Early prenatal diagnosis of alveolar capillary dysplasia with misalignment of pulmonary veins due to a 16q24.1 deletion

Abstract

First trimester ultrasound screening is an essential fetal examination performed generally at 11–13 weeks of gestation (WG). However, it does not allow for an accurate description of all fetal organs, partly due to their development in progress. Meanwhile, increased nuchal translucency (INT) is a widely used marker known to be associated with chromosomal deleterious rearrangements. We report on a 14 WG fetus with an association of INT and univentricular congenital heart malformation (CHM) leading to chorionic villous sampling (CVS). Cytogenetic investigations performed using array‐Comparative Genomic Hybridization (CGH) and fluorescence in situ hybridization (FISH) demonstrated a 1.17 Mb deletion in 16q24.1 encompassing FOXF1 arisen de novo on maternal inherited chromosome. Fetopathological study confirmed CHM with hypoplastic left heart syndrome (HLHS) associating aortic atresia, mitral stenosis, and left ventricular hypoplasia and revealed in addition specific lung lesions corresponding to alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). This is so far the first case of first trimester prenatal diagnosis of ACDMPV due to the deletion of FOXF1 gene. An interpretation of the complex genomic data generated by ultrasound markers is facilitated considerably by the genotype–phenotype correlations on fetopathological examination.

Prenatal Detection of a FOXF1 Deletion in a Fetus with ACDMPV and Hydronephrosis

“…Thus, ACDMPV is rarely suspected prenatally. To date, only seven patients with prenatally-detected ACDMPV ( Figure 1 B) have been reported, including six with 16q24.1 CNV deletion [ 18 , 29 , 30 , 31 , 32 , 33 ]. Due to the severity of the malformations, infants passed away soon after birth, or the parents elected to terminate the pregnancy after genetic confirmation of ACDMPV [ 18 , 29 , 30 , 31 , 32 , 33 ].…”

“…In another patient with CNV deletion at 16q24.1 identified in prenatal screening, autopsy examination confirmed ACDMPV with AVSD and bilateral superior vena cava [ 31 ]. Puisney-Dakhli et al described a fetus with a suspected single ventricular congenital heart malformation in whom prenatal testing identified a CNV deletion at 16q24.1, and post mortem evaluation confirmed hypoplastic left heart syndrome and ACDMPV [ 32 ]. Another patient with prenatally identified CNV deletion at 16q24.1q24.2 had esophageal dilation, kidney malformation, lymphedema, AVSD, ventricular septal defect, and other abnormalities within the cardiovascular system [ 33 ].…”

“…( A ) Genome sequencing display on Integrated Genome Viewer (IGV) showing a heterozygous ~0.74 Mb CNV deletion (chr16:85,952,700/85,952,726-86,694,061/86,694,087, hg38) in the assessed patient (LLDD006.3). ( B ) Comparison of ACDMPV-related CNV deletion identified in our patient during prenatal testing (LLDD006.3) with six previously described patients with prenatal ACDMPV diagnosis and 16q24.1 CNV deletion (P1 [ 29 ], P2 [ 31 ], P3 [ 32 ], P4 [ 18 ], P5 [ 18 ], P6 [ 33 ]). CNV deletions that arose on the maternal chromosome 16 are marked in red; CNV deletions with unknown parental origin are marked in black.…”

“…Thus far, a couple hundred cases of ACDMPV have been described worldwide. The vast majority of diagnoses have been made post mortem, based on histopathological evaluation and/or genetic testing, and only seven cases of ACDMPV have been detected prenatally [ 18 , 29 , 30 , 31 , 32 , 33 ]. Here, we present a patient with hydronephrosis and 16q24.1 CNV deletion identified in prenatal genetic testing, indicating the diagnosis of ACDMPV.…”