13 |
CPS1
| chr2:NM_001875.4 | c.1289C>G/p.Ser430a
| Novel | mat | c.3971_3972delT/p.1323Ile_1324Leufs | Novel | pat | comphtz | AR | 40 |
DMD
| chr X:NM_004006 | c.31+1G>A/p.? | Novel | mat | – | – | hemi | XLR | 38 | |
DYSF
| chr2:NM_003494.3 | c.1180+5G>A/p.? | Known | ND | c.6124C>T/p.Arg2042Cys | Known | ND | comphtz | AR | 45 |
GBE1
| chr3:NM_000158.3 | c.1621A>T/p.Asn541Tyr | Novel | mat | c.263G>A/p.Cys88Tyr | Novel | pat | comphtz | AR | 14 |
GFAP
| chr17:NM_002055.4 | c.1100G>C/p.Arg367Thr | Novel | de novo | – | – | htz | AD | 42 | |
HSD17B4
| chr5:NM_000414.3 | c.46G>A/p.Gly16Ser | Known | ND | c.367C>T/p.His123Tyr | Novel | ND | comphtz | AR | 30 |
MECP2
| chrX:NM_004992.3 | c.89delA/p.Lys30Argfs | Novel | de novo | – | – | hemi | XLD | 106 | |
MYBPC3
| chr11:NM_000256.3 | c.1351+1G>A/p.? | Known | pat | – | – | htz | AD | 8 | |
PEX5
| chr12:NM_001131025.1 | c.1669C>T/p.Arg557Trp | Known | mat | c.1799C>T/p.Ser600Leu | Novel | pat | comphtz | AR | 20 |
PGAP2
| chr11:NM_001256240.1 | c.2T>G/p.Met1? | Known | mat | c.221G>A/p.Arg74His | Known | pat | comphtz | AR | 73 |
PIGN
| chr18:NM_176787.4 | c.932T>G/p.Leu311Trp | Known | mat | c.790G>A/p.Gly264Arg | Known | pat | comphtz | AR | 6 |
PRF1
| chr10:NM_001083116.1 | c.808_812delGGCAG/p.Gly270 fs | Novel | mat | c.658G>A/p.Gly220Ser | Known | pat | comphtz | AR | 2 |
SBDS
| chr7:NM_016038.2 | c.258+2T>C/p.? | Known | pat | c.184A>T/p.Lys62a
| Novel | mat | comphtz | AR | 95 |
SCN2A
| chr2:NM_021007.2 | c.2948T>G/p.Leu983Trp | Novel | de novo | – | – | htz | AD | 47 | |
New candidate gene for mitochondrial disease | ||||||||||
NDUFB8
| chr10:NM_005004.3 | c.432C>G/p.Cys144Trp | Novel | mat | c.227C>A/p.Pro76Gln | Novel | pat | comphtz | AR | 26 |
Gene | Variant | MAF | Pathogenicity statusa
| Genotype–Phenotype correlationb
| Parental results status | Family history | ID patient | |
---|---|---|---|---|---|---|---|---|
1000 G | POL 400 | |||||||
ACAD9
| c.514G>A/p.Gly172Arg | 0 | 0 | Pathogenic | Moderate | in-trans | Negative | 15 |
ACAD9
| c.803C>T/p.Ser268Phe | 0 | 0 | Pathogenic | Moderate | in-trans | Negative | 15 |
ACAD9
| c.728C>G/p.Thr243Arg | 0 | 0 | Pathogenic | Low | in-trans | Negative | 53 |
ADAR
| c.3202+1G>A/p.? | 0 | 0.0014 | Pathogenic | Moderate | ND | Affected brother | 18 |
ADCK3
| c.827A>G/p.Lys276Arg | 0 | 0 | Pathogenic | High | in-trans | Negative | 61 |
ADCK3
| c.1702delG/p.Gly568Argfs | 0 | 0 | Pathogenic | High | in-trans | Negative | 61 |
AIFM1
| c.1474T>C/p.Tyr492His | 0 | 0 | Pathogenic | Moderate | X-linked | Negative | 25 |
CDKL5
| c.1942C>T/p.Gln648a
| 0 | 0 | Pathogenic | Moderate | X-linked | Negative | 65 |
COX10
| c.1030A>G/p.Met344Val | 0 | 0.0007 | Pathogenic | Moderate | in-trans | Negative | 9 |
COX10
| c.1270dupC/p.Leu424Profs | 0 | 0 | Pathogenic | Moderate | in-trans | Negative | 9 |
CPS1
| c.3691G>C/p.Ala1231Pro | 0 | 0.0014 | Pathogenic | Low | In-trans | Affected sister | 13 |
CPS1
| c.1289C>G/p.Ser430a
| 0 | 0.0014 | Pathogenic | Moderate | in-trans | Affected brother | 40 |
CPS1
| c.3971_3972delT/p.1323Ile_1324Leufs | 0 | 0.0014 | Pathogenic | Moderate | in-trans | Affected brother | 40 |
DMD
| c.31+1G>A/p.? | 0 | 0 | Pathogenic | Low | X-linked | Affected many males | 38 |
EARS2
| c.325G>C/p.Gly109Arg | 0 | 0.0014 | Likely pathogenic | High | in-trans | Negative | 7 |
EARS2
| c.1256C>T/p.Pro419Leu | 0 | 0 | Likely pathogenic | Moderate | in-trans | Negative | 70 |
FBXL4
| c.858+1G>T/p.? | 0 | 0 | Pathogenic | High | in-trans | Miscarriage | 3 |
FBXL4
| c.585+5G>C/p.? | 0 | 0 | Pathogenic | High | in-trans | Miscarriage | 3 |
FBXL4
| c.64C>T/p.Arg22a
| 0 | 0 | Pathogenic | Moderate | in-trans | Empty ovum | 52 |
FBXL4
| c.64C>T/p.Arg22a
| 0 | 0 | Pathogenic | Moderate | in-trans | Negative | 55 |
GBE1
| c.1621A>T/p.Asn541Tyr | 0 | 0 | Pathogenic | Moderate | in-trans | Negative | 14 |
GBE1
| c.263G>A/p.Cys88Tyr | 0 | 0 | Possibly pathogenic | Moderate | in-trans | Negative | 14 |
GFAP
| c.1100G>C/p.Arg367Thr | 0 | 0 | Pathogenic | Moderate | de novo | Negative | 42 |
HSD17B4
| c.367C>T/p.His123Tyr | 0 | 0.0014 | Pathogenic | Moderate | ND | Affected brother | 30 |
MECP2
| c.89delA/p.Lys30Argfs | 0 | 0.0 | Pathogenic | High | de novo | Negative | 106 |
NDUFB8
| c.432C>G/p.Cys144Trp | 0 | 0.0014 | Possibly pathogenic | Moderate | in-trans | Negative | 26 |
NDUFB8
| c.227C>A/p.Pro76Gln | 0 | 0 | Pathogenic | Moderate | in-trans | Negative | 26 |
NDUFS6
| c.313_315delAAAG/p.104Lys_106Thrfs | 0 | 0 | Pathogenic | Moderate | in-trans | Affected brother | 1 |
NDUFS6
| c.334_359del26ins13/p.Glu112 fs | 0 | 0 | Pathogenic | Moderate | in-trans | Affected brother | 1 |
NDUFS7
| c.376C>T/p.Leu126Phe | 0 | 0 | Pathogenic | Moderate | ND | Similar symptoms in brother | 75 |
NDUFS7
| c.504G>C/p.Arg168Ser | 0 | 0 | Likely Pathogenic | Moderate | ND | Similar symptoms in brother | 75 |
NDUFV1
| c.733G>A/p.Val245Met | 0.0005 | 0 | Pathogenic | High | in-trans | Negative | 10 |
NDUFV1
| c.383G>T/p.Arg128Leu | 0 | 0 | Pathogenic | High | in-trans | Negative | 10 |
PARS2
| c.1091C>G/p.Pro364Arg | 0.0014 | 0.003 | Pathogenic | Moderate | in trans | Affected sibs | 60 |
PARS2
| c.239T>C/p.Ile80Thr | 0 | 0 | Pathogenic | Moderate | in trans | Affected sibs | 60 |
PC
| c.2381_2383delTGG/p.Val794del | 0 | 0 | uncertain Pathogenic | High | in-trans | Affected brother | 29 |
PC
| c.1487G>A/p.Arg496Gln | 0 | 0 | Pathogenic | High | ND | Negative | 71 |
PC
| c.584C>T/p.Ala195Val | 0 | 0 | Pathogenic | High | ND | Negative | 71 |
PDHA1
| c.856_859dupACTT/p. Arg288Leufs | 0 | 0 | Pathogenic | High | de novo | Negative | 56 |
PDHA1
| c.291G>A/p.? | 0 | 0.0000 | Uncertain pathogenic | Moderate | de novo | Negative | 68 |
PEX5
| c.1799C>T/p.Ser600Leu | 0 | 0 | Pathogenic | Low | in-trans | Negative | 20 |
POLG
| c.2639C>A/p.Ala880Asp | 0 | 0 | Pathogenic | Moderate | in-trans | Negative | 113 |
PRF1
| c.808_812delGGCAG/p.Gly270 fs | 0 | 0.0000 | Pathogenic | Low | in trans | Negative | 2 |
RARS2
| c.1026G>A/p.Met342Ile | 0 | 0 | Likely pathogenic | Moderate | in-trans | Affected brother | 41 |
RARS2
| c.622C>T/p.Gln208a
| 0 | 0.0014 | Pathogenic | Moderate | in-trans | Affected brother | 41 |
RRM2B
| c.414_415delCA/p.Tyr138a
| 0 | 0.0014 | Pathogenic | High | ND | Negative | 21 |
SBDS
| c.184A>T/p.Lys62a
| 0 | 0.002 | Pathogenic | Low | in-trans | PI neural tube defect | 95 |
SCN2A
| c.2948T>G/p.Leu983Trp | 0 | 0.0013 | Pathogenic | High | de novo | Negative | 47 |
SLC25A12
| c.1335C>A/p.Asn445Lys | 0 | 0 | Pathogenic | Moderate | in-trans | Negative | 24 |
TAZ
| c.684_685insC/p.227Phe_228Profs | 0 | 0.0012 | Pathogenic | Low | ND | Negative | 28 |
VARS2
| c.1490G>A/p.Arg497His | 0 | 0 | Pathogenic | Low | ND | Similar disease in sibs | 97 |
Subgroup of neonates
Subgroup with 3-methylglutaonic aciduria
Basal ganglia involvement (Leigh syndrome, Leigh-like, others)
Defects in non MD-related genes
New MD-related disorders
Mitochondrial disease criteria score
WES diagnostics of current cases vs. archival DNA samples
Subgroups of patients | MD or non-MD genes loci of variants | Diagnostics based on archival material | Current diagnostics | Total |
---|---|---|---|---|
Disease onset (year) | 1996–2012 | 2013–2014 | 1996–2014 | |
Number of patients | 88 (5.5/year) | 25 (12.5/year) | 113 | |
Period from onset to WES qualification (years) | 2–25 (mean 5.5 ± 5.9 ) | 0 | 0–25 | |
MDC scale (A+B, without C) | 4.2 ± 1.5 (2–8) | 3.6 ± 1.2 (2–6) | 4.1 ± 1.5 | |
Ratio of MD-related/non MD related genes | 3.4 | 1.0 | 2.4 | |
Patients deceased | Total no. | 41 | 8 | 44 % |
MD
|
51.2 % (21)
|
2
|
47 % (23)
| |
non MD
|
(3)
|
2
|
(5)
| |
Patients with neonatal onset | Total no. | 41 | 6 | 42 % |
MD
|
53.7 % (22)
|
2
|
51 % (24)
| |
non MD
|
(5)
|
2
|
(7)
| |
Patients with LS or other basal ganglia involvement | Total no. | 21 | 7 | 25 % |
MD
|
61.9 % (13)
|
3
|
57 % (16)
| |
non MD
|
(2)
|
0
|
(2)
| |
3-methylglutaconic aciduria | Total no. | 13 | 3 | 14 % |
MD
|
53.8 % (7)
|
2
|
53 % (9)
| |
non MD
|
0
|
1
|
(1)
| |
Muscle biopsy | Total no. | 62 | 5 | 67/113 |
MD
|
56.4 % (35)
|
(4)
|
58 % (39)
| |
non MD
|
(10)
|
(0)
|
(10)
| |
Percentage of muscle biopsy | 70 % | 20 % | 59 % |