Introduction
Fetal anomalies, defined as single or multiple structural malformations
or functional changes, occur in 2–3% of fetuses and account for
20-30% of perinatal mortality.1 In 9.5% and 13.7%
stillbirth cases, respectively, fetal structural malformations and
genetic abnormalities (e.g. aneuploidy) were identified as potential
causes of death.2-5 Other forms of genetic
abnormalities such as copy number variants (CNVs) occurring as deletion
or duplication of genomic material > 1000 base pairs in
length, can influence phenotype and cause disease by disrupting
genes.6, 7
Recent studies showed associations between pathogenic CNV deletions and
duplications with stillbirth cases and anomalous live-born
fetuses.4, 5 However, the relationship between CNVs
and fetal structural malformations among stillbirth cases is uncertain.
Routine ultrasound is utilized for detecting fetal structural
malformation but remains limited in detecting organ system level
malformations. For example, detection rate for all congenital cardiac
malformations using ultrasound is only a 36 to 39%.8As chromosomal microarray assessments aid standard genetic testing for
perinatal diagnoses,9 identifying pathogenic CNVs
associated with fetal structural malformations can guide the management
and counseling of families at risk for stillbirth. As such, information
about the likelihood of associated anomalies that are not apparent in
the second trimester may inform important medical
decisions.8
Interpreting the pathogenicity of CNVs, however, remains
challenging,6 as limited studies link relevant
clinical information to genetic observations in a structured way.
Following our recent work on CNVs and placental
abnormalities,10 we used our multicenter setting of
stillbirth population to determine specific CNVs associated with fetal
structural malformations. We hypothesized that duplicated or deleted
pathogenic CNVs in fetal/placental genes are associated with fetal
structural malformations. Determining specific pathogenic chromosomal
abnormalities associated with fetal anomalies in stillbirth will improve
databases that are essential for the interpretation of variants in
diagnostic and research contexts.11