Assessing the clinical application value of SNP-array in fetal central nervous system malformations

Single nucleotide polymorphism array (SNP-array) has been introduced for prenatal diagnosis. This study aims to evaluate the clinical utility of SNP-array in the prenatal central nervous system (CNS) malformations.

A retrospective study was conducted on 437 prenatal cases involving CNS malformations and other structural abnormalities detected by ultrasound. Samples were categorized into three groups: Single CNS malformation, Multiple CNS malformations, and CNS malformations with multiple system malformations. SNP-array and karyotype analysis were simultaneously performed on the Fetal samples. Comparative analysis of data was conducted using SPSS (χ2).

SNP-array analysis of 437 samples revealed an overall abnormality detection rate of 19.0%, which was significantly higher than the 11.7% positive rate detected by karyotype analysis in 427 samples (χ2 = 8.797, P = 0.003). The positivity rates detected by SNP-array were 11.4%, 43.3%, and 63.0% in the above three groups, respectively, and these differences were statistically significant (χ2 = 83.247, P = 8.379×10^- 19). The detection rate of clinically significant copy number variants (CNVs) (pathogenic/likely pathogenic, P/LP) was also statistically significant among the three groups (χ2 = 42.000, P = 9.127×10^- 11). In pathogenic CNVs, dose-sensitive regions or genes that occur more frequently include the 4p16.3 terminal region, the 17p13.3 region, the 22q11.2 recurrent region, and DLL1, TGIF1, EBF3. We also did an analysis for pregnancy data of advanced maternal age (AMA) and found that the ratio of chromosomal abnormalities in samples was 18.8% tested by SNP-array. The postnatal follow-up data were analyzed. Compared to the group with normal chromosomal microarray analysis (CMA) result and isolated CNS malformation, the proportions of termination of pregnancy (TOP)/perinatal mortality/spontaneous abortion (27.2% vs. 69.6%, P < 0.0001), liveborn infants requiring medical attention (6.3% vs. 21.7%, P < 0.01), infants being alive and well at birth (66.5% vs. 8.7%, P < 0.0001) were all statistically significant in the group with normal CMA result and non-isolated CNS malformation. The proportions of TOP/perinatal mortality/spontaneous abortion (27.2% vs. 76.7%, P < 0.0001), infants being alive and well at birth (66.5% vs. 23.3%, P < 0.0001) were also statistically significant in the group with abnormal CMA result and isolated CNS malformation compared to the same group mentioned above.

This study evaluated the application of SNP-array in the prenatal CNS malformations in terms of detection of positive rates, advantages in prenatal diagnosis, AMA, genotype-phenotype correlations, pregnancy outcomes and follow-up data, which could assist in the clinical diagnosis and assessment of fetal CNS malformations.