Giulia F Del Gobbo1,2, Yue Yin3, Sanaa Choufani3, Emma A Butcher3, John Wei4, Evica Rajcan-Separovic5, Hayley Bos6,7, Peter von Dadelszen8, Rosanna Weksberg3,9,10,11, Wendy P Robinson12,13, Ryan K C Yuen14,15. 1. BC Children's Hospital Research Institute, 950 W 28th Ave, Vancouver, V5Z 4H4, Canada. 2. Department of Medical Genetics, University of British Columbia, 4500 Oak St, Vancouver, V6H 3N1, Canada. 3. Genetics and Genome Biology Program, The Hospital for Sick Children, 686 Bay St, Toronto, M5G 0A4, Canada. 4. The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay St, Toronto, M5G 0A4, Canada. 5. Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, V6T 2B5, Canada. 6. Department of Perinatology, Victoria General Hospital, 1 Hospital Way, Victoria, V8Z 6R5, Canada. 7. Department of Obstetrics & Gynecology, University of British Columbia, Suite 930, 1125 Howe St, Vancouver, BC, V6Z 2K8, Canada. 8. Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, SE1 7EU, UK. 9. Department of Molecular Genetics, Institute of Medical Sciences, University of Toronto, 1 King's College Circle, Toronto, M5S 1A8, Canada. 10. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Suite 940, 525 University Avenue, Toronto, ON, M5G 1X8, Canada. 11. Department of Paediatrics, University of Toronto, 555 University Avenue, Toronto, ON, M5G 1X8, Canada. 12. BC Children's Hospital Research Institute, 950 W 28th Ave, Vancouver, V5Z 4H4, Canada. wrobinson@bcchr.ca. 13. Department of Medical Genetics, University of British Columbia, 4500 Oak St, Vancouver, V6H 3N1, Canada. wrobinson@bcchr.ca. 14. The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay St, Toronto, M5G 0A4, Canada. ryan.yuen@sickkids.ca. 15. Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, M5S 1A8, Canada. ryan.yuen@sickkids.ca.
Abstract
BACKGROUND: Fetal growth restriction (FGR) is associated with increased risks for complications before, during, and after birth, in addition to risk of disease through to adulthood. Although placental insufficiency, failure to supply the fetus with adequate nutrients, underlies most cases of FGR, its causes are diverse and not fully understood. One of the few diagnosable causes of placental insufficiency in ongoing pregnancies is the presence of large chromosomal imbalances such as trisomy confined to the placenta; however, the impact of smaller copy number variants (CNVs) has not yet been adequately addressed. In this study, we confirm the importance of placental aneuploidy, and assess the potential contribution of CNVs to fetal growth. METHODS: We used molecular-cytogenetic approaches to identify aneuploidy in placentas from 101 infants born small-for-gestational age (SGA), typically used as a surrogate for FGR, and from 173 non-SGA controls from uncomplicated pregnancies. We confirmed aneuploidies and assessed mosaicism by microsatellite genotyping. We then profiled CNVs using high-resolution microarrays in a subset of 53 SGA and 61 control euploid placentas, and compared the load, impact, gene enrichment and clinical relevance of CNVs between groups. Candidate CNVs were confirmed using quantitative PCR. RESULTS: Aneuploidy was over tenfold more frequent in SGA-associated placentas compared to controls (11.9% vs. 1.1%; p = 0.0002, OR = 11.4, 95% CI 2.5-107.4), was confined to the placenta, and typically involved autosomes, whereas only sex chromosome abnormalities were observed in controls. We found no significant difference in CNV load or number of placental-expressed or imprinted genes in CNVs between SGA and controls, however, a rare and likely clinically-relevant germline CNV was identified in 5.7% of SGA cases. These CNVs involved candidate genes INHBB, HSD11B2, CTCF, and CSMD3. CONCLUSIONS: We conclude that placental genomic imbalances at the cytogenetic and submicroscopic level may underlie up to ~ 18% of SGA cases in our population. This work contributes to the understanding of the underlying causes of placental insufficiency and FGR, which is important for counselling and prediction of long term outcomes for affected cases.
BACKGROUND: Fetal growth restriction (FGR) is associated with increased risks for complications before, during, and after birth, in addition to risk of disease through to adulthood. Although placental insufficiency, failure to supply the fetus with adequate nutrients, underlies most cases of FGR, its causes are diverse and not fully understood. One of the few diagnosable causes of placental insufficiency in ongoing pregnancies is the presence of large chromosomal imbalances such as trisomy confined to the placenta; however, the impact of smaller copy number variants (CNVs) has not yet been adequately addressed. In this study, we confirm the importance of placental aneuploidy, and assess the potential contribution of CNVs to fetal growth. METHODS: We used molecular-cytogenetic approaches to identify aneuploidy in placentas from 101 infants born small-for-gestational age (SGA), typically used as a surrogate for FGR, and from 173 non-SGA controls from uncomplicated pregnancies. We confirmed aneuploidies and assessed mosaicism by microsatellite genotyping. We then profiled CNVs using high-resolution microarrays in a subset of 53 SGA and 61 control euploid placentas, and compared the load, impact, gene enrichment and clinical relevance of CNVs between groups. Candidate CNVs were confirmed using quantitative PCR. RESULTS:Aneuploidy was over tenfold more frequent in SGA-associated placentas compared to controls (11.9% vs. 1.1%; p = 0.0002, OR = 11.4, 95% CI 2.5-107.4), was confined to the placenta, and typically involved autosomes, whereas only sex chromosome abnormalities were observed in controls. We found no significant difference in CNV load or number of placental-expressed or imprinted genes in CNVs between SGA and controls, however, a rare and likely clinically-relevant germline CNV was identified in 5.7% of SGA cases. These CNVs involved candidate genes INHBB, HSD11B2, CTCF, and CSMD3. CONCLUSIONS: We conclude that placental genomic imbalances at the cytogenetic and submicroscopic level may underlie up to ~ 18% of SGA cases in our population. This work contributes to the understanding of the underlying causes of placental insufficiency and FGR, which is important for counselling and prediction of long term outcomes for affected cases.
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