The Genetic Etiology Diagnosis of Fetal Growth Restriction Using Single-Nucleotide Polymorphism-Based Chromosomal Microarray Analysis

Abstract

Background: An increase in pathogenic copy number variants (pCNVs) has been recognized to associate with fetal growth restriction (FGR). Here, we aim to explore the application value of chromosomal microarray analysis (CMA) in prenatal diagnosis of FGR.Methods: Prenatal ultrasound was applied to identify FGR. A total of 149 pregnant women with FGR were enrolled in our study. All subjects underwent karyotype analysis and CMA to reveal the chromosomal abnormalities.Results: In this study, all subjects were successfully detected by karyotype and CMA analyses. Of these subjects, the chromosomal abnormalities detection rate was 5.37% (8/149) for karyotyping and 13.42% (20/149) for CMA, respectively. Among them, an 8.05% (12/149) incremental yield of CMA over karyotype analysis was observed (p = 0.004). In addition, a significant difference of pCNV detection rate was observed between the groups with different high-risk factors (p = 0.005). The FGR with structural anomalies group showed the highest pCNV detection rate (33.33%), followed by the FGR with non-structural anomalies group (8.77%) and the isolated FGR group (8.06%).Conclusion: In conclusion, CMA technology showed an effective application value in etiology diagnosis of FGR. We believe that CMA should be recommended as first-line detection technology for prenatal diagnosis in FGR.

Genetics Etiologies Associated with Fetal Growth Restriction

“…6 The most common chromosomal numerical abnormalities associated with FGR were triploid (69,XXX and 69,XXY) and trisomy 18, 21, and 13. 6,7 Trisomy 18 was identified in over 50% of chromosomal numerical abnormalities in severe FGR, defined as AC 3 rd percentile for GA. 8 For FGR associated with fetal structural abnormalities (FGR defined as AC < 5 th percentile for GA), the detection rate of fetal aneuploidy was 21% (4/19), while for isolated FGR diagnosed before 24 weeks of gestational age, the detection rate of fetal aneuploidy was 20% (3/15). 9 Despite the heterogeneity in definitions for FGR, the studies above all indicated that amniocentesis with karyotyping should be offered to rule out chromosomal abnormalities for FGR with fetal structural anomalies, severe FGR defined as AC 3 rd percentile for GA or earlyonset FGR diagnosed before 24 weeks gestational age even if isolated.…”

“…The detection rate of diagnostic CNVs was significantly different among three FGR groups; 33.33% for the FGR with fetal structural anomalies group; 8.77% FGR with soft markers and without structural anomalies group; and 8.06% isolated FGR group. 7 A recent retrospective study from 13 fetal medicine centers including 146 fetuses diagnosed with isolated FGR (defined as EFW < 10 th percentile for GA), demonstrated that the total genetic anomalies identified by CMA were 7.5% (11/146); furthermore, CMA provided an incremental diagnostic rate of 3.4% (5/146) compared with karyotype analysis, with the detection of duplication at 16p12.2 and deletions at 19q12q13.12, 12q13.13, and 19p13.2p13.11. 14 Another study analyzed 133 fetuses with FGR (defined as EFW < 3 th percentile for GA) before 32 weeks of gestation and showed that the incremented yield of the diagnostic CNVs by CMA compared with karyotyping was 10.5% for FGR with fetal structural abnormalities, 10.0% for FGR with soft markers and without structural anomalies, and 4.8% for isolated FGR.…”

“…Fetal chromosomal abnormalities include numerical and structural anomalies and accounted for 19.4% (89/458) of the etiologies of FGR (defined as AC < 5 th percentile for gestational age (GA)) at 17 to 39 weeks of gestation by conventional karyotyping, of which 92.13% (82/89) were numerical and 7.87% (7/89) were structural abnormalities on traditional karyotyping 6 . The most common chromosomal numerical abnormalities associated with FGR were triploid (69,XXX and 69,XXY) and trisomy 18, 21, and 13 6,7 . Trisomy 18 was identified in over 50% of chromosomal numerical abnormalities in severe FGR, defined as AC ≤ 3 rd percentile for GA 8 .…”

Fetal growth restriction: associated genetic etiology and pregnancy outcomes in a tertiary referral center

“…Previous research focused on diagnosis, intrauterine monitoring, treatment, and prognosis of fetuses with FGR; however, currently there are only a few studies on the genetic etiology of FGR. Genetic factors that cause FGR have rarely been reported, and some studies that reported a genetic association were conducted with small sample sizes [ 5 ]. Single-nucleotide polymorphism array (SNP-array) can detect copy number variations (CNVs) at a genome-wide level, as well as chimeras (> 30%), loss of heterozygosity, and uniparental disomy (UPD) [ 6 , 7 ].…”

Advances in ligase-based nucleic acid amplification technology for detecting gene mutations: a review

“…Base mismatch in DNA molecules easily causes gene mutations, especially point mutations, which are often an important cause of hereditary and genetic predisposition diseases [ 1 ]. In recent years, the detection and analysis of gene mutations have become a topic of increasing interest, such as pathogenic gene screening and prenatal diagnosis, which can provide the basis for early diagnosis and precise treatment of diseases [ 2 ]. At present, many methods are in place for detecting gene mutations, such as whole-genome sequencing, but they still have certain limitations in terms of experimental cost, sensitivity, and accuracy.…”