New perspective in diagnostics of mitochondrial disorders: two years’ experience with whole-exome sequencing at a national paediatric centre

Pronicka, Ewa; Piekutowska-Abramczuk, Dorota; Ciara, Elżbieta; Trubicka, Joanna; Rokicki, Dariusz; Karkucińska-Więckowska, Agnieszka; Pajdowska, Magdalena; Jurkiewicz, Elżbieta; Halat, Paulina; Kosińska, Joanna; Pollak, Agnieszka; Rydzanicz, Małgorzata; Stawinski, Piotr; Pronicki, Maciej; Krajewska-Walasek, Małgorzata; Płoski, Rafał

doi:10.1186/s12967-016-0930-9

Table 3 Novel molecular variants identified in the study; pathogenicity status

From: New perspective in diagnostics of mitochondrial disorders: two years’ experience with whole-exome sequencing at a national paediatric centre

Gene	Variant	MAF		Pathogenicity status^a	Genotype–Phenotype correlation^b	Parental results status	Family history	ID patient
Gene	Variant	1000 G	POL 400	Pathogenicity status^a	Genotype–Phenotype correlation^b	Parental results status	Family history	ID patient
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.Gln648^a	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.Ser430^a	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.Arg22^a	0	0	Pathogenic	Moderate	in-trans	Empty ovum	52
FBXL4	c.64C>T/p.Arg22^a	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.Gln208^a	0	0.0014	Pathogenic	Moderate	in-trans	Affected brother	41
RRM2B	c.414_415delCA/p.Tyr138^a	0	0.0014	Pathogenic	High	ND	Negative	21
SBDS	c.184A>T/p.Lys62^a	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

ND not determined due to lack of clinical data or DNA not available
^aPathogenicity status evaluated according to in silico prediction algorithms (CADD, MetaSVM, Polyphen2 HDIV, Polyphen HVAR, mutation assessor, LRT, MetaLR, SIFT, mutationtaster) and classified as: pathogenic—nonsense, frameshift, splicesite and missense variants with pathogenic status at least in 7 of used algorithms; likely pathogenic - missense variants with pathogenic status in 4–6 of used algorithms; possibly pathogenic—missense variants with pathogenic status <4 of used algorithms
^bGenotype-Phenotypecorrelationassessed by two independent specialists in clinical genetics and metabolic medicine

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