Prenatal diagnosis in fetal right aortic arch using chromosomal microarray analysis and whole exome sequencing: a...

Right aortic arch (RAA) is a common congenital aortic arch abnormality. Fetuses with RAA frequently have good outcomes after birth. However, chromosomal abnormalities and genetic syndromes suggest poor prognosis for these patients. So far the underlying genetic etiology is still not identified in most RAA patients based on traditional genetic techniques and a problem is still debated whether fetuses with isolated RAA should be referred for CMA. Our study aims to investigate the genetic etiology of fetuses with right aortic arch (RAA) by chromosomal microarray analysis (CMA) and whole exome sequencing (WES) and evaluate the efficacy of CMA in fetal isolated RAA.

Among these 153 fetuses, 99 (64.7%) with isolated RAA and 54 (35.3%) with non-isolated RAA; 25.5% (39/153) with additional intracardiac anomalies (ICA), and 19.0% (29/153) with extracardiac anomalies (ECA). Tetralogy of Fallot (n = 10) and persistent left superior vena cava (n = 11) are the most common ICA and ECA, respectively. CMA detected 15 clinically significant copy number variations (CNVs) in 14 cases (9.2%); microdeletion of 22q11.21 was the most common pathogenic CNVs (7.8%). The chromosomal abnormalities rate was higher in non-isolated RAA and RAA with ICA groups than in isolated RAA group (16.7% vs. 5.1%; 20% vs. 5.1%, both p < 0.05). From five cases further undergoing WES, a diagnostic variant in MTOR gene (c.7255G > A, de novo) was first reported in prenatal, extending the prenatal manifestation of Smith-Kingsmore syndrome (OMIM: 616638); a clinically relevant variant c.3407A > T in STAG2 was identified, being inherited from the healthy mother. Moreover, the premature birth and termination rates were higher in non-isolated RAA group than in isolated RAA group (11.1% vs. 1.0%; 37.0% vs. 2.0%, both p < 0.01).

We demonstrate that CMA and WES are useful diagnostic tools for fetal RAA, particularly non-isolated RAA, and all fetuses with RAA should be referred for CMA. The data probably aids in prenatal diagnosis and prenatal counseling of fetal RAA.