Next-generation sequencing of 500 POI patients identified novel responsible monogenic and oligogenic variants

Luo, Wei; Ke, Hanni; Tang, Shuyan; Jiao, Xue; Li, Zhuqing; Zhao, Shidou; Zhang, Feng; Guo, Ting; Qin, Yingying

doi:10.1186/s13048-023-01104-6

Journal of Ovarian Research

Table 1 Clinical characteristics and molecular findings of POI patients carrying pathogenic or likely pathogenic variants

From: Next-generation sequencing of 500 POI patients identified novel responsible monogenic and oligogenic variants

Patients ID	Phenotype^a	Menarche age	POI onset age	Hormone values^b			Gene	Accession number	Mutation		SNP ID	Classification^d	Allele frequency
Patients ID	Phenotype^a	Menarche age	POI onset age	FSH (IU/L)	LH (IU/L)	E2 (ng/L)	Gene	Accession number	Sequence variation	Protein position	SNP ID	Classification^d	GnomAD	ExAC_EAS
POI-1	SA	15	26	73.35	41.08	5.60	NOBOX	NM_001080413.3	c.2041dupG	p.A681fs		P	1.46E-05
POI-2	SA	15	15	109.90	57.32	< 5.00	FOXL2	NM_023067.4	c.1045C > G	p.R349G	rs201840174	LP	3.14E-04	2.40E-03
POI-3	SA	12	31	39.91	36.25	80.60	FOXL2	NM_023067.4	c.1045C > G	p.R349G	rs201840174	LP	3.14E-04	2.40E-03
POI-4	SA	13	17	101.80	40.84	< 11.80	BMPR2	NM_001204.7	c.1042G > A	p.V348I	rs201067849	LP	5.23E-04	6.40E-03
POI-5 ^#	PA	19	19	43.56	40.01	16.40	SMC1B	NM_148674.5	c.863A > G	p.E288G	rs781614640	LP	1.30E-05	2.00E-04
							FSHR	NM_000145.4	c.884C > T	p.S295F		LP
							FSHR	NM_000145.4	c.374 T > G	p.L125R		LP
POI-6	SA	15	28	69.89	32.20	73.21	MSH4	NM_002440.4	c.2220_2223del	p.M740fs		P	4.77E-06
POI-6	SA	15		69.89	32.20	73.21	MSH4	NM_002440.4	c.2728C > T	p.R910X	rs771456188	P	8.71E-06
POI-7	SA	11	20	74.41	30.80	2.12	FIGLA	NM_001004311.3	c.11C > A	p.A4E	rs71647803	LP
POI-8	SA	12	25	81.03	55.21	11.40	FOXL2	NM_023067.4	c.789C > A	p.S263R		LP
POI-9 ^#	SA	15	20	46.08	32.33	80.67	MSH5	NM_002441.4	c.826C > T	p.R276C	rs144471639	LP	4.07E-06
POI-9 ^#	SA	15		46.08	32.33	80.67	MSH4	NM_002440.4	c.1063A > G	p.I355V	rs116141807	LP	1.71E-04	2.90E-03
POI-10 ^#	SA	14	24	62.40	11.80	< 20.00	SPIDR	NM_001282916.1	c.566 + 1G > T	-	rs781987881	P	4.15E-06	1.00E-04
							SPIDR	NM_001282916.1	c.2054delC	p.S685fs	rs754810654	P	3.25E-05	6.00E-04
							GDF9	NM_005260.5	c.1283G > C	p.S428T	rs118080183	LP	2.34E-04	4.00E-03
POI-11	SA	15	ND	54.61	66.21	13.50	MSH4	NM_002440.4	c.2220_2223del	p.M740fs		P	4.77E-06
POI-11	SA	15		54.61	66.21	13.50	MSH4	NM_002440.4	c.2374A > G	p.T792A	rs557796016	LP		5.00E-04
POI-12	SA	13	28	40.59	27.66	35.71	FSHR	NM_000145.4	c.374 T > G	p.L125R		LP
POI-13	SA	13	23	18.11	6.22	11.43	BMPR2	NM_001204.7	c.1585C > T	p.R529C	rs140049204	LP	4.87E-05
POI-14	SA	14	16	71.56	45.34	42.70	BMPR2	NM_001204.7	c.2618G > A	p.R873Q	rs201781338	LP	9.74E-05	1.50E-03
POI-15	PA	16	23	59.93	18.96	7.20	FIGLA	NM_001004311.3	c.319C > T	p.L107F		LP	4.17E-06
POI-16	SA	13	26	65.71	42.52	18.80	FIGLA	NM_001004311.3	c.11C > A	p.A4E	rs71647803	LP
POI-17	PA	18	18	131.1	58.19	< 5.00	AMHR2	NM_020547.3	c.775C > T	p.R259X	rs746905091	P	4.06E-06	1.00E-04
POI-18	SA	12	18	77.54	36.67	< 5.00	AMHR2	NM_020547.3	c.515G > A	p.R172Q		LP	4.10E-06
POI-19	SA	14	14	24.89	8.18	51.20	FOXL2	NM_023067.4	c.1045C > G	p.R349G	rs201840174	LP	3.14E-04	2.40E-03
POI-20	SA	13	20	77.32	38.22	< 5.00	GDF9	NM_005260.5	c.946C > T	p.R316C	rs751894227	LP	8.12E-06
POI-21	SA	12	27	92.73	56.51	52.20	POLR2C	NM_032940.3	c.544G > T	p.V182L		LP
POI-22	PA	16	20	ND	ND	ND	HFM1	NM_001017975.6	c.1978-2A > C	-		P
							HFM1	NM_001017975.6	c.1880 T > C	p.V627A		LP	4.10E-06
POI-23 ^#	SA	15	17	107.78	29.87	24.08	BMP15	NM_005448.2	c.208A > C	p.M70L	rs782325962	LP	7.05E-06	5.00E-04
POI-23 ^#	SA	15		107.78	29.87	24.08	FOXL2	NM_023067.4	c.1045C > G	p.R349G	rs201840174	LP	3.14E-04	2.40E-03
POI-24	SA	14	30	33.59	17.86	103.77	NR5A1	NM_004959.5	c.250C > T	p.R84C		LP
POI-25 ^#	PA	17	17	36.98	10.56	5.30	MSH4	NM_002440.4	c.1855A > G	p.M619V		LP	0.00E + 00
POI-25 ^#	PA	17		36.98	10.56	5.30	FOXL2	NM_023067.4	c.1045C > G	p.R349G	rs201840174	LP	3.14E-04	2.40E-03
POI-26	SA	14	30	76.15	57.85	12.90	NOBOX	NM_001080413.3	c.1298G > T	p.G433V		LP	4.31E-06
POI-27	SA	15	31	134.50	64.46	32.43	SOHLH1	NM_001101677.2	c.244C > G	p.Q82E		LP
POI-28	SA	14	30	90.65	59.31	< 5.00	BMPR2	NM_001204.7	c.1481C > T	p.A494V	rs2229778	LP	6.13E-05	6.00E-04
POI-29	SA	12	32	71.96	48.51	21.53	NR5A1	NM_004959.5	c.565C > A	p.P189T		LP
POI-30	SA	13	23	113.67	31.46	5.79	PGRMC1	NM_006667.5	c.418G > C	p.D140H		LP
POI-31	SA	12	27	ND	ND	ND	ERCC6-PGBD3	NM_001277059.2	c.814G > A	p.E272K	rs768589918	LP	8.12E-06
POI-32	SA	12	26	ND	ND	ND	PGRMC1	NM_006667.5	c.533C > T	p.T178I	rs201254642	LP	2.55E-04	3.50E-03
POI-33	SA	13	24	ND	ND	ND	PGRMC1	NM_006667.5	c.272 T > C	p.M91T	rs776947628	LP	3.86E-05	2.00E-04
POI-34	SA	14	35	ND	ND	ND	FOXL2	NM_023067.4	c.1045C > G	p.R349G	rs201840174	LP	3.14E-04	2.40E-03
POI-35	SA	15	ND	ND	ND	ND	FSHR	NM_000145.4	c.1396G > A	p.E466K		LP
POI-36	SA	14	ND	ND	ND	ND	PGRMC1	NM_006667.5	c.533C > T	p.T178I	rs201254642	LP	2.55E-04	3.50E-03
POI-37	SA	13	24	125.53	57.32	< 5.00	FOXL2	NM_023067.4	c.1045C > G	p.R349G	rs201840174	LP	3.14E-04	2.40E-03
POI-38 ^#	PA	16	24	59.18	28.09	40.32	NR5A1	NM_004959.5	c.559delG	p.A187fs		P
POI-38 ^#	PA	16		59.18	28.09	40.32	FOXL2	NM_023067.4	c.1045C > G	p.R349G	rs201840174	LP	3.14E-04	2.40E-03
POI-39	SA	ND	ND	49.22	21.95	17.64	FOXL2	NM_023067.4	c.553G > C	p.G185R		LP
POI-40	SA	13	37	58.16	18.42	20.24	FSHR	NM_000145.4	c.349C > T	p.Q117X		P
POI-41	SA	14	14	60.82	9.75	< 20.00	NR5A1	NM_004959.5	c.909C > A	p.S303R		LP
POI-42	SA	14	20	121.53	110.57	20.53	BMPR2	NM_001204.7	c.1042G > A	p.V348I	rs201067849	LP	5.23E-04	6.40E-03
POI-43	SA	14	31	60.13	37.06	5.20	NOBOX	NM_001080413.3	c.1131delT	p.P377fs		P
POI-44	PA	16	30	36.21	40.54	88.54	PGRMC1	NM_006667.5	c.533C > T	p.T178I	rs201254642	LP	2.55E-04	3.50E-03
POI-45	SA	13	25	60.49	39.16	48.68	ERCC6-PGBD3	NM_001277059.2	c.3100G > T	p.E1034X	rs866374385	P	3.23E-05
POI-46	SA	10	26	77.32	44.05	14.32	PGRMC1	NM_006667.5	c.533C > T	p.T178I	rs201254642	LP	2.55E-04	3.50E-03
POI-47	PA	17	20	76.23	22.59	39.64	FOXL2	NM_023067.4	c.871dupC	p.H291fs		P
POI-48	SA	ND	ND	ND	ND	ND	POLR2C	NM_032940.3	c.77C > G	p.T26S	rs770336099	LP	8.28E-05	1.30E-03
POI-49	SA	13	35	91.58	37.34	10.35	MSH5	NM_002441.4	c.1051C > G	p.R351G	rs28399976	P
POI-50	PA	16	16	46.34	9.54	< 5.00	NOBOX	NM_001080413.3	c.1199C > T	p.P400L	rs568492478	LP	5.92E-05	2.70E-03
POI-51	PA	17	17	ND	ND	ND	NR5A1	NM_004959.5	c.937C > T	p.R313C		LP
POI-52	SA	14	25	59.32	17.78	12.32	NOBOX	NM_001080413.3	c.1674_1677del	p.L558fs		P
							NOBOX	NM_001080413.3	c.1064G > A	p.R355H	rs201947677	P	1.59E-04
POI-53	PA	19	19	ND	ND	ND	AMHR2	NM_020547.3	c.55C > G	p.P19A	rs756301317	LP	5.28E-05	1.50E-03
POI-54 ^#	PA	17	17	83.46	39.56	9.20	FOXL2	NM_023067.4	c.1045C > G	p.R349G	rs201840174	LP	3.14E-04	2.40E-03
POI-54 ^#	PA	17		83.46	39.56	9.20	BMPR2	NM_001204.7	c.1042G > A	p.V348I	rs201067849	LP	5.23E-04	6.40E-03
POI-55	SA	13	19	79.35	44.95	3.99	AMH	NM_000479.5	c.1393C > T	p.R465C		LP
POI-56	PA	16	16	75.53	24.05	5.50	AMHR2	NM_020547.3	c.355A > G	p.N119D		LP
POI-57	SA	12	20	91.66	41.98	14.20	PGRMC1	NM_006667.5	c.533C > T	p.T178I	rs201254642	LP	2.55E-04	3.50E-03
POI-58	SA	14	31	66.95	37.22	24.43	BMP15	NM_005448.2	c.919C > T	p.H307Y	rs782540417	LP	1.23E-05	3.00E-04
POI-59	SA	15	37	55.49	40.04	59.33	FOXL2	NM_023067.4	c.1045C > G	p.R349G	rs201840174	LP	3.14E-04	2.40E-03
POI-60	SA	13	ND	40.65	20.09	< 10.00	FIGLA	NM_001004311	c.326G > A	p.G109D		LP
POI-61	SA	15	ND	96.01	60.93	71.34	FSHR	NM_001004311.3	c.1763 T > C	p.I588T		LP
POI-61	SA	15		96.01	60.93	71.34	FSHR	NM_000145.4	c.683C > T	p.T228I	rs776897994	LP	4.08E-06	0.00E + 00
POI-62	PA	18	18	51.89	33.83	26.55	FSHR	NM_000145.4	c.1679_1685del	p.N560fs		P
POI-63	PA	19	26	117.83	41.01	7.83	MSH4	NM_000145.4	c.2220_2223del	p.M740fs		P	4.77E-06
POI-63	PA	19		117.83	41.01	7.83	MSH4	NM_002440.4	c.2374A > G	p.T792A	rs557796016	LP		5.00E-04
POI-64	SA	13	22	104.93	33.36	59.22	FIGLA	NM_002440.4	c.11C > A	p.A4E	rs71647803	LP
POI-65	SA	14	25	107.22	57.03	18.35	FOXL2	NM_001004311.3	c.1045C > G	p.R349G	rs201840174	LP	3.14E-04	2.40E-03
POI-66	SA	15	28	65.96	22.86	35.15	NR5A1	NM_023067.4	c.938G > A	p.R313H	rs1554721235	P
POI-67	PA	16	16	54.97	16.16	19.32	FOXL2	NM_023067.4	c.1045C > G	p.R349G	rs201840174	LP	3.14E-04	2.40E-03
POI-68	SA	15	18	124.66	47.81	16.21	BMPR2	NM_001204.7	c.960_961insCGA	p.P320fs		P
POI-69 ^#	PA	16	26	91.68	58.68	< 5.00	PGRMC1	NM_006667.5	c.533C > T	p.T178I	rs201254642	LP	2.55E-04	3.50E-03
POI-69 ^#	PA	16		91.68	58.68	< 5.00	FOXL2	NM_023067.4	c.1045C > G	p.R349G	rs201840174	LP	3.14E-04	2.40E-03
POI-70	SA	15	21	98.26	36.23	23.13	NOBOX	NM_001080413.3	c.1199C > T	p.P400L	rs568492478	LP	5.92E-05	2.70E-03
POI-71	SA	15	27	141.95	57.14	< 5.00	PGRMC1	NM_006667.5	c.533C > T	p.T178I	rs201254642	LP	2.55E-04	3.50E-03
POI-72 ^#	SA	15	ND	41.11	24.45	< 5.00	MSH5	NM_002441.4	c.1051C > G	p.R351G	rs28399976	P
							MSH4	NM_002440.4	c.1025C > T	p.T342I	rs777079867	LP	4.72E-06	2.00E-04
							MSH4	NM_002440.4	c.2220_2223del	p.M740fs		P	4.77E-06
							PGRMC1	NM_006667.5	c.533C > T	p.T178I	rs201254642	LP	2.55E-04	3.50E-03

^aPA Primary amenorrhea, SA Secondary amenorrhea
^b The clinical features of some patients are not determined (ND)
^c The splicing region mutations are marked as “-”; the frameshift mutations are marked as “fs”
^d The classification of variation: pathogenic as “P”; likely pathogenic as “LP”
^# The patients with digenic or multigenic pathogenic variants

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