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