Ultrasound and genetic findings in a case series of fetuses presenting vertebral defects.

Purpose: This study aimed to summarize the ultrasound and genetic features in a case series of fetuses presenting vertebral defects, to provide useful information for prenatal counseling and prognostic evaluation.

Methods: Fetuses with vertebral anomalies by a second or third trimester ultrasound screening between January 2020 and April 2024 at a single center were included in the study. Chromosome microarray analysis (CMA) as a first-line diagnostic test was performed. Whole exome sequencing (WES) was further applied to the cases with negative CMA results.

Results: A total of 12 fetuses presenting vertebral defects were included. Isolated and non-isolated vertebral malformations were reported for eight (66.7%, 8/12) and four (33.3%, 4/12) fetuses, respectively. Congenital heart defects, microphthalmia, and duplicated kidney were among other structural anomalies associated with vertebral malformation in non-isolated cases. Of the 12 fetuses, five (41.7%) had positive results for prenatal diagnosis. CMA detected 16p11.2 deletions (including the gene) in three fetuses and a 7q36.1-q36.3 deletion in one fetus, respectively. WES followed by Sanger sequencing validation identified a novel frameshift duplication mutation NM_004608.4: c.989_990dup p.(G331Pfs*168) in trans with the hypomorphic T-C-A haplotype (defined by SNPs rs2289292, rs3809624, and rs3809627) on the opposite allele in a fetus with a negative result for pathogenic copy number variants. There was no statistically significant difference in diagnostic yield between the isolated (25.0%, 2/8) and non-isolated (75%, 3/4) cases (Fisher exact test,  = 0.141). In all cases, six (50%, 6/12) had termination of pregnancy, three (25%, 3/12) had live birth with normal development at the latest follow-up, and three declined or were lost to follow-up. All live births were from cases with negative CMA and WES results.

Conclusion: CMA has a good performance for the diagnosis of fetuses presenting vertebral defects, and WES can further improve the diagnostic yield from the cases with negative CMA results. More studies are needed to reveal the etiologies and enhance the prenatal management of fetal vertebral defects.