Meredith M Howley1, Eva Williford1, A J Agopian2, Angela E Lin3, Lorenzo D Botto4, Christopher M Cunniff5, Paul A Romitti6, Eirini Nestoridi7, Marilyn L Browne1,8. 1. Birth Defects Registry, New York State Department of Health, Albany, New York, USA. 2. Department of Epidemiology, Human Genetics, and Environmental Sciences, UTHealth School of Public Health, Houston, Texas, USA. 3. Medical Genetics Unit, Department of Pediatrics, MassGeneral Hospital for Children, Boston, Massachusetts, USA. 4. Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA. 5. Division of Medical Genetics, Department of Pediatrics, Weill Cornell Medical College, New York, New York, USA. 6. Department of Epidemiology, University of Iowa, Iowa City, Iowa, USA. 7. Center for Birth Defects Research and Prevention, Massachusetts Department of Public Health, Boston, Massachusetts, USA. 8. Department of Epidemiology and Biostatistics, School of Public Health, Rensselaer, New York, USA.
Abstract
BACKGROUND: About 20%-30% of children with birth defects have multiple major birth defects in more than one organ system, often referred to as multiple congenital anomalies (MCAs). Evaluating the patterns of MCAs can provide clues to the underlying causes, pathogenic mechanisms, and developmental pathways. We sought to explore selected patterns of MCAs within the National Birth Defects Prevention Study (NBDPS), a population-based, case-control study that excluded cases attributed to known chromosomal or single-gene abnormalities. METHODS: We defined MCAs as having two or more NBDPS-eligible birth defects and calculated the adjusted observed-to-expected ratio for all observed MCA patterns using co-occurring defect analysis. RESULTS: Of the 50,186 case infants eligible for NBDPS, 2,734 (3.7%) had at least two eligible birth defects. We observed 209 distinct 2-way combinations of birth defects, 297 distinct 3-way combinations, 179 distinct 4-way combinations, and 69 distinct 5-way combinations. Sacral agenesis had the largest proportion of cases with MCAs (70%), whereas gastroschisis had the lowest (3%). Among the cases with MCAs, 63% had a heart defect, 23% had an oral cleft, and 21% had anorectal atresia/stenosis. Of the patterns with adjusted observed-to-expected ratios in the top 20%, most were consistent with the known associations or syndromes, including VATER/VACTERL association and CHARGE syndrome. CONCLUSIONS: Most but not all patterns that had the highest adjusted observed-to-expected ratios were instances of known syndromes or associations. These findings highlight the importance of considering birth defect combinations that suggest syndromic patterns in the absence of a formal syndromic diagnosis. New approaches for screening for sequences and associations, and VATER/VACTERL in particular, in surveillance systems with limited resources for manual review may be valuable for improving surveillance system quality. The observed MCA patterns within NBDPS may help focus future genetic studies by generating case groups of higher yield.
BACKGROUND: About 20%-30% of children with birth defects have multiple major birth defects in more than one organ system, often referred to as multiple congenital anomalies (MCAs). Evaluating the patterns of MCAs can provide clues to the underlying causes, pathogenic mechanisms, and developmental pathways. We sought to explore selected patterns of MCAs within the National Birth Defects Prevention Study (NBDPS), a population-based, case-control study that excluded cases attributed to known chromosomal or single-gene abnormalities. METHODS: We defined MCAs as having two or more NBDPS-eligible birth defects and calculated the adjusted observed-to-expected ratio for all observed MCA patterns using co-occurring defect analysis. RESULTS: Of the 50,186 case infants eligible for NBDPS, 2,734 (3.7%) had at least two eligible birth defects. We observed 209 distinct 2-way combinations of birth defects, 297 distinct 3-way combinations, 179 distinct 4-way combinations, and 69 distinct 5-way combinations. Sacral agenesis had the largest proportion of cases with MCAs (70%), whereas gastroschisis had the lowest (3%). Among the cases with MCAs, 63% had a heart defect, 23% had an oral cleft, and 21% had anorectal atresia/stenosis. Of the patterns with adjusted observed-to-expected ratios in the top 20%, most were consistent with the known associations or syndromes, including VATER/VACTERL association and CHARGE syndrome. CONCLUSIONS: Most but not all patterns that had the highest adjusted observed-to-expected ratios were instances of known syndromes or associations. These findings highlight the importance of considering birth defect combinations that suggest syndromic patterns in the absence of a formal syndromic diagnosis. New approaches for screening for sequences and associations, and VATER/VACTERL in particular, in surveillance systems with limited resources for manual review may be valuable for improving surveillance system quality. The observed MCA patterns within NBDPS may help focus future genetic studies by generating case groups of higher yield.
Authors: Sarah C Tinker; Suzanne M Gilboa; Cynthia A Moore; D Kim Waller; Regina M Simeone; Shin Y Kim; Denise J Jamieson; Lorenzo D Botto; Jennita Reefhuis Journal: Am J Obstet Gynecol Date: 2019-08-24 Impact factor: 8.661
Authors: Renata H Benjamin; Xiao Yu; Maria Luisa Navarro Sanchez; Han Chen; Laura E Mitchell; Peter H Langlois; Mark A Canfield; Michael D Swartz; Angela E Scheuerle; Daryl A Scott; Hope Northrup; Christian P Schaaf; Joseph W Ray; Scott D McLean; Philip J Lupo; A J Agopian Journal: Birth Defects Res Date: 2019-07-16 Impact factor: 2.344
Authors: Vijaya Kancherla; Paul A Romitti; Lixian Sun; John C Carey; Trudy L Burns; Anna Maria Siega-Riz; Charlotte M Druschel; Angela E Lin; Richard S Olney Journal: Eur J Med Genet Date: 2014-02-24 Impact factor: 2.708