Howley Meredith M, Williford Eva, Agopian A J, Lin Angela E, Botto Lorenzo D, Cunniff Christopher M, Romitti Paul A, Nestoridi Eirini, Browne Marilyn L
Birth Defects Registry, New York State Department of Health, Albany, New York, USA.
Department of Epidemiology, Human Genetics, and Environmental Sciences, UTHealth School of Public Health, Houston, Texas, USA.
Birth Defects Res. 2023 Jan 1;115(1):43-55. doi: 10.1002/bdr2.2003. Epub 2022 Mar 11.
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.
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.
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.
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.
约20%-30%的出生缺陷儿童在一个以上器官系统中存在多种主要出生缺陷，通常称为多发性先天性异常（MCA）。评估MCA的模式可为潜在病因、致病机制和发育途径提供线索。我们试图在国家出生缺陷预防研究（NBDPS）中探索选定的MCA模式，这是一项基于人群的病例对照研究，排除了已知染色体或单基因异常导致的病例。
我们将MCA定义为有两个或更多符合NBDPS标准的出生缺陷，并使用共现缺陷分析计算所有观察到的MCA模式的调整后观察与预期比率。
在符合NBDPS标准的50186例病例婴儿中，2734例（3.7%）至少有两个符合标准的出生缺陷。我们观察到209种不同的出生缺陷双向组合、297种不同的三向组合、179种不同的四向组合和69种不同的五向组合。骶骨发育不全在MCA病例中所占比例最大（70%），而腹裂所占比例最低（3%）。在MCA病例中，63%有心脏缺陷，23%有口腔腭裂，21%有肛门直肠闭锁/狭窄。在调整后观察与预期比率排名前20%的模式中，大多数与已知关联或综合征一致，包括VATER/VACTERL关联和CHARGE综合征。
调整后观察与预期比率最高的模式中，大多数但并非全部是已知综合征或关联的实例。这些发现凸显了在没有正式综合征诊断的情况下，考虑提示综合征模式的出生缺陷组合的重要性。在资源有限、无法进行人工审查的监测系统中，筛选序列和关联尤其是VATER/VACTERL的新方法，可能对提高监测系统质量具有重要价值。NBDPS中观察到的MCA模式可能通过生成更高产率的病例组，有助于为未来的基因研究指明方向。
