Genome-wide DNA methylation analysis of pseudohypoparathyroidism patients with GNAS imprinting defects

Rochtus, Anne; Martin-Trujillo, Alejandro; Izzi, Benedetta; Elli, Francesca; Garin, Intza; Linglart, Agnes; Mantovani, Giovanna; Perez de Nanclares, Guiomar; Thiele, Suzanne; Decallonne, Brigitte; Van Geet, Chris; Monk, David; Freson, Kathleen

doi:10.1186/s13148-016-0175-8

Clinical Epigenetics

Table 1 Clinical and molecular characteristics of the PHP patients enrolled in the genome-wide DNA methylation study

From: Genome-wide DNA methylation analysis of pseudohypoparathyroidism patients with GNAS imprinting defects

1. Clinical characteristics									2. Initial diagnostic screening							3. HM450k
Patient	Gender	PTH-res	TSH-res	Ca ↓	P ↑	OS	BD	Additional features	STX16	LAB	Label	NESP	AS	XL	A/B	NESP	AS1	AS2	XL	A/B
1	F	Yes	Yes	Yes	Yes	No	No	Two café-au-lait spots, autoimmune thyroiditis		4	Full PHP1B—broad	94	7	27	3	90^**	10^**	8^**	34^*	13^**
2^*	M	Yes	Yes	Yes	Yes	No	No			3	Full PHP1B—broad	80	7	8	2	89^**	10^**	8^**	6^**	12^**
3	M	Yes		Yes	Yes	No	No	Von Willebrand disease		5	Full PHP1B—broad	88	4	6	0	88^**	10^**	8^**	7^**	13^**
4^*	M	Yes	No	Yes	Yes	No	No			1	Full PHP1B—broad	92		8	7	89^**	10^**	8^**	7^**	13^**
5^*	M	Yes	No	Yes	Yes	No	No			3	Full PHP1B—broad	82	7	8	2	89^**	9^**	8^**	7^**	12^**
6	F	Yes	No	Yes	Yes	No	No			1	Full PHP1B—broad	92		10	9	89^**	9^**	7^**	5^**	12^**
7	M	Yes	No	Yes	Yes	No	No	Bilateral cryptorchidism, osteopenia of hands, behavior problems		4	Full PHP1B—broad	95	5	4	3	89^**	9^**	8^**	5^**	12^**
8^*	F	Yes		Yes	No	No	Yes			5	Full PHP1B—broad	90	3	4	0	89^**	10^**	8^**	6^**	12^**
9	F	Yes	Yes	Yes	No		No	Enchondromatosis		5	Partial PHP1B—broad	83	23	34	33	63	27	23	24^*	35
10	F	Yes	No	Yes	Yes	No	Yes	Exostosis		4	Partial PHP1B—broad	84	20	24	13	75^*	22^*	16^**	33^*	31
11	F	Yes								5	Partial PHP1B—broad	80	10	27	14	78^*	23^*	19^*	34^*	28
12^*	M	Yes	Yes	Yes	No	No	No	Severe hypertension with organ damage, hypercalciuria		3	Full PHP1B—broad	77	8	8	3	75^*	12^**	8^**	7^**	17^**
13^*	F	Yes	Yes	Yes	Yes	No	Yes			3	Partial PHP1A—broad	76	8	7	5	73^*	15^**	9^**	5^**	21^*
14^*	M	Yes	Yes	Yes	No	No	No			3	Partial PHP1B—broad	80	10	19	29	76^*	19^**	13^**	30^*	21^*
15	F	Yes	Yes	Yes	Yes	Yes	No	Langerhans cell histiocytosis, neonatal hydrocephaly, sessile exostosis		4	Partial PHP1A—broad	86	18	18	7	81^**	18^**	15^**	32^*	21^*
16	F	Yes	Yes	Yes	Yes	No	No	Fahr’s syndrome (calcifications of basal ganglia), autoimmune thyroiditis		4	Partial PHP1B—broad	91	12	30	7	85^**	17^**	16^**	43	21^*
17	F	Yes	No	Yes	No	No	No		ΔSTX16	3	PHP1B—A/B only	42	36	44	6	46	36	16^**	45	14^**
18^*	F	Yes	Yes	No	No				ΔSTX16	2	PHP1B—A/B only	-	-	-	4	50	37	14^**	47	14^**
19	M	Yes	Yes	Yes	Yes	Yes	No	Calcifications of basal ganglia	ΔSTX16	4	PHP1B—A/B only	49	42	52	3	50	41	18^**	48	15^**
20	F	Yes	No	Yes	Yes	No	Yes		ΔSTX16	1	PHP1B—A/B only	39	-	36	10	50	40	16^**	50	15^**
21	M	Yes	Yes	No	Yes				ΔSTX16	2	PHP1B—A/B only	-	-	-	4	52	41	16^**	51	13^**
22	M	Yes	No	Yes	No	No	No		ΔSTX16	1	PHP1B—A/B only	29	-	38	14	53	42	14^**	51	14^**
23^*	F	Yes	No	Yes	Yes	No	No			3	Partial PHP1B—broad	54	26	30	7	55	36	26	40	41
24	M	Yes	No	Yes	Yes	No	No	Severe osteopenia without ossifications		5	Partial PHP1B—broad	70	35	46	44	57	39	34	41	43
																50 ± 7	46 ± 7	39 ± 7	50 ± 4	51 ± 9

From left to right: (1) clinical characteristics; (2) mean methylation values of GNAS studies that were performed previously by five different European centers as described in Fig. 1; and (3) mean methylation values of GNAS investigated with HM450k. Ordering of the patients according to unsupervised hierarchical clustering of GNAS methylation investigated with HM450k. Patients* have methylation changes at imprinted genes other than GNAS. Methylation values are presented as percentage. Mean ± SD of the 20 controls from the HM450k array is shown below the HM450k columns
BD brachydactyly, Ca calcium, F female, LAB laboratory of initial diagnostic screening, annotation as shown in Fig. 1, M male, OS heterotopic ossifications, P phosphate, PTH-res parathyroid hormone resistance, TSH-res thyroid-stimulating hormone resistance, ΔSTX16 patients with underlying STX16 deletion
^*Methylation < or >3SD outside the mean of the controls
^**Methylation < or >3SD outside the mean of the controls and <0.20 or >0.80 absolute methylation

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ISSN: 1868-7083

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