Genetic Investigation of Fetal Left‐Right Laterality Defects Identified in the Second Trimester of Pregnancy

OBJECTIVE: To explore genetic investigative results in fetuses with left-right (LR) laterality defects. METHODS: This was a retrospective study of 138 cases with LR defects diagnosed on second trimester anatomy ultrasound. All cases underwent invasive prenatal diagnosis for copy number variant (CNV) detection by chromosomal microarray analysis (CMA). For those with a negative CNV, trio exome sequencing (ES) was an option. RESULTS: A total of 138 fetuses, including 79 cases of situs inversus totalis (SIT) and 59 of situs ambiguous (SA), underwent CMA, and none of which revealed clinically significant CNVs. Trio-based ES was performed in 97 cases, including 61 with SIT and 36 with SA. Definitive molecular diagnoses - supported by (likely) pathogenic variants - were established in 8 cases (8.2%). VUS was identified in seven additional cases; all affected genes (DNAH5, DNAH11, TTC21 B, SMAD2, BBS7 and DNAI1) have been reported in association with ciliopathies or LR defects. Collectively, the overall diagnostic yield of ES for LR defects was 15.5% (15/97). CONCLUSIONS: Although monogenic causes were identified in only a small subset of LR defective fetuses, the identification of this condition in the prenatal setting warrants comprehensive fetal anatomic evaluation and invasive genetic testing.