Abstract: Objective  To investigate the clinicopathological features and associated genetic as well as chromosomal abnormalities in fetuses with aberrant right subclavian artery (ARSA) complicated by complex cardiovascular malformations. Methods  The retrospective analysis was conducted on 18 fetuses diagnosed with ARSA combined with complex cardiovascular malformations by fetal autopsy at Beijing Anzhen Hospital, Capital Medical University from 2011 to 2020. General data and autopsyproven malformations were collected and analyzed. Ten of these cases underwent copy number variation sequencing (CNVseq), and those with negative results were further examined by whole-exome sequencing (WES). Statistical analysis was performed on fetal gender, maternal age, autopsy malformations, and molecular testing results.  Results  Among the 18 fetuses, there were 4 male and 14 female fetuses. The proportion of female fetuses was higher than that of male fetuses (P< 0.05). The mean maternal age was (32.1±5.4) years, with 14 cases in the nonadvanced maternal age group (<35 years) and 4 cases in the advanced maternal age group (≥35 years). All cases were anatomically classified as the retroesophageal type of aberrant right subclavian artery. No Kommerell diverticulum (KD) was found in any cases at autopsy. Associated cardiovascular malformations included atrial/ventricular septal defects (10 cases), valvular malformations (10 cases), aortic dysplasia (8 cases), pulmonary atresia/stenosis (7 cases), and persistent left superior vena cava (6 cases), etc. Among them, 11 cases (61.1%) were classified as conotruncal anomalies. Seven fetuses had extracardiac malformations, mainly pulmonary dysplasia (4 cases), limb malformations (3 cases), and hepatic abnormalities (3 cases). Of the 10 fetuses with molecular testing, abnormalities were identified in 7 cases: CNVseq detected trisomy 18 in 2 cases, trisomy 21 in 1 case, and 22q11.2 microdeletion in 1 case; WES identified KMT2D gene mutations in 2 cases and ZIC3 gene mutation in 1 case. The proportion of conotruncal anomalies in cases with abnormal molecular testing results was higher than that in cases with normal results (P< 0.05).  Conclusion  Non-isolated ARSA may be more prevalent in female fetuses and it is frequently associated with intracardiac malformations, especially conotruncal anomalies. Extracardiac malformations may include pulmonary hypoplasia, hand and foot deformities, and other anomalies. Chromosomal and genetic abnormalities such as trisomy 18, trisomy 21, 22q11.2 microdeletion, as well as KMT2D and ZIC3 gene mutations may be present. When fetal ARSA is detected on prenatal ultrasound, further evaluation for associated intracardiac and extracardiac malformations as well as genetic abnormalities is warranted. In addition to routine genetic testing, whole-exome sequencing can be performed as a supplementary examination.

Key words: aberrant right subclavian artery, congenital heart disease, fetal autopsy, genetic mutation, whole-exome sequencing, prenatal diagnosis