The yield of SNP microarray analysis for fetal ultrasound cardiac abnormalities.

BACKGROUND: Chromosomal microarray analysis (CMA) has emerged as a critical instrument in prenatal diagnostic procedures, notably in assessing congenital heart diseases (CHD). Nonetheless, current research focuses solely on CHD, overlooking the necessity for thorough comparative investigations encompassing fetuses with varied structural abnormalities or those without apparent structural anomalies. OBJECTIVE: This study sought to assess the relation of single nucleotide polymorphism-based chromosomal microarray analysis (SNP-based CMA) in identifying the underlying causes of fetal cardiac ultrasound abnormalities. METHODS: A total of 2092 pregnant women who underwent prenatal diagnosis from 2017 to 2022 were included in the study and divided into four groups based on the presence of ultrasound structural abnormalities and the specific type of abnormality. The results of the SNP-Array test conducted on amniotic fluid samples from these groups were analyzed. RESULTS: Findings from the study revealed that the non-isolated CHD group exhibited the highest incidence of aneuploidy, overall chromosomal abnormalities, and trisomy 18, demonstrating statistically significant differences from the other groups (p < 0.001). Regarding the distribution frequency of copy number variation (CNV) segment size, no statistically significant distinctions were observed between the isolated CHD group and the non-isolated CHD group (p > 0.05). The occurrence rates of 22q11.2 and 15q11.2 were also not statistically different between the isolated CHD group and the non-isolated congenital heart defect group (p > 0.05). CONCLUSION: SNP-based CMA enhances the capacity to detect abnormal CNVs in CHD fetuses, offering valuable insights for diagnosing chromosomal etiology and facilitating genetic counseling. This research contributes to the broader understanding of the utility of SNP-based CMA in the context of fetal cardiac ultrasound abnormalities.

From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease.

NKAP mutations are associated with Hackmann-Di Donato-type X-linked syndromic intellectual developmental disorder (MRXSHD, MIM: #301039). Here, we elucidate the potential prenatal manifestation of NKAP mutation-associated disorder for the first time, alongside revealing the relationship between NKAP mutations and congenital heart defect (CHD) in the Chinese population. An NKAP mutation (NM_024528.4: c.988C>T, p.Arg330Cys) was identified in two foetuses presenting with CHD. Subsequent mechanistic exploration revealed a marked downregulation of NKAP transcription within HEK293T cells transfected with NKAP p.R330C. However, no significant change was observed at the protein level. Moreover, the mutation led to a dysregulation in the transcription of genes associated with cardiac morphogenesis, such as DHRS3, DNAH11 and JAG1. Additionally, our research determined that NKAP p.R330C affected Nkap protein intra-nuclear distribution, and binding with Hdac3. Summarily, our study strengthens NKAP mutations as a cause of CHD and prompts the reclassification of NKAP p.R330C as likely pathogenic, thereby establishing a prospective prenatal phenotypic spectrum that provides new insight into the prenatal diagnosis of CHD. Our findings also provide evidence of NKAP p.R330C pathogenicity and demonstrate the potential mechanism by which p.R330C dysregulates cardiac developmental gene transcription by altering Nkap intra-nuclear distribution and obstructing the interaction between Nkap and Hdac3, thereby leading to CHD.

[Application of chromosomal microarray analysis for fetuses with choroid plexus cysts].

OBJECTIVE: To assess the value of chromosomal microarray analysis (CMA) for fetuses with choroid plexus cysts (CPC) detected by prenatal ultrasonography. METHODS: Amniotic fluid chromosomal karyotype was analyzed in 104 fetuses with CPC, and copy number variations (CNVs) among the fetuses were detected by using CMA. RESULTS: Ten fetuses (9.62%) were found to have an abnormal karyotype, and 14 additional CNVs were detected in those with a normal karyotype. The fetuses were divided into isolated CPC group (n = 87) and non-isolated CPC group (n = 17) based on the presence of additional ultrasonographic abnormalities. The detection rates for karyotypic abnormalities of the two groups were 4.6% and 35.3%, respectively, whilst those for the CMA were 4.6% and 47.1%, respectively. The detection rates for karyotypic abnormalities and CMA of the non-isolated CPC group were significantly higher than those of the isolated CPC group (P < 0.05). The detection rate for CMA in the non-isolated group was significantly higher than chromosomal karyotype abnormalities (P < 0.05). Among the 8 fetuses with abnormal CMA, 4 had single umbilical artery, 3 had abnormal cardiac structure, and 2 had enhanced intestinal echo. CONCLUSION: CPC is closely associated with chromosomal abnormalities. Chromosome karyotype analysis in combination with CMA can effectively detect fetal chromosomal abnormalities and provide a basis for genetic counseling.