First step towards a consensus strategy for multi-locus diagnostic testing of imprinting disorders

Mackay, Deborah; Bliek, Jet; Kagami, Masayo; Tenorio-Castano, Jair; Pereda, Arrate; Brioude, Frédéric; Netchine, Irène; Papingi, Dzhoy; de Franco, Elisa; Lever, Margaret; Sillibourne, Julie; Lombardi, Paola; Gaston, Véronique; Tauber, Maithé; Diene, Gwenaelle; Bieth, Eric; Fernandez, Luis; Nevado, Julian; Tümer, Zeynep; Riccio, Andrea; Maher, Eamonn R.; Beygo, Jasmin; Tannorella, Pierpaola; Russo, Silvia; de Nanclares, Guiomar Perez; Temple, I. Karen; Ogata, Tsutomu; Lapunzina, Pablo; Eggermann, Thomas

doi:10.1186/s13148-022-01358-9

Clinical Epigenetics

Table 1 Detection rates from the different centres for the imprinting disorders associated with aberrant imprinting marks

From: First step towards a consensus strategy for multi-locus diagnostic testing of imprinting disorders

Laboratory		Aachen/DE^a	Amsterdam/NL	Essen/DE	Madrid/ES	Milano/IT	Paris/FR	Salisbury/UK	Tokyo, Hamamatsu/JP	Vitoria-Gasteiz/ES	Total
First-line test	Molecular diagnosis	ME030/ME032 + ME034	ME030/ME032	ME030/ME032; ME034 for research	ME030/ME032 + ME034 + SNParray	ME030/ME032	ASMM-RT qPCR (IC2, MEST, GRB10, MEG3, IG-DMR}	ME030/ME032	MS- pyrosequencing (IC1, IC2, IG-DMR, PEG 10, MEST)	ME030/ME032;ME034 for research	Total number	ratio of molecular subgroups (resolved + unresolved) in the total cohort
SRS
Referrals (total number)		1164	546	287	348	586	876	388	455	71	4721
"Expected" molecular diagnoses	IC1 LOM	158	36	27	44	62	97	27	113	8	572	67,6
	11p15CNVs	8	4	1	2	2	NA	1	2	0	20	2,4
	upd(11)mat	0	0	0	3	0	0	1	1	0	5	0,6
	upd(7)mat	37	3	5	9	17	21	10	31	1	134	15,8
Sum "expected" diagnoses		203	43	33	58	81	118	39	147	9	731
% "Expected" positive diagnoses		17,4	7,9	11,5	16,7	13,8	13,5	8,2	32,3	12,7	15,5
Unexpected molecular diagnoses	IC2 LOM	3	2	0	4	1	2	0	1	0	13	1,5
	chromosome 7 alterations	3	1	0	1	3	0	0	0	0	8	0,9
	14q32 alterations^b	10	0	0	8	5	27	5	14	1	70	8,3
	upd(6)mat	2	NA	0	2	1	NA	NA	2	NA	7	0,8
	upd(20)mat	1	NA	0	0	3	NA	NA	6	NA	10	1,2
	PWS	1	NA	0	0	0	NA	NA	2	NA	3	0,4
	upd(11)pat			0			3	1			4	0,5
Sum "unexpected" diagnoses		20	3	0	15	13	32	6	25	1	115
% total diagnostic yield (expected + unexpected)		19,2	8,4	11,5	21,0	16,0	17,1	11,6	37,8	14,1	17,9
percentage of unexpected finding among the total findings		9,0	6,5	0,0	20,5	13,8	21,3	13,3	14,5	10,0	13,6
MLID^c,d		10	0		NA	0	14	0	3	2	29	5,1

First-line test***		ME030 + ME034	ME030	ME030; ME034 for research	ME030	ME030; ME034 for research	ASMM-RTqPCR (IC1/IC2/M EST, G RB10 /DLK 1/GTL2)	ME030	MS-Pyrosequencing H19 IGF2, IG-DMR, PEG10, MEST)	ME030; ME034 if positive in ME030	Total number	Ratio of molecular subgroups (resolved + unresolved) in the total cohort
BWS
Referrals (total number)		475	756	400	679	1028	1258	269	169	66	5100
Expected molecular diagnoses	IC1 GOM	16	16	10	4	17	73	1	15	1	153	11,8
	IC2 LOM	78	84	60	152	184	201	27	32	15	833	64,0
	CNVs 11p	9	5	4	2	7	0	1	2	2	32	2,5
	upd(11)pat	44	39	20	14	83	0	16	32	6	254	19,5
	Of these uniparental diploidy^d	4	2	1	2		0	1	1	0	11
Sum "expected" diagnoses		147	144	94	172	291	274	45	81	24	1272
% "expected" positive diagnose^e		30,9	19,0	23,5	25,3	28,3	27,8	16,7	47,9	36,4	24,9
unexpected molecular diagnoses	IC1 LOM	3	0	0	11	3	9	0	0	1	27	2,1
unexpected molecular diagnoses	PHP	0	NA	NA	0	0	NA	NA	2	NA	2	0,2
Sum "unexpected" diagnoses		3	0	0	11	3	9	0	2	1	29
% total diagnostic yield (expected + unexpected)		31,6	19,0	23,5	27,0	28,6	22,5	16,7	49,1	37,9	25,5
Percentage of unexpected findings among the total findings		2,0	0,0	0,0	6,0	1,0	3,2	0,0	2,4	4,0	2,2
MLID^cd		21	3	3	20	25	22	3	2	8	107	12,8

Laboratory		Aachen/DE	Amsterdam/NL	Essen/DE	Madrid/ES	Milano/IT	Salisbury/UK	Tokyo, Hamamatsu/JP	Vitoria- Gasteiz/ES	Additional specialist laboratories^f	Total number	ratio of molecular subgroups in the total cohort
First-line test	Molecular diagnosis	disease-specific (MLPA) assays
PWS^g
Referrals (total number)		33	344	825	218	420	400	260	87	420	3007
Molecular diagnoses	SNRPN ID	4	0	32	2	13	1	9	1	2	64	10,0
	del 15 pat	6	20	59	9	22	15	18	3	100	252	39,4
	upd(15)mat	1	7	48	13	20	10	49	10	0	158	24,7
	dup 15 mat	0	3	6	8		18	2		29	66	10,3
	upd(15)mat/ID unresolved	0	2	32	0	26	5	35	0	0	− 100	15,6
	total	11	32	177	32	81	49	113	14	131	640
	% positive diagnoses	33,3	9,3	21,5	14,7	19,3	12,3	43,5	16,1	3f,2	21,3
AS^g
Referrals (total number)		17	103	631	131	630	165	49	87	NA	1813
Molecular diagnoses	SNRPN ID	2	0	77	4	20	0	10	3	116	232	28,5
	del 15 mat	2	6	31	10	88	6	10	7	160	320	39,3
	upd(15)pat	0	2	13	3	12	2	5	1	38	76	9,3
	dup 15 pat	0	3	0	1	1	1	0	0	6	12	1,5
	UBE3A^h	NA	3	3	1	52	NA	2	3	64	128	15,7
	upd(15)paVID unresolved	0	4	0	NA	6	3	10	0	23	46	5,7
	total	4	18	124	19	179	12	37	14	407	814
	% positive diagnoses^h	23,5	17,5	19,7	14,5	28,4	7,3	75,5	16,1	NA	NA
TS14^b,g
Referrals (total number)				144	8	1	73	57	1		284
Molecular diagnoses	upd(14)mat	NA	NA	3	3	1	11	21	1	NA	40	48,8
	del(14q32)pat	NA	NA	1	1	0	1	6	0	NA	9	11.0
	ID	NA	NA	9	0	0	3	13	0	NA	25	30,5
	upd(14)mat/ID unresolved	NA	NA	1	0	0	2	5	0	NA	8	9,8
	total			14	4	1	17	45	1		82
	% positive diagnoses			9,7	50,0	100,0	23,3	78,9	100,0		28,9
KOS14^g
Referrals (total number)		NA	NA	8	4	1	8	76	1	NA	98
Molecular diagnoses	upd(14)pat	NA	NA	2	2	0	3	26	0	NA	33	46,5
	del(14q32)mat	NA	NA	2	0	1	1	9	1	NA	14	19,7
	ID	NA	NA	1	0	0	1	15	0	NA	17	23,9
	upd(14)pat/ID unresolved	NA	NA	0	0	0	3	4	0	NA	7	9,9
	total			5	2	1	8	54	1		71
	% positive diagnoses			62,5	50,0	100,0	100,0	71,1	100,0		72,4
_PHp^g,h
Referrals (total number)		NA	NA	NA	4		335	175	239	NA	753
Molecular diagnoses	upd(20)pat	NA	NA	NA	1		4	0	7	NA	12	2,5
	del(20)mat	NA	NA	NA	0		1	0	8	NA	9	1,9
	ID	NA	NA	NA	0		117	27	58	NA	202	42,6
	upd(20)mat/ID unresolved	NA	NA	NA	0		1	19		NA	20	4,2
	STX16 del	NA	NA	NA	0		34	36	19	NA	89	18,8
	GNAS mutations	NA	NA	NA	0			43	99	NA	142	30,0
	total				1		157	125	191		474
	% positive diagnoses				25,0		46,9	71,4	79,9		62,9
TNDM^g
Referrals (total number)		NA	NA	12	6	NA	272	6	1	291	588
Molecular diagnoses	upd(6)pat	NA	NA	0	1	NA	44	2	1	22	70	34,0
	dup(6)pat	NA	NA	2		NA	23	1	0	26	52	25,2
	ID	NA	NA	0	2	NA	45	3	0	16	66	32,0
	of these, ZFP5T	NA	NA	NA	NA	NA	17	NA	NA	7	24
	upd(6)pat/ID unresolved	NA	NA	0	0	NA	9	0	0	9	18	8,7
	total			2	3		121	6	1	73	206
	% positive diagnoses			16,7	50,0		44,5	100,0	100,0	25,1	35,0

(ID imprinting defect (epimutation). NA not assessed/assessable.
^athe majority of data from Aachen/DE have already been included in [22]]
^bTS14 overlaps with SRS and PWS and does not have strict clinical criteria
^cMLID detection rate depends on the tests applied by the laboratory. MLID % given as percentage of individuals with an imprinting anomaly, not as percentage of total referrals.
^dnot (systematically) analysed by all laboratories and not in all patients.
^ein some laboratories, CDKN1C sequencing is included in first-line testing but results are not listed here.
^fadditional specialist centres with expertise in the respective disorders are: Exeter/UK (TNDM); Toulouse/FR (PWS).
^gReferral for these disorders is biased, e.g. because samples were forwarded after exclusion of large deletions (e.g. in case of PWS, AS) or other pretesting steps.
^hUBE3A and GNAS sequencing analysis have not been performed in all laboratories. Unresolved: Some MS tests do not discriminate the molecular cause of DNA methylation change: for example, MS PCR does not discriminate between CNV, UPD or imprinting defect; MS-MLPA cannot distinguish between UPD and imprinting defects. Discrimination entails additional tests such as microsatellite analysis or SNP array analysis, but these tests require parental DNA samples and/or allow identification only of uniparental isodisomy. In some patients with PWS, AS, TS14, KOS14 and TNDM, parental DNA samples were not available, additional testing was not performed, and therefore, discrimination between UPD and imprinting defects was not possible. These samples are identified as “unresolved”.)

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ISSN: 1868-7083

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