The Ultrasound and Genetic Characteristics of Fetuses With Laterality Defects-A Prenatal Cohort in Asian Population.

Objective: To investigate the distribution of laterality defects in fetuses, including situs inversus totalis (SIT) and situs ambiguous (SA), and to explore the potential genetic etiology of these laterality defects.

Methods: Detailed fetal echocardiography and extracardiac structural evaluations were performed. Genetic testing, including chromosomal microarray analysis, and trio exome sequencing was conducted to identify potential genetic variants.

Results: The incidence of heart malformation was significantly higher in SA fetuses than in SIT group (30/31 vs. 2/36, p < 0.001). The incidence of univentricular heart with single atrium was significantly higher in right isomerism compared with left isomerism (12/19 vs. 3/12, p = 0.029), while the incidence of double outlet right ventricle was significantly higher in left isomerism (5/12 vs. 1/19, p = 0.022). Genetic testing identified variation within candidate genes of cardiac development. Except for CFAP300 c.604delG and KMT2D c.16351T>C, which were rated as "likely pathogenic", all other variants were categorized as variants of uncertain significance, with some fetuses having compound heterozygous variations.

Conclusion: Fetuses with SA have a significantly higher likelihood of concurrent heart malformations compared with those with SIT. Genetic testing identified potential genetic variants that may play crucial roles in the mechanisms underlying normal fetal visceral positioning. Further studies are needed to explore the clinical significance of these genetic variants and to improve our understanding of the etiology and management of fetal laterality defects.