Abstract
BackgroundThe implementation of genomic testing in pregnancy means that couples have access to more information about their child’s genetic make-up before birth than ever before. One of the resulting challenges is the management of genetic variations with unclear clinical significance. This population-based study will help to close this critical knowledge gap through a multidisciplinary cohort study of children with and without genomic copy number variants (CNVs) diagnosed before birth. By comparing children with prenatally-ascertained CNVs to children without a CNV, we aim to (1) examine their developmental, social-emotional and health status; (2) measure the impact of prenatal diagnosis of a CNV on maternal perceptions of child health, behavior and development; and (3) determine the proportion of prenatally-ascertained CNVs of unknown or uncertain significance that are reclassified as benign or pathogenic after 2 or more years.MethodsThis study will establish and follow up a cohort of mother-child pairs who have had a prenatal diagnosis with a chromosomal microarray from 2013-2019 in the Australian state of Victoria. Children aged 12 months to 7 years will be assessed using validated, age-appropriate measures. The primary outcome measures will be the Wechsler Preschool and Primary Scale of Intelligence IV (WPSSI-IV) IQ score (2.5 to 7 year old’s), the Ages and Stages Questionnaire (12-30 months old), and the Brief Infant- Toddler Social and Emotional Assessment (BITSEA) score. Clinical assessment by a pediatrician will also be performed. Secondary outcomes will be scores obtained from the: Vineland Adaptive Behavior Scale, Maternal Postnatal Attachment Questionnaire, the Vulnerable Child Scale, Profile of Mood States, Parent Sense of Competence Scale. A descriptive analysis of the reclassification rates of CNVs after ≥2 years will be performed.DiscussionThis study protocol describes the first Australian cohort study following children after prenatal diagnostic testing with chromosomal microarray. It will provide long-term outcomes of fetal genomic variants to guide evidence-based pre-and postnatal care. This, in turn, will inform future efforts to mitigate the negative consequences of conveying genomic uncertainty during pregnancy.Trial registrationACTRN12620000446965p; Registered on April 6, 2020.
Highlights
The implementation of genomic testing in pregnancy means that couples have access to more information about their child’s genetic make-up before birth than ever before
chromosomal microarray (CMA) interrogates the genome at a higher resolution than conventional karyotyping, allowing previously undetected submicroscopic copy number variants (CNVs) to be detected
A National Institute of Child Health and Human Development (NICHD) multicenter trial in the United States (US) provided the first large-scale report on the use of CMA for fetal chromosome analysis [6]. This landmark trial compared the accuracy of prenatal CMA to that of standard karyotyping and found that 5.8% of pregnancies with a fetal structural anomaly and a normal karyotype had a clinically significant CNV detected
Summary
The implementation of genomic testing in pregnancy means that couples have access to more information about their child’s genetic make-up before birth than ever before. One of the resulting challenges is the management of genetic variations with unclear clinical significance This population-based study will help to close this critical knowledge gap through a multidisciplinary cohort study of children with and without genomic copy number variants (CNVs) diagnosed before birth. A National Institute of Child Health and Human Development (NICHD) multicenter trial in the United States (US) provided the first large-scale report on the use of CMA for fetal chromosome analysis [6]. This landmark trial compared the accuracy of prenatal CMA to that of standard karyotyping and found that 5.8% of pregnancies with a fetal structural anomaly and a normal karyotype had a clinically significant CNV detected. This has rapidly transitioned to being the ‘default’ investigation for any prenatal diagnostic test and in Victoria, the annual proportion of prenatal diagnoses utilizing CMA has exceeded 80% since 2015 [3]
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