. 2016 Aug 24;36(6):561–572. doi: 10.3343/alm.2016.36.6.561

Table 2. Diagnosis of inherited metabolic diseases using an integrated screening model.

Sample ID	Metabolite	cut-off^*	NBS tests^*	Gene	NT alteration	AA alteration	Conventional criteria	ACMG category	Zygosity	Disease	Frequency in APC
IMD_26	C3	5	10	MUT	c.2179C > T	p.R727X	KP	P	ComHet	MMA	1/54
IMD_26	C3	5	10	MUT	c.322C > T	p.R108C	KP	LP		MMA	1/54
IMD_30	C5OH	0.6	1.102	MCCC1	c.475T > C	p.C159R	KP	LP	Het	3-MCC deficiency	1/54
IMD_31	Cit	55	348	*SLC25A13*	c.851delGTAT	p.M285Pfs^*2	KP	P	Het	CTLN2	3/54
IMD_32	Cit	55	430	*SLC25A13*	c.851delGTAT	p.M285Pfs^*2	KP	P	Het	CTLN2	3/54
IMD_39	FT4	0.8	0.4	DUOX2	c.1232G > A	p.R411K	EP	VUS	NA	CH	1/54
IMD_42	FT4	0.8	0.6	*TSHR*	c.1454C > A	p.A485D	EP	VUS	NA	CH	2/54
IMD_44	TSH	12	23.3	*DUOX2*	c.1588A > T	p.K530X	KP	P	Het	CH	2/54
IMD_47	TSH	12	13.1	*DUOX2*	c.2654G > A	p.R885Q	KP	LP	Het	CH	3/54
IMD_48	TSH	12	25.5	*DUOXA2*	c.413dupA	p.Y138X	KP	LP	Het	CH	4/54
IMD_50	TSH	12	34.6	TSHR	c.403A > T	p.N135Y	EP	VUS	NA	CH	1/54
IMD_50	TSH	12	34.6	TSHR	c.1349G > A	p.R450H	KP	LP	Het	CH	4/54
IMD_52	TSH	12	16.5	PAX8	c.300dupTACC	p.M102fs	EP	LP	Het	CH	1/54
IMD_54	TSH	12	13.2	*TSHR*	c.611C > T	p.A204V	KP	LP	Het	CH	2/54
IMD_56	TSH	12	12.1	DUOXA2	c.535T > C	p.Y179H	EP	VUS	NA	CH	1/54
IMD_57	TSH	12	12.1	PAX8	c.192G > C	p.R64S	EP	VUS	NA	CH	1/54
IMD_66	TSH	12	21.9	DUOX2	c.4010G > T	p.G1337V	EP	VUS	Het	CH	1/54
IMD_66	TSH	12	21.9	*DUOX2*	c.1588A > T	p.K530X	KP	P	Het	CH	2/54
IMD_68	TSH	12	17	*DUOX2*	c.1462G > A	p.G488R	KP	LP	Het	CH	4/54
IMD_79	Gal	13	21.7	GALE	c.1002G > A	p.W334X	EP	P	Het	Galactosemia	1/54
IMD_80	Gal	13	19	GALT	c.50+1G > A	NA	KP	P	Het	Galactosemia	1/54
IMD_81	Gal	13	32.2	GALE	c.47G > A	p.S16N	EP	VUS	NA	Galactosemia	1/54
IMD_83	Gal	13	19.8	*GALE*	c.905G > A	p.G302D	KP	LP	Het	Galactosemia	2/54
IMD_87	Gal	13	16.5	GALT	c.998G > A	p.R333Q	KP	LP	Het	Galactosemia	1/54
IMD_89	Gal	13	40.4	GALT	c.1034C > A	p.A345D	KP	LP	Het	Galactosemia	1/54
IMD_92	TSH	12	28.5	*TSHR*	c.1349G > A	p.R450H	KP	LP	Het	CH	4/54
IMD_100	C5OH	0.6	2.571	*MCCC1*	c.288+2T > A	NA	KP	P	Het	3-MCC deficiency	2/54
IMD_101	TSH	12	14.6	DUOX2	c.2635G>A	p.E879K	KP	LP	Het	CH	1/54
IMD_106	C5OH	0.6	1.016	*MCCC1*	c.288+2T > A	NA	KP	P	Het	3-MCC deficiency	2/54
IMD_112	Gal	13	17	GALE	c.264delT	p.F88fs	EP	LP	Het	Galactosemia	1/54
IMD_113	FT4	0.8	0.3	*DUOXA2*	c.413dupA	p.Y138X	KP	LP	Het	CH	4/54
IMD_124	Gal	13	17.6	*GALE*	c.905G > A	p.G302D	KP	LP	Het	Galactosemia	2/54
IMD_125	TSH	12	12.9	*TSHR*	c.1349G > A	p.R450H	KP	LP	Het	CH	4/54
IMD_139	Gal	13	27	GALE	c.38A > G	p.Y13C	EP	VUS	NA	Galactosemia	1/54
IMD_139	Gal	13	27	GALE	c.10A > G	p.K4E	EP	VUS	NA	Galactosemia	1/54
IMD_142	Phe	130	142.216	PAH	c.1065+1G > A	NA	KP	P	Het	PKU	1/54
IMD_144	TSH	12	23.1	*TSHR*	c.611C > T	p.A204V	KP	LP	Het	CH	2/54
IMD_144	TSH	12	23.1	*DUOX2*	c.2654G > A	p.R885Q	KP	LP	Het	CH	3/54
IMD_149	TSH	12	14.2	DUOX2	c.3616G > A	p.A1206T	EP	VUS	NA	CH	1/54
IMD_149	TSH	12	14.2	*DUOX2*	c.1462G > A	p.G488R	KP	LP	Het	CH	4/54
IMD_152	TSH	12	12.3	DUOX2	c.3329G > A	p.R1110Q	KP	LP	Het	CH	1/54
IMD_152	TSH	12	12.3	*DUOXA2*	c.738C > G	p.Y246X	KP	P	Het	CH	3/54
IMD_153	TSH	12	13.6	*DUOXA2*	c.738C > G	p.Y246X	KP	P	Het	CH	3/54
IMD_153	TSH	12	13.6	PAX8	c.739G > A	p.E247K	EP	VUS	NA	CH	1/54
IMD_159	Cit	55	128.9	SLC25A13	c.1180+1G > A	NA	KP	P	ComHet	CTLN2	1/54
IMD_159	Cit	55	128.9	*SLC25A13*	c.851delGTAT	p.M285Pfs^*2	KP	P		CTLN2	3/54
IMD_164	C3	5	9.126	MUT	c.1228A > G	p.I410V	EP	VUS	NA	MMA	1/54
IMD_186	TSH/GAL	12.0/13.0	31.3/13.5	*DUOXA2*	c.413dupA	p.Y138X	KP	LP	Hom	CH	4/54
IMD_189	TSH/FT4	12.0/0.8	55.7/0.4	*DUOX2*	c.1462G > A	p.G488R	KP	LP	Het	CH	4/54
IMD_191	TSH/17α-OHP/FT4	12/12/0.8	54.9/18.1/0.2	SLC5A5	c.1060A > C	p.T354P	KP	LP	ComHet	CH	1/54
IMD_191	TSH/17α-OHP/FT4	12/12/0.8	54.9/18.1/0.2	SLC5A5	c.1605del	p.G535fs	EP	LP		CH	1/54
IMD_196	TSH	12	94.1	*DUOX2*	c.1462G > A	p.G488R	KP	LP	Het	CH	4/54
IMD_197	TSH	12	14.8	*TSHR*	c.1349G > A	p.R450H	KP	LP	Het	CH	4/54
IMD_203	TSH	12	12.4	TSHR	c.1556G > A	p.R519H	EP	VUS	NA	CH	1/54
IMD_206	TSH	12	54.8	DUOXA2	c.280C > T	p.R94C	EP	VUS	NA	CH	1/54
				*DUOXA2*	c.413dupA	p.Y138X	KP	LP	Het	CH	4/54
IMD_209	TSH	12	15.1	DUOX2	c.1319G > A	p.S440N	EP	VUS	NA	CH	1/54
IMD_210	TSH	0012	0054.8	TSHR	c.1449C > A	p.N483K	EP	VUS	NA	CH	1/54
IMD_211	TSH	12	13	DUOX2	c.227C > T	p.P76L	EP	VUS	NA	CH	1/54
IMD_221	TSH	12	25.7	*TSHR*	c.1454C > A	p.A485D	EP	VUS	NA	CH	2/54
IMD_234	Gal	13	27.7	*GALK1*	c.1159G > A	p.A387T	EP	VUS	NA	Galactosemia	2/54
IMD_235	Gal	13	19.6	*GALK1*	c.1159G > A	p.A387T	EP	VUS	NA	Galactosemia	2/54
IMD_237	FT4	0.8	0.2	*DUOX2*	c.2654G > A	p.R885Q	KP	LP	Het	CH	3/54
IMD_238	FT4	0.8	0.4	TPO	c.1061G > T	p.W354L	EP	VUS	NA	CH	1/54
IMD_264	17α-OHP/FT4	12.0/0.7	17.9/0.4	*DUOXA2*	c.738C > G	p.Y246X	KP	P	Het	CH	3/54

Reference sequences of MUT, MCCC1, SLC25A13, DUOX2, TSHR, DUOXA2, PAX8, GALE, GALT, GALT, PAH, SLC5A5, GALK1, and TPO were NM_000255, NM_001293273, NM_001160210, NM_014080, NM_000369, NM_207581, NM_003466, NM_001127621, NM_001258332, NM_000155, NM_000277, NM_000453, NM_000154, and NM_175722, respectively.

^*The metabolite units of C3, C5OH, Phe, Cit, Gal, TSH, FT4 and 17α-OHP were µmol/L, µmol/L, µmol/L, µmol/L, µmol/L, mU/L, ng/dL, ng/mL, respectively. Recurrent mutations are in bold.

Abbreviations: KP, known pathogenic mutation based on the Human Genome Mutation Database (DM) or ClinVar (pathogenic) databases; EP, expected pathogenic mutation based on population frequency, in silico prediction, and mutation type (loss of function mutations); P, pathogenic; LP, likely pathogenic; VUS, variant of unknown significance; NA, not applicable; Het, heterozygous; ComHet, compound heterozygous; Hom, homozygous; Cit, citrulline; GAL, galactose; TSH, thyroid stimulating hormone; FT4, free T4; MMA, Methylmalonic aciduria; 3-MCC deficiency, 3-methylcrotonyl-CoA carboxylase deficiency; PKU, Phenylketonuria; CTLN2, Type II citrullinemia; CH, Congenital hypothyroidism.