A comprehensive multiplex PCR based exome-sequencing assay for rapid bloodspot confirmation of inborn errors of metabolism

Wang, Wenjie; Yang, Jianping; Xue, Jinjie; Mu, Wenjuan; Zhang, Xiaogang; Wu, Wang; Xu, Mengnan; Gong, Yuyan; Liu, Yiqian; Zhang, Yu; Xie, Xiaobing; Gu, Weiyue; Bai, Jigeng; Cram, David S.

doi:10.1186/s12881-018-0731-5

Table 3 Comparison of MS MS and gene testing for diagnosis of IEM

From: A comprehensive multiplex PCR based exome-sequencing assay for rapid bloodspot confirmation of inborn errors of metabolism

MS MS positive bloodspot	MS MS test		Clinical diagnosis	PEARS-101 test
MS MS positive bloodspot	Primary metabolite changes	Suspected IEM	Clinical diagnosis	Gene	Relevant pathogenic variants detected	Predicted aa change	Pathogenicity Classification^a	Indicated IEM status
True positives
NB-1	Cit ↑	Citrullinemia type 1	Citrullinemia type 1	ASS1	c.815G > A	p.R272H	Pathogenic	Citrullinemia type 1
NB-1	Cit ↑	Citrullinemia type 1	Citrullinemia type 1	ASS1	c.1168G > A	p.G390R	Pathogenic	Citrullinemia type 1
NB-2	Cit ↑	Citrullinemia type 2	Citrullinemia type 2	ASS1	c.19G > A	p.V7M	Pathogenic	Citrullinemia type 2
NB-2	Cit ↑	Citrullinemia type 2	Citrullinemia type 2	ASS1	c.851C > T	p.T284I	Pathogenic	Citrullinemia type 2
NB-3	C3 ↑	Methylmalonic acidemia	Methylmalonic acidemia	MUT	c.2032C > G	p.H678D	Pathogenic	Methylmalonic academia
NB-3	C3 ↑	Methylmalonic acidemia	Methylmalonic acidemia	MUT	c.2080C > T	p.R694W	Pathogenic	Methylmalonic academia
NB-4	C4 ↑	Isobutyryl-CoA dehydrogenase deficiency	Isobutyryl-CoA dehydrogenase deficiency	ACAD8	c.705 + 1G > A	No change	Pathogenic	Isobutyryl-CoA dehydrogenase deficiency
NB-4	C4 ↑	Isobutyryl-CoA dehydrogenase deficiency	Isobutyryl-CoA dehydrogenase deficiency	ACAD8	c.1176G > T	p.R392S	Pathogenic	Isobutyryl-CoA dehydrogenase deficiency
NB-5	C4 ↑ C4/C2 ↑	Short chain acyl-CoA dehydrogenase deficiency	Short chain acyl-CoA dehydrogenase deficiency	ACADS	c.1031A > G	p.E344G	Pathogenic	Short chain acyl-CoA dehydrogenase deficiency
NB-5	C4 ↑ C4/C2 ↑	Short chain acyl-CoA dehydrogenase deficiency	Short chain acyl-CoA dehydrogenase deficiency	ACADS	c.1054G > A	p.A352T	Pathogenic	Short chain acyl-CoA dehydrogenase deficiency
NB-6	C4↑, C5↑, C5DC↑, C6↑, C8↑, C10↑	Glutaric aciduria type II	Glutaric aciduria type II	ETFA	c.52C > T	p.R18X	Pathogenic	Glutaric aciduria type II
NB-6	C4↑, C5↑, C5DC↑, C6↑, C8↑, C10↑	Glutaric aciduria type II	Glutaric aciduria type II	ETFA	c.347G > T	p.G116 V	Pathogenic	Glutaric aciduria type II
NB-7	Met ↑	Methioninemia	Methioninemia	MAT1A	c.791G > A	p.R264H	Pathogenic	Methioninemia
NB-8	Met ↑	Methioninemia	Methioninemia	MAT1A	c.315C > A	p.N105K	Pathogenic	Methioninemia
False positives
NB-9	Cit ↓	Ornithine transcarbamylase deficiency (male)	Normal	OTC	c.809A > G	p.Q270R	Uncertain	Male carrier of Ornithine transcarbamylase deficiency
NB-9	Cit ↓	Ornithine transcarbamylase deficiency (male)	Normal	OTC	c.137A > G	p.K46R	Likely benign	Male carrier of Ornithine transcarbamylase deficiency
NB-10	Ala ↑	Hyperalaninemia	Normal	SARDH	c.2050A > G	p.S684G	Uncertain	Compound heterozygote for Sarcosinuria
NB-10	Ala ↑	Hyperalaninemia	Normal	SARDH	c.1738 T > C	p.Y580H	Uncertain	Compound heterozygote for Sarcosinuria
NB-11	Leu ↑	Maple syrup urine disease	Normal	MMACHC	c.458G > A	p.R153Q	Uncertain	Compound heterozygote for Methylmalonic aciduria
NB-11	Leu ↑	Maple syrup urine disease	Normal	MMACHC	c.799C > T	p.R267W	Uncertain	Compound heterozygote for Methylmalonic aciduria
NB-12	Leu ↑	Maple syrup urine disease	Normal	ETFDH	c.1823G > A	p.G608D	Uncertain	Compound heterozygote for Glutaric aciduria type II
NB-12	Leu ↑	Maple syrup urine disease	Normal	ETFDH	c.770A > G	p.Y257C	Uncertain	Compound heterozygote for Glutaric aciduria type II
NB-13	C4 ↑	Short-chain acyl-CoA dehydrogenase deficiency	Normal	ACADS	c.1153G > A	p.A385T	Uncertain	Carrier of Short-chain acyl-CoA dehydrogenase deficiency
NB-14	Cit ↑	Citrullinemia type I	Normal	ASS1	c.910C > T	p.R304W	Uncertain	Carrier of Citrullinemia type I
NB-15	Cit ↑	Citrullinemia type 1	Normal	ASS1	c.1176_1178del	p.392_393del	Uncertain	Carrier of Citrullinemia type I
NB-16	C0 ↓	Primary carnitine deficiency	Normal	SLC22A5	c.1400C > G	p.S467C	Uncertain	Carrier of Primary carnitine deficiency
NB-17	C5OH ↑	3 Methylcrotonyl Coenzyme A dehydrogenase deficiency	Normal	MCCC1	c.328C > T	p.Q110X	Uncertain	Carrier of 3 Methylcrotonyl Coenzyme A dehydrogenase deficiency
NB-18	C4 ↑	Isobutyryl-CoA dehydrogenase deficiency	Normal	ACAD8	c.712delT	p.W238 fs	Uncertain	Carrier of Isobutyryl-CoA dehydrogenase deficiency
NB-19	C14:1 ↑ C14:2 ↑ C14 ↑	Very long-chain 3-OH acyl-CoA dehydrogenase deficiency	Normal	ACADVL	c.1748C > T	p.S583 L	Uncertain	Carrier of very long-chain 3-OH acyl-CoA dehydrogenase deficiency
NB-20	C0 ↓	Primary carnitine deficiency	Normal	SLC25A1	c.845G > C	p.R282P	Uncertain	Non-carrier of Primary carnitine deficiency
NB-20	C0 ↓	Primary carnitine deficiency	Normal	FTCD	c.610C > T	p.R204W	Uncertain	Non-carrier of Primary carnitine deficiency

^aBy definition of the clinical diagnosis confirming the IEM (NB 1–8), all newly detected DNA variants were re-classified as pathogenic

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