A compound heterozygous mutation in ZP1 and two novel heterozygous cis mutations in ZP3 causes infertility in women presenting with empty follicle syndrome

Wang, Xiaoxiao; Liu, Yingxue; Yuan, Guanghui; Yang, Jingjie; Liu, Xiaowen; Chen, Shuyuan; Dou, Huaiqian; Lu, Panpan; Han, Linfang; Li, Duan; Hao, Cuifang

doi:10.1186/s13048-025-01674-7

Table 1 Summarize of the ZP gene variants associated with EFS reported in the literature to date

From: A compound heterozygous mutation in ZP1 and two novel heterozygous cis mutations in ZP3 causes infertility in women presenting with empty follicle syndrome

Gene	DNA variation	Protein variation	Domain	Heredity	Genotype	Type of variant	Phenotype	Treatment outcome	Ref.
ZP1	c.2T > A	p.Met1?	SP	AR	Comp het	Start-loss	No oocytes	Not pregnant	[8, 9] Our case report
	c.123 C > A	p.Tyr41*	ZP-N1	AR	Comp het	Nonsense	No oocytes, degenerated oocyte	Not pregnant	[10]
	c.161_165del	p.Gly57Aspfs*9	ZP-N1	AR	Comp het	Frameshift	No oocytes	Not pregnant	[11]
	c.181 C > T	p.Arg61Cys	ZP-N1	AR	Comp het	Missense	No oocytes, degenerated oocyte	Not pregnant	[12]
	c.199G > T	p.Glu67*	ZP-N1	AR	Comp het, Hom	Nonsense	No oocytes degenerated oocyte, oocyte without ZP	Not pregnant	[9, 13, 14]
	c.238T > G	p.Cys80Gly	ZP-N1	AR	Comp het	Missense	No oocytes, degenerated oocyte	Not pregnant	[9]
	c.239G > A	p.Cys80Tyr	ZP-N1	AR	Comp het	Missense	No oocytes	The patient was infertile but his sister gave birth to a son of her own.	[15]
	c.241T > C	p. Tyr81His	ZP-N1	AR	Comp het	Missense	No oocytes	The patient was infertile but his sister gave birth to a son of her own.	[15]
	c.247T > C	p.Trp83Arg	ZP-N1	AR	Comp het	Missense	No oocytes, degenerated oocyte	Not pregnant	[9]
	c.325 C > T	p.Arg109Cys	ZP-N1	AR	Comp het	Missense	No oocytes	Not pregnant	[13]
	c.507delC	p.His170Ilefs*52	/	AR	Het, Hom	Frameshift	No oocytes	Not pregnant	[15, 16]
	c.508delC	p.His170Ilefs*52	/	AR	Comp het	Frameshift	No oocytes, degenerated oocyte	Not pregnant	[9, 10]
	c.706T > C	p.Cys236Arg	TD	AR	Hom	Missense	No oocytes, oocyte without ZP	Successful delivery of a son by diagnostic intracytoplasmic sperm injection	[17]
	c.769 C > T	p.Gln257*	TD	AR	Comp het, Hom	Nonsense	No oocytes, degenerated oocyte	Not pregnant	[13, 18]
	c.780 C > A	p.Cys260*	TD	AR	Comp het	Nonsense	No oocytes, degenerated oocyte	Not pregnant	[9]
	c.784_785delTA	p.Tyr262*	TD	AR	Comp het	Frameshift	No oocytes, degenerated oocyte	Not pregnant	[9]
	c.800_801delAG	p.Glu267Glyfs*80	TD	AR	Comp het	Frameshift	No oocytes	Not pregnant	[13]
	c.874 C > T	p.Gln292*	ZP-N	AR	Hom	Nonsense	No oocytes, degenerated oocyte	Not pregnant	[9, 19]
	c.916_919dupCACC	p. Leu307Profs*42	ZP-N	AR	Comp het	Frameshift	No oocytes, degenerated oocyte	Not pregnant	[9]
	c.1014 + 1G > A	p.?	ZP-N	AR	Hom	Splicing	No oocytes, degenerated oocyte	Not pregnant	[10]
	c.1096 C > T	p.Arg366Trp	ZP-N	AR	Hom	Missense	No oocytes, degenerated oocyte	Not pregnant	[30]
	c.1097G > A	p.Arg366Gln	ZP-N	AR	Hom	Missense	No oocytes, degenerated oocyte, oocytes with abnormal morphology	Not pregnant	[20]
	c.1112 + 1G > T	p.Val339Aspfs*11	ZP-N	AR	Comp het	Splicing	No oocytes	Not pregnant	[8]
	c.1126_1127delTG	p.Val377Leufs*5	ZP-N	AR	Comp het	Frameshift	No oocytes, degenerated oocyte, oocyte without ZP	Not pregnant	[9]
	c.1127G > A	p.Cys376Tyr	ZP-N	AR	Comp het	Missense	No oocytes	Not pregnant	[13]
	c.1129_1130del	p.Val377Leufs*5	ZP-N	AR	Hom	Frameshift	No oocytes, degenerated oocyte	Not pregnant	[10]
	c.1166_1173del	p.Ile390Thrfs*16	/	AR	Comp het	Frameshift	No oocytes	Not pregnant	[11]
	c.1169_1176delTTTTCCCA	p.Ile390Thrfs*16	/	AR	Comp het, Hom	Frameshift	No oocytes, degenerated oocyte, oocyte without ZP	Not pregnant	[9, 12, 13, 21]
	c.1260 C > G	p.Tyr420*	ZP-C	AR	Comp het, Hom	Nonsense	No oocytes, degenerated oocyte	Not pregnant	[22]
	c.1297 C > T	p.Arg433*	ZP-C	AR	Comp het	Nonsense	No oocytes, degenerated oocyte	Not pregnant	[9]
	c.1319T > C	p.Val440Ala	ZP-C	AR	Comp het	Missense	No oocytes, degenerated oocyte, oocyte without ZP	Not pregnant	[9]
	c.1413G > A	p.Trp471*	ZP-C	AR	Comp het	Nonsense	No oocytes, degenerated oocyte	Not pregnant	[9]
	c.1429G > T	p.Gly477*	ZP-C	AR	Comp het	Nonsense	No oocytes, degenerated oocyte	Not pregnant	[9] Our case report
	c.1430 + 1G > T	p.Cys478*	ZP-C	AR	Hom	Splicing	No oocytes, oocyte without ZP	Not pregnant	[13]
	c.1495 C > T	p.Gln499*	ZP-C	AR	Hom	Nonsense	No oocytes, degenerated oocyte	Not pregnant	[9]
	c.1510 C > T	p.Arg504*	ZP-C	AR	Hom	Nonsense	No oocytes, degenerated oocyte	Not pregnant	[10]
	c.1511G > A	p.Arg504Gln	ZP-C	AR	Hom	Missense	No oocytes, degenerated oocyte	Not pregnant	[9]
	c.1573–2 A > G	p.?	ZP-C	AR	Comp het	Splicing	No oocytes, degenerated oocyte	Not pregnant	[10]
	c.1602_1603insAGTCT	p.His535Serfs*38	ZP-C	AR	Comp het	Frameshift	No oocytes, degenerated oocyte	Not pregnant	[9]
	c.1663 C > T	p.Arg555*	CFCS	AR	Comp het	Nonsense	No oocytes, degenerated oocyte	Not pregnant	[10]
	c.1708G > A	p.Val570Met	/	AR	Hom	Missense	No oocytes, oocyte without ZP	Not pregnant	[16]
	c.1775–3 C > T	p.?	/	AR	Comp het	Splicing	No oocytes, degenerated oocyte	Not pregnant	[9]
	c.1815_1825delGGTCCTTTTGC	p.Val606Alafs*42	TMD	AR	Comp het	Frameshift	No oocytes	Not pregnant	[13]
ZP2	c.1695–2 A > G	p.?	ZP-C	AD	Comp het	Splicing	No oocytes, oocyte with abnormal ZP, oocyte without ZP, degenerated oocyte	Not pregnant	[23]
	c.1856T > A	p.Ile619Asn	ZP-C	AD	Het	Missense	No oocytes, degenerated oocyte	Not pregnant	[9]
	c.1924 C > T	p.Arg642*	CFCS	AD	Comp het	Nonsense	No oocytes, oocyte with abnormal ZP, oocyte without ZP, degenerated oocyte	Not pregnant	[23]
	c.1925G > A	p.Arg642Gln	CFCS	AD	Het	Missense	No oocytes, degenerated oocyte	Not pregnant	[9, 24]
ZP3	c.176T > A	p.Leu59His	ZP-N	AD	Hom	Missense	No oocytes	Not pregnant	[25]
	c.400G > A	p.Ala134Thr	ZP-N	AD	Het	Missense	No oocytes, oocyte without ZP, degenerated oocyte	Not pregnant	[9, 26, 33]
	c.502_504delGAG	p.Glu168del	ZP-C	AD	Het	In-frame	No oocytes	Patient and her sister conceived through egg donation	[27]
	c.518 C > G	p.Ser173Cys	ZP-C	AD	Het	Missense	No oocytes, oocyte without ZP, degenerated oocyte	Not pregnant	[28]
	c.565_579del	p.Thr189_Gly193del	ZP-C	AD	Het	In-frame	No oocytes, oocyte without ZP,	Not pregnant	[29]
	c.724G > T	p.Asp242Tyr	ZP-C	AD	Het	Missense	No oocytes	Not pregnant	Our case report
	c.763 C > G	p.Arg255Gly	ZP-C	AD	Het	Missense	No oocytes, oocyte without ZP	Not pregnant	[16]
	c.815 A > G	p.Asn272Ser	ZP-C	AD	Het	Missense	No oocytes	Not pregnant	Our case report

AR: autosomal recessive; AD: autosomal dominant; SP: signal peptide; ZP-N: ZP-N domain; ZP-N1: N-terminal isolated ZP-N; TD: trefoil domain; ZP-C: ZP-C domain; CFCS: consensus furin cleavage site; TMD: transmembrane-like domain; Comp het: compound heterozygous; Het: heterozygous; Hom: Homozygous; ZP: zona pellucida; *: stop codon

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ISSN: 1757-2215

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