Intrauterine growth restriction and genetic determinants - existing findings, problems, and further direction

Table 1 IGF-I receptor mutations

Gene mutation	Birth weight (SD)	Birth height (SD)	Complications
Arg108Gln/Lys115Asn	-3.5	-4.8	Microcephaly, abnormal speech[29]
Arg59Ter	-3.5	-3.0	Microcephaly, Delay in speech[29]
Arg709Gln	-1.5	-2.6	Mental retardation[28]
Gly1050Lys	-2.1	-4.0	Insulin resistance[32]
Arg281Gln	-3.1	-5.0	Decreased cell proliferation[31]
Val599Glu	-2.3	-2.1	Developmental delay[33]
Gly1125Ala	-1.8	-3.6	Microcephaly, clinodactyly, delayed menarche, diabetes mellitus[30]

Table 2 Maternal AGT Thr235 genotypes[40]

Groups	No.	Genotype			P value
		MM (%)	MT (%)	TT (%)
Control	400	170 (42.5)	158 (39.5)	72 (18.0)
IUGR	174	33 (19.0)	66 (37.9)	75 (43.1)	< 0.001
Preeclampsia + IUGR	60	11 (18.3)	24 (40.0)	25 (41.7)	< 0.001
Placental abruption	62	9 (14.5)	27 (43.5)	26 (41.9)	< 0.001

IUGR: Intrauterine growth restriction.

Table 3 AGT Thr235 alleles frequencies analysis[40]

Groups	AGT genotype		T Allele Freq.	P value
	Met235 alleles	Thr235 alleles
Maternal DNA
Control (400)	498	302	0.378
IUGR (174)	140	208	0.598	< 0.001
Preeclampsia + IUGR (60)	44	76	0.633	< 0.001
Placental abruption (62)	45	79	0.637	< 0.001
Fetal DNA
Control (240)	298	182	0.379
IUGR (160)	131	189	0.591	< 0.001

IUGR: Intrauterine growth restriction.

Table 4 AGT genotype and placental findings[42]

AGT genotype	MM	MT	TT
No. of placentas	8	13	14
Clinical findings
Maternal age (yr)	26.0 ± 4.7	26.6 ± 6.6	29.8 ± 6.5
Gestational age (wk)	36.2 ± 4.5	36.6 ± 1.9	36.7 ± 3.1
Fetal birth wt. (g)	2730 ± 967	2642 ± 541	2620 ± 535
Placental quantitative findings:
Number of villi (mm2)	155.3 ± 14.1	145.8 ± 28.0	146.3 ± 27.7
Villous CS area (μm2/villous)	4422.2 ± 550.0	4400.9 ± 813.5	4248.6 ± 1191.9
Villous volume/1 cm3 placenta (cm3)	0.668 ± 0.034	0.626 ± 0.022b	0.587 ± 0.059bc
Capillary volume/1 cm3 placenta (cm3)	0.131 ± 0.029	0.107 ± 0.034	0.070 ± 0.030b
Intervillous volume/1 cm3 placenta (cm3)	0.332 ± 0.034	0.374 ± 0.022b	0.413 ± 0.059bc
Placental quantitative analysis:
Volume of trimmed placenta (cm3)	324.8 ± 128.0	355.2 ± 80.3	374.1 ± 70.2
Villous total volume per placenta (cm3)	215.8 ± 81.8	222.1 ± 50.7	219.9 ± 52.6
Intervillous space per placenta (cm3)	108.9 ± 47.8	133.1 ± 31.1	154.2 ± 38.6a
Villous capillary volume per placenta (cm3)	45.1 ± 27.4	41.4 ± 23.2	26.6 ± 14.4a
Percentage of villous capillary volume (%)	19.81 ± 5.12	17.41 ± 7.3	12.06 ± 5.45a
Villous surface area per placenta (m2)	9.029 ± 3.285	9.560 ± 2.031	10.370 ± 2.725
Villous surface per 1 g plac. Villi (cm2)	390.6 ± 35.0	401.6 ± 40.5	438.6 ± 73.8

^aP < 0.05,

^bP < 0.01 vs MM;

^cP < 0.05 vs MT.

Table 5 Gene and fetal growth

Gene	Gene mutation/expression	Phneotypic effects/complications
CDK19	Chromosome breakpoints in 6p12.1 and 6q21	Microcephaly, congenital bilateral falciform retinal folds, nystagmus, and mental retardation[9]
NFIA	Chromosome 1p32-p31 deletion syndrome	Ventriculomegaly, corpus callosum hypogenesis, abnormal external genitalia, and intrauterine growth restriction in the third trimester[44]
IGF1R	Novel c.420del mutation in exon 2 of the IGF1R gene	Reduced IGF1R expression and represents haploinsufficiency of the IGF1R gene. IUGR and neonatal growth retardation[10]
hPGH, IGF-I, IGFBP-1	Decreased expression	Decreased expression is associated with IUGR[27]
c-fos	Decreased expression	Fetal alcohol syndrome[45]
11b-HSD2	Glucocorticoid metabolism	Under expression cause IUGR, small placenta[55]
GSTP1	Glutathione transferase enzymes pathway	Fetal growth and neonatal growth[56]
ZMPSTE24	Fetal growth	IUGR, dermopathy, neonatal death[43]
Ascl2	Placenta development	Three layers malformation, IUGR[44]
TFRC	Transferrin receptor function	IUGR[13]
DIO3	Type 3 deiodinase	Highly expressed in placenta and fetus. IUGR and hypothyroidism[47]
DLK1	Growth promoter	Expressed in placental villi. Methylation defects associated with IUGR[16]
HYMAI	Non-coding RNA	Transient neonatal diabetes and IUGR[57]
IGF2	Growth Factor	Placental and fetal growth restriction[58]
KCNQ1OT1	Non-coding RNA	Control placental Kcnq1 domain. Involved in Beckwith-Wiedemann syndrome[59]
MAGEL2/NDNL1	Similarity to NDN	Neonatal growth retardation, alter metabolism[60]
MEST	Neuronal differentiation	Fetal growth restriction, smaller placentas[52]
PEG10	Retrotransposon-derivedgene	Severe growth retardation, absence of spongiotrophoblast layer, embryonic lethality[61]
PEG3	Inhibits WNT-signalling	Placental and fetal growth restriction and abnormal maternal behavior[62]
PLAGL1 Zac1	Tumor suppressor	Skeletal defects, neonatal lethality, IUGR, and disrupted transactivation of Igf2[63]
SFRP2	WNT signaling	Reduction in vitro of extra villous trophoblast invasion[64]
HBII-85/PWScr	C/D Box small RNA	Implicated in Prader Willi, Postnatal growth retardation[65]

IUGR: Intrauterine growth restriction.