Detection of submicroscopic chromosomal aberrations by chromosomal microarray analysis for the prenatal diagnosis of central nervous system abnormalities

Abstract

Background Central nervous system (CNS) abnormalities are a group of serious birth defects associated with high rates of stillbirths, infant death, or abnormal development, and various disease‐causing copy number variations play a much more important role in the etiology of CNS abnormalities. This study intends to present a retrospective study of the prenatal diagnosis and the pregnancy outcome of fetuses diagnosed with CNS abnormalities, and evaluate the clinical value of chromosomal microarray analysis (CMA) in prenatal diagnosis of CNS abnormalities. Methods A total of 356 fetuses with CNS abnormalities with or without other ultrasound abnormalities subjected to invasive prenatal diagnosis at the first affiliated hospital of Air Force Medical University from January 2015 to August 2018. All cases have performed both karyotyping and CMA concurrently, but 20 fetuses with chromosome aneuploidy were excluded in the current study. Results The CMA identified pathogenic copy number variants (pCNVs) in 27/336 (8.03%) fetuses, likely pCNVs in 8/336 (2.38%) fetuses, and variants of unknown significance (VOUS) in 11/336 (3.27%) fetuses. A total of 222 cases had single CNS abnormalities and the pCNVs detection rate was 5.86% (13/222), the remaining 114 cases including CNS abnormalities plus other structural abnormalities, ultrasonographic soft markers and two or more CNS abnormalities, the pCNVs detection rate was 12.3% (14/114). Conclusions Fetuses with CNS abnormalities have a higher risk of chromosomal abnormalities, our study showed that CNVs play an important role in the etiology of CNS abnormalities. The application of CMA could increase the detection rate of pCNVs causing CNS abnormalities.

Application of Single Nucleotide Polymorphism Microarray in Prenatal Diagnosis of Fetuses with Central Nervous System Abnormalities

“…These findings are similar to previous reports, although some of the studies only showed a higher detection rate of non-isolated CNS abnormalities and no significant difference between the two groups. 3,32 In this study, detection of holoprosencephaly (66.7%, 4/6) had the highest positive rate among the different types of CNS abnormalities. All abnormal cases were trisomy 18 syndromes.…”

“…These findings are similar to previous reports, although some of the studies only showed a higher detection rate of non-isolated CNS abnormalities and no significant difference between the two groups. 3 , 32 …”

Exome sequencing as first‐tier test for fetuses with severe central nervous system structural anomalies

“…Moreover, CNS abnormalities are often diagnosed late in pregnancy 10 . When applying conventional methods (karyotyping followed by CMA or CMA alone) to the diagnosis of fetal CNS anomalies, the estimated diagnostic yield does not exceed 20% [11][12][13] . Thus, more than 80% of cases remain without a genetic diagnosis, probably owing to a large proportion of cases having monogenic etiology.…”

Prenatal exome sequencing: A useful tool for the fetal neurologist

“…At present, standard genetic diagnostic tools include quantitative fluorescent–polymerase chain reaction for aneuploidy screening and Chromosomal microarray analysis (CMA) for detecting copy number variants. 7 …”

“…genetic diagnostic tools include quantitative fluorescent-polymerase chain reaction for aneuploidy screening and Chromosomal microarray analysis (CMA) for detecting copy number variants. 7 Next generation sequencing, such as whole exome sequencing (WES) and whole genome sequencing, is emerging as a valuable tool to diagnose prenatal monogenetic disorders. By sequencing all coding parts of the DNA, WES can detect single nucleotide variants, copy number variants and small deletions or insertions.…”