Genetic and Clinical Features of Heterotaxy in a Prenatal Cohort

Abstract

Objectives: Some genetic causes of heterotaxy have been identified in a small number of heterotaxy familial cases or animal models. However, knowledge on the genetic causes of heterotaxy in the fetal population remains scarce. Here, we aimed to investigate the clinical characteristics and genetic spectrum of a fetal cohort with heterotaxy.Methods: We retrospectively investigated all fetuses with a prenatal diagnosis of heterotaxy at a single center between October 2015 and November 2020. These cases were studied using the genetic testing data acquired from a combination of copy number variation sequencing (CNV-seq) and whole-exome sequencing (WES), and their clinical phenotypes were also reviewed.Result: A total of 72 fetuses diagnosed with heterotaxy and complete clinical and genetic results were enrolled in our research. Of the 72 fetuses, 18 (25%) and 54 (75%) had left and right isomerism, respectively. Consistent with the results of a previous study, intracardiac anomalies were more severe in patients with right atrial isomerism than in those with left atrial isomerism (LAI) and mainly manifested as atrial situs inversus, bilateral right atrial appendages, abnormal pulmonary venous connection, single ventricles or single atria, and pulmonary stenosis or atresia. In 18 fetuses diagnosed with LAI, the main intracardiac anomalies were bilateral left atrial appendages. Of the 72 fetuses that underwent CNV-seq and WES, 11 (15.3%) had positive genetic results, eight had definitive pathogenic variants, and three had likely pathogenic variants. The diagnostic genetic variant rate identified using WES was 11.1% (8/72), in which primary ciliary dyskinesia (PCD)-associated gene mutations (CCDC40, CCDC114, DNAH5, DNAH11, and ARMC4) accounted for the vast majority (n = 5). Other diagnostic genetic variants, such as KMT2D and FOXC1, have been rarely reported in heterotaxy cases, although they have been verified to play roles in congenital heart disease.Conclusion: Thus, diagnostic genetic variants contributed to a substantial fraction in the etiology of fetal heterotaxy. PCD mutations accounted for approximately 6.9% of heterotaxy cases in our fetal cohort. WES was identified as an effective tool to detect genetic causes prenatally in heterotaxy patients.

Diagnostic Value of Chromosomal Microarray Analysis for Fetal Congenital Heart Defects with Different Cardiac Phenotypes and Extracardiac Abnormalities

“…Wang et al’s results demonstrate that heterotaxy frequently associated with CA (11.7%), especially CNVs. However, other scholars conducted a CNV-seq analysis on heterotaxy and found that the incidence of CA was 4.2% (3/72) [ 17 ]. In other studies, the incidence of CA was also mostly concentrated at 2% [ 18 , 19 , 20 ].…”

The incremental yield of prenatal exome sequencing over chromosome microarray for congenital heart abnormalities: A systematic review and meta‐analysis

“…[19][20][21][22] This left 21 studies included in the final metaanalysis (incorporating 1957 cases). [19][20][21][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] Of the 21 studies in this paper, 8 were used in the previous analysis by Mone, et al 10 Table S1 outlines the study characteristics. Supplementary Figure S1 demonstrates the quality assessment.…”

Understanding laterality disorders and the left-right organizer: Insights from zebrafish

“…The term isomerism refers to cases in which right-sided structures or left-sided structures are found on both sides of the body. Patients with right isomerism typically present with the most severe phenotypes on the HTX spectrum (Yi et al, 2022). These patients often have bilaterally trilobed lungs, and the absence of a spleen (asplenia) that leaves them at risk for infections (Loomba et al, 2016a;Buca et al, 2018).…”

“…These patients often have bilaterally trilobed lungs, and the absence of a spleen (asplenia) that leaves them at risk for infections (Loomba et al, 2016a;Buca et al, 2018). Characteristic cardiac defects include atrioventricular canal defects, a single functional ventricle (or large ventricular septal defect), pulmonary valve stenosis or atresia, anomalous pulmonary venous return, and transposition of the great arteries (Saba et al, 2022;Yi et al, 2022). On the other hand, individuals with left isomerism will often have bilaterally bilobed lungs and multiple spleens (polyspenia).…”