Analysis Of Chromosomal Aberrations In Fetuses With Growth Restriction

BackgroundFetal growth restriction is recognized as the failure of an infant to achieve his or her genetic growth potential in utero due to various pathological factors,characteristic with an estimated fetal weight that is less than the 10th percentile for gestational age,below the 3th percentile is a severe FGR.FGR affects approximately 6.39%-8.77%of pregnancies in China.It is a common yet complex obstetric challenge and is associate with significant perinatal morbidity and mortality.Fetuses that suffer FGR have a perinatal mortality 4-6 times higher than normal birth weight babies,which is the second primary cause of perinatal mortality.Later in life,FGR will affect the physical development of children and are also at greater risk of metabolic syndrome.Multiple factors have been implicated in the process of fetal growth,the precise molecular and cellular mechanisms by which fetal growth restriction occurs are still not well understood,the etiology of FGR can be broadly categorized into maternal,fetal,and placental factors.Genetic contribution such as chromosomal abnormalities(number and structural abnormalities),epigenetic abnormalities(methylation abnormalities,miRNA interference),and gene mutations has been proposed to be responsible for this condition.Chromosomal anomalies are considered to be the most common genetics factors leading to FGR,which have been reported to account for up to 19%of fetuses presenting FGR.Triploid,Tuner syndrome and trisomy of chromosomes 13,18,21 are the most common anomalise in FGR fetuses.Furthermore,chromosomal structural abnormalities like microdeletion or microduplication syndrome such as Williams-Beuren syndrome(7q11.23 microdeletion),22qll.2 microduplication syndrome,Xp22.3 microdeletion syndrome have also been associated with fetal growth restriction.FGR affected by chromosomal aberrance often have malformation or psychomotor developmental delay after birth and lack of effective therapeutic method at present that make patients with FGR have have an extremely low quality of life.Therefore,chromosomes analysis for cases with FGR by karyotype and chromosome microarray analysis can help us to explore the causes of FGR and assess its impact on perinatal outcomes,improve our prenatal diagnosis and intervention of FGR,further reduce the incidence of birth defects.ObjectiveThe research cases included group of cases of idiopathic FGR and group of cases of FGR with additional ultrasound findings.Karyotype and chromosome microarray analysis were performed for the subjects in order to aquire to the incidence and types of abnormal chromosome,the role of chromosome microarray analysis in the prenatal diagnosis of FGR was evaluated as well.Fetal growth is a complex,dynamic course.As opposed to early onset of growth restriction,part of cases manifest fetures of FGR in the third trimester.By comparing the genetic abnormal rate of FGR in different diagnosed gestation,we aim to investigate whether late onset FGR requires invasive prenatal diagnosis and the perinatal outcomes to the fetuses with FGR at different diagnosed gestation.Methods1.Collecting the amniotic fluid,cord blood,or umbilical cord tissue after termination from women of single pregnency with fetal growth restriction during 21-37 gestational weeks.2.G-banding karyotype analysis was routinely performed on amniotic fluid and cord blood specimens.Umbilical cord tissue specimens and samples without aneuploid anomalies screened by G-banding karyotype were further to carry out CMA.Cases with FGR were divided into groups of idiopathic FGR and FGR with additional ultrasound findings.The abnormal detection rate of CMA in different groups was calculated.According to different diagnosed gestation,fetues with FGR were divided into early onset FGR group(<32 weeks)and late onset FGR group and compare their genetic abnormalities.Finally,all pregnancy outcomes were followed up.Results95 fetuses with FGR between 21 and 32 gestational weeks were collected during the study period,of which 18 cases were considered to be abnormal,including 12 pathogenic variations,1 possible pathogenic variation and 5 variations of unknown clinical signi:ficance.The overall data revealed a 19%(18/95)detection rate of chromosomal abnormalities among FGR cases,and the proportion of pathogenic variations was 13.7%(13/95).A total of 92 specimens were analyzed by CMA after excluding 3 cases with aneuploid detected by karyotype analysis.CMA identified chromosomal aberrations in 15 of 92 cases(16.3%),including 9 pathogenic variations,1 possible pathogenic variation and 5 variations of unknown clinical significance.The detection rate of pathogenic variations was 10.9%(10/92).CMA successfully identified 2 cases of pathogenic chromosome structural variations diagnosed by karyotype,revealed a higher positive rate up to 14.4%(13/90)compared to conventional karyotyping.Among idiopathic FGR group,FGR with additional ultrasound findings group,early onset FGR group and late onset FGR group,the positive rate of CMA was 19%(8/42),14%(7/50),13.8%(9/65)and 22.2%(6/27),respectively.There was no statistical difference among the groups mentioned above.Following up for the pregnancy outcomes,we found that there was a higher perinatal mortality rate in the early onset FGR group(53.7%(36/67))in comparison with late onset FGR group(19.2%(5/26)).The difference between the two groups was statistically significant(p<0.05).The 12 cases of pathogenic variations included 1 case of 18 trisomy,1 case of 21 trisomy,1 case of 45,X/46,XX mosaicism(mosaic ratio 50%),2 cases of chromosomal imbalance translocation,4 cases of 7q11.23 microdeletion,1 case of 4pl6.3pl6.2 microdeletion,1 case of 22q11.2 microdeletion and 1 case of Xp21.1 microdeletion.One possible pathogenic variation refers to uniparental disomy of chromosome 16.5 cases ofvariations of unknown clinical significance were 2q11.1q11.2,4q21.21,5q11.2,6q22.31,16p13.2 and Xp22.33 or Yp11.32.Conclusions1.18 cases were found to have chromosomal abnormalities in 95 FGR samples with a 19%abnormal rate.In addition to common aneuploid,7q 11.23 microdeletions are the most common structural variation leading to fetal growth restriction.2.CMA is an effective method to investigate the chromosomal abnormalities for fetuses with growth restriction and has a higher positive rate of 14.4%compared to conventional karyotyping.Invasive prenatal diagnosis is recommended for early or late onset growth restricted fetuses with or without additional ultrasound abnormalities.3.Fetueses with early onset of FGR have a higher risk of poor pregnancy outcomes than late onset of FGR.Early diagnosis,intensive monitoring,and timely delivery are essential for improving the prognosis of FGR,especially early onset FGR.