Table 2 Open in new tab Main functions...

Table 2

Main functions of defined genetic variants and knockout phenotypes of the genes playing roles in spindle assembly, chromosome segregation, meiotic recombination, maternal mRNA clearance, and other cellular processes in mammalian oocytes and early embryos.

Gene	Main functions	Variant (type, zygosity)	Embryonic arrest stage	Reference	Knockout phenotype (reference)
*TUBB8*	Microtubule formation Spindle assembly	c.A628G, c.C713T, or c.A1043G (Missense mutations, Het)	Early embryos	Feng et al. (2016)	NA
		c.209C>T (Missense, Hom)	Four-cell	Chen et al. (2017a )
		c.990G>A (Missense, Het)	Early embryos
		c.1057G>A (Missense, Het)
		c.613G>A (Missense, Het)
		c.580G>A and c.1245G>A (Missense, Com Het)
		Deletion (Hom)	One-cell
		c.1041C>A (Missense, Hom)	One-cell	Yuan et al. (2018)
		c.10A>C, c.1000C>G, c.1171C>T, c.181C>A, c.1057G>A, c.1249G>T, c.763G>A, c.883G>C, or c.600T>G (Missense mutations, Het) c.721C>T (Missense, Hom)	Early embryos	Chen et al. (2019)
		c.1041C>A (Missense, Het)	Early cleavage	Jia et al. (2020)
		c.1172G>A, c.1139G>A, c.236G>A, c.743C>T, c.940G>T, c.728C>G, c.497C>T, c.736C>G, c.925C>T (Missense mutations, Het) c.1076G>A (Missense, Hom) c.82C>T and c.398T>C (Missense, Com Het) c.400C>T (Nonsense, Het)	Early embryos	Zhao et al. (2020a )
		c.G6T, c.C43A, c.C124G, c.G262C, c.G421C, c.C544T, c.G586Ac.A604C, c.A694T, c.A898T, c.G904A, c.G959A, c.C1055T, c.C1171T, c.G1172T, c.G1172A, c.C1232A (Missense mutations, Het)	Early embryos	Zheng et al. (2021b)
		c.161C>T (Missense, Hom)	Early embryos	Cao et al. (2021)
		c.959G>A (Missense, Het)	Early embryos	Cao et al. (2021)
		c.1045G>A, c.10A>C, c.938C>T, c.136C>T, or c.893A>G (Missense mutations, Het)	Early embryos	Yang et al. (2021b)
		c.524T>C (Missense, Het)	One-cell	Sha et al. (2021)
		c.10_12delinsCTT (Missense, Het)	One-, two- to four-cell
		c.1045G>A (Missense, Het)	Two- to five-cell and seven-cell
		c.208C>A (Missense, Het)	One-cell, two-cell, or three-cell	Lu et al. (2021)
		c.173G>A (Missense, Het)	Eight-cell or cleavage
		c.326T>G (Missense, Het)	Cleavage
		c.907T>C (Missense, Het)
		c.916C>T (Missense, Het)

*CENPH*	Kinetochore binding	c.635T>C (Missense, Hom)	Cleavage	Maddirevula et al. (2020)	NA

*CDC20*	Spindle assembly Coactivator of APC/C Suppressing apoptosis	c.965G>A and c.1176_1179del TCTG (Missense and frameshift deletion, Com Het)	Early embryos	Zhao et al. (2020b)	Infertility or subfertility Failure in embryogenesis Embryonic arrest at two-cell stage Increased cyclin B1 levels Aneuploid oocytes and embryos (Li et al., 2007; Manchado et al., 2010)
		c.683A>G (Missense, Hom)
		c.544C>T and c.965G>A (Nonsense and missense, Com Het)
		c.964C>T and c.965G>A (Stop-gain and missense, Com Het)	Early embryos	Zhao et al. (2021)
		c.330 + 1G>A and c.1155G>C (Splicing and missense, Com Het)	Early embryos	Zhao et al. (2021)
		c.784C>T and c.631G>A (Nonsense and missense, Com Het)	Four-cell, five-cell	Huang et al. (2021)
*FBXO43*	Cell cycle regulation Inhibition of APC/C activity Early embryo development	c.1490_1497dup (Duplication, Hom)	Two-/three- to five-cell	Wang et al. (2021)	Sterility in both sexes Abnormal oocyte morphology Parthenogenetic activation (Gopinathan et al., 2017)
		c.1747C>T (Nonsense, Hom)	Two-cell
		c.154delG (Deletion, Hom)	Three-cell

*MEI1*	Chromosome synapsis Formation of DSBs Initiation of meiotic recombination	c.1792 + 1G>T (Splicing, Hom)	Early embryos	Dong et al. (2021)	Infertility Various ovarian defects Failure in synapsis formation Reduced follicle numbers Aberrant chromosomal arrangement MI-stage arrest (Libby et al., 2002)
		c.1585T>A (Missense, Hom)
		c.186G>C and c.734-2A>C (Missense and splicing, Com Het)
		c.745C>T (Nonsense, Hom)

*REC114*	DNA recombination DSB formation Chromosome synapsis	c.397T>G (Missense, Hom)	Two- to six-cell	Wang et al. (2020)	Sterility in both sexes Impaired meiotic DSB formation Reduced DSB and DMC1 foci levels (Kumar et al., 2018)
*REC114*	DNA recombination DSB formation Chromosome synapsis	c.546 + 5G>A (Splicing, Hom)	Early embryos	Wang et al. (2020)

*TRIP13*	DSB formation Mitotic checkpoint Meiotic recombination DNA repair process Spindle assembly	c.592A>G and c.739G>A (Missense mutations, Com Het)	One-cell or before eight-cell	Zhang et al. (2020)	Infertility in both sexes Oocyte loss Meiotic disruption Decreased follicle numbers (Li et al., 2007)
		c.1141G>A (Missense, Hom)	One-cell, three-cell	Hu et al. (2022)
		c.77A>G and c.1258A>G (Missense mutations, Com Het)	One-cell	Hu et al. (2022)

*BTG4*	Maternal mRNA clearance Inhibiting spontaneous oocyte activation Regulation of mRNA deadenylation Maternal to zygotic transition	c.73C>T (Nonsense, Hom)	One-cell	Zheng et al. (2020b)	Female infertility Embryonic arrest at one- or two-cell stage Decreased follicle numbers Impaired homologous synapsis Defects in DSB formation Impaired EGA Disrupted maternal mRNA clearance and translation (Yu et al., 2016; Brachova et al., 2021)
		c.1A>G (Start-lost, Hom)
		c.475_478del (Frameshift, Hom)
		c.166G>A (Missense, Hom)

*ZFP36L2*	Maternal mRNA clearance	c.922_930del (Non-frameshift deletion, Hom)	Early embryos	Zheng et al. (2022)	Defects in both oocyte maturation and fertility Blocked ovulation Two-cell arrest (Ramos, 2012; Ball et al., 2014 Chousal et al., 2018)
*ZFP36L2*	Maternal mRNA clearance	(c.922_930del and c.922T>G) (Non-frameshift deletion and Missense, Com Het)	Early embryos	Zheng et al. (2022)

*PATL2*	Translational control	c.953T>C and c.839G>A (Missense mutations, Com Het)	Early embryos	Chen et al. (2017b)	Female infertility Disturbed oocyte maturation Decreased translational repression Increased MI-arrested oocytes Reduced litter size and oocyte quality Morphological and developmental defects Dysregulated gene expression (Christou-Kent et al., 2018)
		c.649T>A and c.566T>G (Missense mutations, Com Het)
		c.223-14_223-2del and c.1224þ2T>C (Splicing mutations, Com Het)
		c.877G>T and c.223-14_223-2del (Missense and splicing, Com Het)	Early embryos	Wu et al. (2019)
		c.716delA and c.223-14_223-2del Frameshift deletion and splicing, Com Het)
		c.778G>A and c.223-1_223-2del (Missense and Deletion)
		c.890delC (Frameshift, Hom)	Two-cell	Huang et al. (2022)

*MOS*	Activation ERK signaling Cytoskeleton assembly mRNA clearance Mitochondrial homeostasis Up-regulation of MPF activity Maintenance of MII arrest	c.285C>A (Missense, Hom)	Two- to seven-cell	Zhang et al. (2021b)	Female sterility Failure of meiotic arrest Ovarian cysts and teratomas Parthenogenetic activation Inability of MAPK activation Spindle defect Disrupted asymmetric division
		c.416T>C and c.737G>A (Missense mutations, Com Het)	Two- to six-cell
		c.960C>A (Nonsense, Hom)	Two-, three-, or five-cell
		c.791C>G (Missense, Hom)	Two- to six-cell	Zhang et al. (2022)
		c.875C>T and c.596A>T (Missense mutations, Com Het)	Two- to eight-cell or three- to four-cell	Zhang et al. (2022)
		c.285C>A (Missense, Hom)	Early embryos	Zeng et al. (2022)
		c.467delG and c.956G>A (Frameshift and missense, Com Het)	Early embryos	Zeng et al. (2022)

*TBPL2*	Transcriptional control	c.788 + 3A>G (Splicing, Hom)	Early embryos	Yang et al. (2021a )	Female sterility Defective folliculogenesis Changed chromatin organization Disrupted transcriptional activity (Gazdag et al., 2009)

Gene	Main functions	Variant (type, zygosity)	Embryonic arrest stage	Reference	Knockout phenotype (reference)
*TUBB8*	Microtubule formation Spindle assembly	c.A628G, c.C713T, or c.A1043G (Missense mutations, Het)	Early embryos	Feng et al. (2016)	NA
		c.209C>T (Missense, Hom)	Four-cell	Chen et al. (2017a )
		c.990G>A (Missense, Het)	Early embryos
		c.1057G>A (Missense, Het)
		c.613G>A (Missense, Het)
		c.580G>A and c.1245G>A (Missense, Com Het)
		Deletion (Hom)	One-cell
		c.1041C>A (Missense, Hom)	One-cell	Yuan et al. (2018)
		c.10A>C, c.1000C>G, c.1171C>T, c.181C>A, c.1057G>A, c.1249G>T, c.763G>A, c.883G>C, or c.600T>G (Missense mutations, Het) c.721C>T (Missense, Hom)	Early embryos	Chen et al. (2019)
		c.1041C>A (Missense, Het)	Early cleavage	Jia et al. (2020)
		c.1172G>A, c.1139G>A, c.236G>A, c.743C>T, c.940G>T, c.728C>G, c.497C>T, c.736C>G, c.925C>T (Missense mutations, Het) c.1076G>A (Missense, Hom) c.82C>T and c.398T>C (Missense, Com Het) c.400C>T (Nonsense, Het)	Early embryos	Zhao et al. (2020a )
		c.G6T, c.C43A, c.C124G, c.G262C, c.G421C, c.C544T, c.G586Ac.A604C, c.A694T, c.A898T, c.G904A, c.G959A, c.C1055T, c.C1171T, c.G1172T, c.G1172A, c.C1232A (Missense mutations, Het)	Early embryos	Zheng et al. (2021b)
		c.161C>T (Missense, Hom)	Early embryos	Cao et al. (2021)
		c.959G>A (Missense, Het)	Early embryos	Cao et al. (2021)
		c.1045G>A, c.10A>C, c.938C>T, c.136C>T, or c.893A>G (Missense mutations, Het)	Early embryos	Yang et al. (2021b)
		c.524T>C (Missense, Het)	One-cell	Sha et al. (2021)
		c.10_12delinsCTT (Missense, Het)	One-, two- to four-cell
		c.1045G>A (Missense, Het)	Two- to five-cell and seven-cell
		c.208C>A (Missense, Het)	One-cell, two-cell, or three-cell	Lu et al. (2021)
		c.173G>A (Missense, Het)	Eight-cell or cleavage
		c.326T>G (Missense, Het)	Cleavage
		c.907T>C (Missense, Het)
		c.916C>T (Missense, Het)

*CENPH*	Kinetochore binding	c.635T>C (Missense, Hom)	Cleavage	Maddirevula et al. (2020)	NA

*CDC20*	Spindle assembly Coactivator of APC/C Suppressing apoptosis	c.965G>A and c.1176_1179del TCTG (Missense and frameshift deletion, Com Het)	Early embryos	Zhao et al. (2020b)	Infertility or subfertility Failure in embryogenesis Embryonic arrest at two-cell stage Increased cyclin B1 levels Aneuploid oocytes and embryos (Li et al., 2007; Manchado et al., 2010)
		c.683A>G (Missense, Hom)
		c.544C>T and c.965G>A (Nonsense and missense, Com Het)
		c.964C>T and c.965G>A (Stop-gain and missense, Com Het)	Early embryos	Zhao et al. (2021)
		c.330 + 1G>A and c.1155G>C (Splicing and missense, Com Het)	Early embryos	Zhao et al. (2021)
		c.784C>T and c.631G>A (Nonsense and missense, Com Het)	Four-cell, five-cell	Huang et al. (2021)
*FBXO43*	Cell cycle regulation Inhibition of APC/C activity Early embryo development	c.1490_1497dup (Duplication, Hom)	Two-/three- to five-cell	Wang et al. (2021)	Sterility in both sexes Abnormal oocyte morphology Parthenogenetic activation (Gopinathan et al., 2017)
		c.1747C>T (Nonsense, Hom)	Two-cell
		c.154delG (Deletion, Hom)	Three-cell

*MEI1*	Chromosome synapsis Formation of DSBs Initiation of meiotic recombination	c.1792 + 1G>T (Splicing, Hom)	Early embryos	Dong et al. (2021)	Infertility Various ovarian defects Failure in synapsis formation Reduced follicle numbers Aberrant chromosomal arrangement MI-stage arrest (Libby et al., 2002)
		c.1585T>A (Missense, Hom)
		c.186G>C and c.734-2A>C (Missense and splicing, Com Het)
		c.745C>T (Nonsense, Hom)

*REC114*	DNA recombination DSB formation Chromosome synapsis	c.397T>G (Missense, Hom)	Two- to six-cell	Wang et al. (2020)	Sterility in both sexes Impaired meiotic DSB formation Reduced DSB and DMC1 foci levels (Kumar et al., 2018)
*REC114*	DNA recombination DSB formation Chromosome synapsis	c.546 + 5G>A (Splicing, Hom)	Early embryos	Wang et al. (2020)

*TRIP13*	DSB formation Mitotic checkpoint Meiotic recombination DNA repair process Spindle assembly	c.592A>G and c.739G>A (Missense mutations, Com Het)	One-cell or before eight-cell	Zhang et al. (2020)	Infertility in both sexes Oocyte loss Meiotic disruption Decreased follicle numbers (Li et al., 2007)
		c.1141G>A (Missense, Hom)	One-cell, three-cell	Hu et al. (2022)
		c.77A>G and c.1258A>G (Missense mutations, Com Het)	One-cell	Hu et al. (2022)

*BTG4*	Maternal mRNA clearance Inhibiting spontaneous oocyte activation Regulation of mRNA deadenylation Maternal to zygotic transition	c.73C>T (Nonsense, Hom)	One-cell	Zheng et al. (2020b)	Female infertility Embryonic arrest at one- or two-cell stage Decreased follicle numbers Impaired homologous synapsis Defects in DSB formation Impaired EGA Disrupted maternal mRNA clearance and translation (Yu et al., 2016; Brachova et al., 2021)
		c.1A>G (Start-lost, Hom)
		c.475_478del (Frameshift, Hom)
		c.166G>A (Missense, Hom)

*ZFP36L2*	Maternal mRNA clearance	c.922_930del (Non-frameshift deletion, Hom)	Early embryos	Zheng et al. (2022)	Defects in both oocyte maturation and fertility Blocked ovulation Two-cell arrest (Ramos, 2012; Ball et al., 2014 Chousal et al., 2018)
*ZFP36L2*	Maternal mRNA clearance	(c.922_930del and c.922T>G) (Non-frameshift deletion and Missense, Com Het)	Early embryos	Zheng et al. (2022)

*PATL2*	Translational control	c.953T>C and c.839G>A (Missense mutations, Com Het)	Early embryos	Chen et al. (2017b)	Female infertility Disturbed oocyte maturation Decreased translational repression Increased MI-arrested oocytes Reduced litter size and oocyte quality Morphological and developmental defects Dysregulated gene expression (Christou-Kent et al., 2018)
		c.649T>A and c.566T>G (Missense mutations, Com Het)
		c.223-14_223-2del and c.1224þ2T>C (Splicing mutations, Com Het)
		c.877G>T and c.223-14_223-2del (Missense and splicing, Com Het)	Early embryos	Wu et al. (2019)
		c.716delA and c.223-14_223-2del Frameshift deletion and splicing, Com Het)
		c.778G>A and c.223-1_223-2del (Missense and Deletion)
		c.890delC (Frameshift, Hom)	Two-cell	Huang et al. (2022)

*MOS*	Activation ERK signaling Cytoskeleton assembly mRNA clearance Mitochondrial homeostasis Up-regulation of MPF activity Maintenance of MII arrest	c.285C>A (Missense, Hom)	Two- to seven-cell	Zhang et al. (2021b)	Female sterility Failure of meiotic arrest Ovarian cysts and teratomas Parthenogenetic activation Inability of MAPK activation Spindle defect Disrupted asymmetric division
		c.416T>C and c.737G>A (Missense mutations, Com Het)	Two- to six-cell
		c.960C>A (Nonsense, Hom)	Two-, three-, or five-cell
		c.791C>G (Missense, Hom)	Two- to six-cell	Zhang et al. (2022)
		c.875C>T and c.596A>T (Missense mutations, Com Het)	Two- to eight-cell or three- to four-cell	Zhang et al. (2022)
		c.285C>A (Missense, Hom)	Early embryos	Zeng et al. (2022)
		c.467delG and c.956G>A (Frameshift and missense, Com Het)	Early embryos	Zeng et al. (2022)

*TBPL2*	Transcriptional control	c.788 + 3A>G (Splicing, Hom)	Early embryos	Yang et al. (2021a )	Female sterility Defective folliculogenesis Changed chromatin organization Disrupted transcriptional activity (Gazdag et al., 2009)

All these variants were found to cause embryonic arrests at early stages in humans. NA, not available. All other abbreviations are given in the text.

Table 2

Open in new tab

Gene	Main functions	Variant (type, zygosity)	Embryonic arrest stage	Reference	Knockout phenotype (reference)
*TUBB8*	Microtubule formation Spindle assembly	c.A628G, c.C713T, or c.A1043G (Missense mutations, Het)	Early embryos	Feng et al. (2016)	NA
		c.209C>T (Missense, Hom)	Four-cell	Chen et al. (2017a )
		c.990G>A (Missense, Het)	Early embryos
		c.1057G>A (Missense, Het)
		c.613G>A (Missense, Het)
		c.580G>A and c.1245G>A (Missense, Com Het)
		Deletion (Hom)	One-cell
		c.1041C>A (Missense, Hom)	One-cell	Yuan et al. (2018)
		c.10A>C, c.1000C>G, c.1171C>T, c.181C>A, c.1057G>A, c.1249G>T, c.763G>A, c.883G>C, or c.600T>G (Missense mutations, Het) c.721C>T (Missense, Hom)	Early embryos	Chen et al. (2019)
		c.1041C>A (Missense, Het)	Early cleavage	Jia et al. (2020)
		c.1172G>A, c.1139G>A, c.236G>A, c.743C>T, c.940G>T, c.728C>G, c.497C>T, c.736C>G, c.925C>T (Missense mutations, Het) c.1076G>A (Missense, Hom) c.82C>T and c.398T>C (Missense, Com Het) c.400C>T (Nonsense, Het)	Early embryos	Zhao et al. (2020a )
		c.G6T, c.C43A, c.C124G, c.G262C, c.G421C, c.C544T, c.G586Ac.A604C, c.A694T, c.A898T, c.G904A, c.G959A, c.C1055T, c.C1171T, c.G1172T, c.G1172A, c.C1232A (Missense mutations, Het)	Early embryos	Zheng et al. (2021b)
		c.161C>T (Missense, Hom)	Early embryos	Cao et al. (2021)
		c.959G>A (Missense, Het)	Early embryos	Cao et al. (2021)
		c.1045G>A, c.10A>C, c.938C>T, c.136C>T, or c.893A>G (Missense mutations, Het)	Early embryos	Yang et al. (2021b)
		c.524T>C (Missense, Het)	One-cell	Sha et al. (2021)
		c.10_12delinsCTT (Missense, Het)	One-, two- to four-cell
		c.1045G>A (Missense, Het)	Two- to five-cell and seven-cell
		c.208C>A (Missense, Het)	One-cell, two-cell, or three-cell	Lu et al. (2021)
		c.173G>A (Missense, Het)	Eight-cell or cleavage
		c.326T>G (Missense, Het)	Cleavage
		c.907T>C (Missense, Het)
		c.916C>T (Missense, Het)

*CENPH*	Kinetochore binding	c.635T>C (Missense, Hom)	Cleavage	Maddirevula et al. (2020)	NA

*CDC20*	Spindle assembly Coactivator of APC/C Suppressing apoptosis	c.965G>A and c.1176_1179del TCTG (Missense and frameshift deletion, Com Het)	Early embryos	Zhao et al. (2020b)	Infertility or subfertility Failure in embryogenesis Embryonic arrest at two-cell stage Increased cyclin B1 levels Aneuploid oocytes and embryos (Li et al., 2007; Manchado et al., 2010)
		c.683A>G (Missense, Hom)
		c.544C>T and c.965G>A (Nonsense and missense, Com Het)
		c.964C>T and c.965G>A (Stop-gain and missense, Com Het)	Early embryos	Zhao et al. (2021)
		c.330 + 1G>A and c.1155G>C (Splicing and missense, Com Het)	Early embryos	Zhao et al. (2021)
		c.784C>T and c.631G>A (Nonsense and missense, Com Het)	Four-cell, five-cell	Huang et al. (2021)
*FBXO43*	Cell cycle regulation Inhibition of APC/C activity Early embryo development	c.1490_1497dup (Duplication, Hom)	Two-/three- to five-cell	Wang et al. (2021)	Sterility in both sexes Abnormal oocyte morphology Parthenogenetic activation (Gopinathan et al., 2017)
		c.1747C>T (Nonsense, Hom)	Two-cell
		c.154delG (Deletion, Hom)	Three-cell

*MEI1*	Chromosome synapsis Formation of DSBs Initiation of meiotic recombination	c.1792 + 1G>T (Splicing, Hom)	Early embryos	Dong et al. (2021)	Infertility Various ovarian defects Failure in synapsis formation Reduced follicle numbers Aberrant chromosomal arrangement MI-stage arrest (Libby et al., 2002)
		c.1585T>A (Missense, Hom)
		c.186G>C and c.734-2A>C (Missense and splicing, Com Het)
		c.745C>T (Nonsense, Hom)

*REC114*	DNA recombination DSB formation Chromosome synapsis	c.397T>G (Missense, Hom)	Two- to six-cell	Wang et al. (2020)	Sterility in both sexes Impaired meiotic DSB formation Reduced DSB and DMC1 foci levels (Kumar et al., 2018)
*REC114*	DNA recombination DSB formation Chromosome synapsis	c.546 + 5G>A (Splicing, Hom)	Early embryos	Wang et al. (2020)

*TRIP13*	DSB formation Mitotic checkpoint Meiotic recombination DNA repair process Spindle assembly	c.592A>G and c.739G>A (Missense mutations, Com Het)	One-cell or before eight-cell	Zhang et al. (2020)	Infertility in both sexes Oocyte loss Meiotic disruption Decreased follicle numbers (Li et al., 2007)
		c.1141G>A (Missense, Hom)	One-cell, three-cell	Hu et al. (2022)
		c.77A>G and c.1258A>G (Missense mutations, Com Het)	One-cell	Hu et al. (2022)

*BTG4*	Maternal mRNA clearance Inhibiting spontaneous oocyte activation Regulation of mRNA deadenylation Maternal to zygotic transition	c.73C>T (Nonsense, Hom)	One-cell	Zheng et al. (2020b)	Female infertility Embryonic arrest at one- or two-cell stage Decreased follicle numbers Impaired homologous synapsis Defects in DSB formation Impaired EGA Disrupted maternal mRNA clearance and translation (Yu et al., 2016; Brachova et al., 2021)
		c.1A>G (Start-lost, Hom)
		c.475_478del (Frameshift, Hom)
		c.166G>A (Missense, Hom)

*ZFP36L2*	Maternal mRNA clearance	c.922_930del (Non-frameshift deletion, Hom)	Early embryos	Zheng et al. (2022)	Defects in both oocyte maturation and fertility Blocked ovulation Two-cell arrest (Ramos, 2012; Ball et al., 2014 Chousal et al., 2018)
*ZFP36L2*	Maternal mRNA clearance	(c.922_930del and c.922T>G) (Non-frameshift deletion and Missense, Com Het)	Early embryos	Zheng et al. (2022)

*PATL2*	Translational control	c.953T>C and c.839G>A (Missense mutations, Com Het)	Early embryos	Chen et al. (2017b)	Female infertility Disturbed oocyte maturation Decreased translational repression Increased MI-arrested oocytes Reduced litter size and oocyte quality Morphological and developmental defects Dysregulated gene expression (Christou-Kent et al., 2018)
		c.649T>A and c.566T>G (Missense mutations, Com Het)
		c.223-14_223-2del and c.1224þ2T>C (Splicing mutations, Com Het)
		c.877G>T and c.223-14_223-2del (Missense and splicing, Com Het)	Early embryos	Wu et al. (2019)
		c.716delA and c.223-14_223-2del Frameshift deletion and splicing, Com Het)
		c.778G>A and c.223-1_223-2del (Missense and Deletion)
		c.890delC (Frameshift, Hom)	Two-cell	Huang et al. (2022)

*MOS*	Activation ERK signaling Cytoskeleton assembly mRNA clearance Mitochondrial homeostasis Up-regulation of MPF activity Maintenance of MII arrest	c.285C>A (Missense, Hom)	Two- to seven-cell	Zhang et al. (2021b)	Female sterility Failure of meiotic arrest Ovarian cysts and teratomas Parthenogenetic activation Inability of MAPK activation Spindle defect Disrupted asymmetric division
		c.416T>C and c.737G>A (Missense mutations, Com Het)	Two- to six-cell
		c.960C>A (Nonsense, Hom)	Two-, three-, or five-cell
		c.791C>G (Missense, Hom)	Two- to six-cell	Zhang et al. (2022)
		c.875C>T and c.596A>T (Missense mutations, Com Het)	Two- to eight-cell or three- to four-cell	Zhang et al. (2022)
		c.285C>A (Missense, Hom)	Early embryos	Zeng et al. (2022)
		c.467delG and c.956G>A (Frameshift and missense, Com Het)	Early embryos	Zeng et al. (2022)

*TBPL2*	Transcriptional control	c.788 + 3A>G (Splicing, Hom)	Early embryos	Yang et al. (2021a )	Female sterility Defective folliculogenesis Changed chromatin organization Disrupted transcriptional activity (Gazdag et al., 2009)

Gene	Main functions	Variant (type, zygosity)	Embryonic arrest stage	Reference	Knockout phenotype (reference)
*TUBB8*	Microtubule formation Spindle assembly	c.A628G, c.C713T, or c.A1043G (Missense mutations, Het)	Early embryos	Feng et al. (2016)	NA
		c.209C>T (Missense, Hom)	Four-cell	Chen et al. (2017a )
		c.990G>A (Missense, Het)	Early embryos
		c.1057G>A (Missense, Het)
		c.613G>A (Missense, Het)
		c.580G>A and c.1245G>A (Missense, Com Het)
		Deletion (Hom)	One-cell
		c.1041C>A (Missense, Hom)	One-cell	Yuan et al. (2018)
		c.10A>C, c.1000C>G, c.1171C>T, c.181C>A, c.1057G>A, c.1249G>T, c.763G>A, c.883G>C, or c.600T>G (Missense mutations, Het) c.721C>T (Missense, Hom)	Early embryos	Chen et al. (2019)
		c.1041C>A (Missense, Het)	Early cleavage	Jia et al. (2020)
		c.1172G>A, c.1139G>A, c.236G>A, c.743C>T, c.940G>T, c.728C>G, c.497C>T, c.736C>G, c.925C>T (Missense mutations, Het) c.1076G>A (Missense, Hom) c.82C>T and c.398T>C (Missense, Com Het) c.400C>T (Nonsense, Het)	Early embryos	Zhao et al. (2020a )
		c.G6T, c.C43A, c.C124G, c.G262C, c.G421C, c.C544T, c.G586Ac.A604C, c.A694T, c.A898T, c.G904A, c.G959A, c.C1055T, c.C1171T, c.G1172T, c.G1172A, c.C1232A (Missense mutations, Het)	Early embryos	Zheng et al. (2021b)
		c.161C>T (Missense, Hom)	Early embryos	Cao et al. (2021)
		c.959G>A (Missense, Het)	Early embryos	Cao et al. (2021)
		c.1045G>A, c.10A>C, c.938C>T, c.136C>T, or c.893A>G (Missense mutations, Het)	Early embryos	Yang et al. (2021b)
		c.524T>C (Missense, Het)	One-cell	Sha et al. (2021)
		c.10_12delinsCTT (Missense, Het)	One-, two- to four-cell
		c.1045G>A (Missense, Het)	Two- to five-cell and seven-cell
		c.208C>A (Missense, Het)	One-cell, two-cell, or three-cell	Lu et al. (2021)
		c.173G>A (Missense, Het)	Eight-cell or cleavage
		c.326T>G (Missense, Het)	Cleavage
		c.907T>C (Missense, Het)
		c.916C>T (Missense, Het)

*CENPH*	Kinetochore binding	c.635T>C (Missense, Hom)	Cleavage	Maddirevula et al. (2020)	NA

*CDC20*	Spindle assembly Coactivator of APC/C Suppressing apoptosis	c.965G>A and c.1176_1179del TCTG (Missense and frameshift deletion, Com Het)	Early embryos	Zhao et al. (2020b)	Infertility or subfertility Failure in embryogenesis Embryonic arrest at two-cell stage Increased cyclin B1 levels Aneuploid oocytes and embryos (Li et al., 2007; Manchado et al., 2010)
		c.683A>G (Missense, Hom)
		c.544C>T and c.965G>A (Nonsense and missense, Com Het)
		c.964C>T and c.965G>A (Stop-gain and missense, Com Het)	Early embryos	Zhao et al. (2021)
		c.330 + 1G>A and c.1155G>C (Splicing and missense, Com Het)	Early embryos	Zhao et al. (2021)
		c.784C>T and c.631G>A (Nonsense and missense, Com Het)	Four-cell, five-cell	Huang et al. (2021)
*FBXO43*	Cell cycle regulation Inhibition of APC/C activity Early embryo development	c.1490_1497dup (Duplication, Hom)	Two-/three- to five-cell	Wang et al. (2021)	Sterility in both sexes Abnormal oocyte morphology Parthenogenetic activation (Gopinathan et al., 2017)
		c.1747C>T (Nonsense, Hom)	Two-cell
		c.154delG (Deletion, Hom)	Three-cell

*MEI1*	Chromosome synapsis Formation of DSBs Initiation of meiotic recombination	c.1792 + 1G>T (Splicing, Hom)	Early embryos	Dong et al. (2021)	Infertility Various ovarian defects Failure in synapsis formation Reduced follicle numbers Aberrant chromosomal arrangement MI-stage arrest (Libby et al., 2002)
		c.1585T>A (Missense, Hom)
		c.186G>C and c.734-2A>C (Missense and splicing, Com Het)
		c.745C>T (Nonsense, Hom)

*REC114*	DNA recombination DSB formation Chromosome synapsis	c.397T>G (Missense, Hom)	Two- to six-cell	Wang et al. (2020)	Sterility in both sexes Impaired meiotic DSB formation Reduced DSB and DMC1 foci levels (Kumar et al., 2018)
*REC114*	DNA recombination DSB formation Chromosome synapsis	c.546 + 5G>A (Splicing, Hom)	Early embryos	Wang et al. (2020)

*TRIP13*	DSB formation Mitotic checkpoint Meiotic recombination DNA repair process Spindle assembly	c.592A>G and c.739G>A (Missense mutations, Com Het)	One-cell or before eight-cell	Zhang et al. (2020)	Infertility in both sexes Oocyte loss Meiotic disruption Decreased follicle numbers (Li et al., 2007)
		c.1141G>A (Missense, Hom)	One-cell, three-cell	Hu et al. (2022)
		c.77A>G and c.1258A>G (Missense mutations, Com Het)	One-cell	Hu et al. (2022)

*BTG4*	Maternal mRNA clearance Inhibiting spontaneous oocyte activation Regulation of mRNA deadenylation Maternal to zygotic transition	c.73C>T (Nonsense, Hom)	One-cell	Zheng et al. (2020b)	Female infertility Embryonic arrest at one- or two-cell stage Decreased follicle numbers Impaired homologous synapsis Defects in DSB formation Impaired EGA Disrupted maternal mRNA clearance and translation (Yu et al., 2016; Brachova et al., 2021)
		c.1A>G (Start-lost, Hom)
		c.475_478del (Frameshift, Hom)
		c.166G>A (Missense, Hom)

*ZFP36L2*	Maternal mRNA clearance	c.922_930del (Non-frameshift deletion, Hom)	Early embryos	Zheng et al. (2022)	Defects in both oocyte maturation and fertility Blocked ovulation Two-cell arrest (Ramos, 2012; Ball et al., 2014 Chousal et al., 2018)
*ZFP36L2*	Maternal mRNA clearance	(c.922_930del and c.922T>G) (Non-frameshift deletion and Missense, Com Het)	Early embryos	Zheng et al. (2022)

*PATL2*	Translational control	c.953T>C and c.839G>A (Missense mutations, Com Het)	Early embryos	Chen et al. (2017b)	Female infertility Disturbed oocyte maturation Decreased translational repression Increased MI-arrested oocytes Reduced litter size and oocyte quality Morphological and developmental defects Dysregulated gene expression (Christou-Kent et al., 2018)
		c.649T>A and c.566T>G (Missense mutations, Com Het)
		c.223-14_223-2del and c.1224þ2T>C (Splicing mutations, Com Het)
		c.877G>T and c.223-14_223-2del (Missense and splicing, Com Het)	Early embryos	Wu et al. (2019)
		c.716delA and c.223-14_223-2del Frameshift deletion and splicing, Com Het)
		c.778G>A and c.223-1_223-2del (Missense and Deletion)
		c.890delC (Frameshift, Hom)	Two-cell	Huang et al. (2022)

*MOS*	Activation ERK signaling Cytoskeleton assembly mRNA clearance Mitochondrial homeostasis Up-regulation of MPF activity Maintenance of MII arrest	c.285C>A (Missense, Hom)	Two- to seven-cell	Zhang et al. (2021b)	Female sterility Failure of meiotic arrest Ovarian cysts and teratomas Parthenogenetic activation Inability of MAPK activation Spindle defect Disrupted asymmetric division
		c.416T>C and c.737G>A (Missense mutations, Com Het)	Two- to six-cell
		c.960C>A (Nonsense, Hom)	Two-, three-, or five-cell
		c.791C>G (Missense, Hom)	Two- to six-cell	Zhang et al. (2022)
		c.875C>T and c.596A>T (Missense mutations, Com Het)	Two- to eight-cell or three- to four-cell	Zhang et al. (2022)
		c.285C>A (Missense, Hom)	Early embryos	Zeng et al. (2022)
		c.467delG and c.956G>A (Frameshift and missense, Com Het)	Early embryos	Zeng et al. (2022)

*TBPL2*	Transcriptional control	c.788 + 3A>G (Splicing, Hom)	Early embryos	Yang et al. (2021a )	Female sterility Defective folliculogenesis Changed chromatin organization Disrupted transcriptional activity (Gazdag et al., 2009)

All these variants were found to cause embryonic arrests at early stages in humans. NA, not available. All other abbreviations are given in the text.

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