Birth Defects Research Part A - Clinical and Molecular Teratology

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect with complex etiology reflecting the action of multiple genetic and environmental factors. Genome‐wide association studies have successfully identified five novel loci associated with NSCL/P, including a locus on 1p22.1 near theABCA4gene. Because neither expression analysis nor mutation screening support a role forABCA4in NSCL/P, we investigated the adjacent geneARHGAP29.
Mutation screening forARHGAP29protein coding exons was conducted in 180 individuals with NSCL/P and controls from the United States and the Philippines. Nine exons with variants inARHGAP29were then screened in an independent set of 872 cases and 802 controls.Arhgap29expression was evaluated using in situ hybridization in murine embryos.
Sequencing ofARHGAP29revealed eight potentially deleterious variants in cases including a frameshift and a nonsense variant.Arhgap29showed craniofacial expression and was reduced in a mouse deficient forIrf6, a gene previously shown to have a critical role in craniofacial development.
The combination of genome‐wide association, rare coding sequence variants, craniofacial specific expression, and interactions withIRF6support a role forARHGAP29in NSCL/P and as the etiologic gene at the 1p22 genome‐wide association study locus for NSCL/P. This work suggests a novel pathway in which theIRF6gene regulatory network interacts with the Rho pathway viaARHGAP29. Birth Defects Research (Part A) 2012. © 2012 Wiley Periodicals, Inc.

Elizabeth J. Leslie

M. Adela Mansilla

Leah C. Biggs

Kristi Schuette

Steve Bullard

Margaret Cooper

Martine Dunnwald

Andrew C. Lidral

Mary L. Marazita

Terri H. Beaty

Jeffrey C. Murray

Birth Defects Research Part A: Clinical and Molecular Teratology

Birth Defects Research

Expression and mutation analyses implicate ARHGAP29 as the etiologic gene for the cleft lip with or without cleft palate locus identified by genome‐wide association on chromosome 1p22

表达和突变分析提示ARHGAP29为1号染色体1p22区域全基因组关联研究识别的唇裂伴或不伴腭裂位点的致病基因

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect of complex etiology. Several genes have been implicated in the etiology of NSCL/P, although only a few have been replicated across datasets.
ARHGAP29was suggested as a candidate gene for NSCL/P as it is located in close proximity toABCA4(1p22), a gene previously identified in a genome‐wide association study of NSCL/P.
Rare, potentially damaging, coding variants inARHGAP29were found in NSCL/P cases, and its expression was detected during murine craniofacial development. In this study, we investigated whether variations inARHGAP29were associated with NSCL/P in our family based dataset. Five single‐nucleotide polymorphisms (SNPs) flanking and withinARHGAP29were genotyped in our NSCL/P datasets consisting of simplex and multiplex families of non‐Hispanic white (NHW, primarily European) and Hispanic ethnicities. Results showed strong association of threeARHGAP29SNPs with NSCL/P in the NHW families. Two intronic SNPs (rs1541098 and rs3789688) showed strong association with NSCL/P in all NHW families (p= 0.0005 andp= 0.0002, respectively), and simplex NHW families (p= 0.003 for both SNPs). A SNP in the 3′ untranslated region (rs1576593) also showed strong association with NSCL/P in all NHW families (p= 0.002), and the multiplex subset (p= 0.002).ARHGAP29SNP haplotypes were also associated with NSCL/P. Evidence of gene–gene interaction was found betweenARHGAP29and additional cleft susceptibility genes.
This study further supportsARHGAP29as a candidate gene for human NSCL/P in families of Caucasian descent. Birth Defects Research (Part A), 100:679–685, 2014 © 2014 Wiley Periodicals, Inc.

Ariadne Letra

Lorena Maili

John B. Mulliken

Edward Buchanan

Susan H. Blanton

Jacqueline T. Hecht

Further evidence suggesting a role for variation in <i>ARHGAP29</i> variants in nonsyndromic cleft lip/palate

进一步证据表明<i>ARHGAP29</i>变异在非综合征性唇腭裂中的作用

BACKGROUND
Birth defects affect 3% of babies born, and are one of the leading causes of infant mortality. Both younger and older maternal age may pose increased risks for certain birth defects. This study assessed the relationship between maternal age at the estimated delivery date and the risk for birth defects.


METHODS
Data were obtained from the National Birth Defects Prevention Study, a population-based case-control study including mothers across 10 states. Maternal age was stratified into six categories: <20, 20 to 24, 25 to 29, 30 to 34, 35 to 39, and ≥40 years, and also analyzed as a continuous variable. Logistic regression models adjusted formaternal race/ethnicity, education, body mass index (BMI), folic acid use, smoking, gravidity, and parental age difference were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs).


RESULTS
For maternal age <20 years, associations with total anomalous pulmonary venous return (aOR, 2.3; 95% CI, 1.3-4.0), amniotic band sequence (aOR, 2.4; 95% CI, 1.5-3.8), and gastroschisis (aOR, 6.1; 95% CI, 4.8-8.0) were observed. For the ≥40 year age group, associations with several cardiac defects, esophageal atresia (aOR, 2.9; 95% CI, 1.7-4.9), hypospadias (aOR, 2.0; 95% CI, 1.4-3.0), and craniosynostosis (aOR, 1.6; 95% CI, 1.1-2.4) were observed. Results using maternal age as a continuous variable were consistent with those that used categorized maternal age.


CONCLUSION
Elucidating risk factors specific to women ateither extreme of maternal age may offer prevention opportunities. All women should be made aware of prevention opportunities, such as folic acid supplementation, to reduce the occurrence of birth defects.

Simerpal K. Gill

Cheryl Broussard

Owen Devine

Ridgely Fisk Green

Sonja A. Rasmussen

Jennita Reefhuis

and the National Birth Defects Prevention Study

Association between maternal age and birth defects of unknown etiology ― United States, 1997-2007

母亲年龄与不明病因出生缺陷的关联——美国，1997-2007年

BACKGROUND
Congenital rubella syndrome (CRS) has long been characterized by the triad of deafness, cataract, and cardiovascular malformations (CVMs). While initial reports identified patent ductus arteriosus (PDA) as the primary CVM in CRS, the exact nature of the CVMs found in CRS has not been well established.


METHODS
We searched the English literature from 1941 through 2008 to identify studies that used cardiac catheterization or echocardiography to evaluate the CVMs in CRS.


RESULTS
Of the 121 patients in the 10 studies with catheterization data, 78% had branch pulmonary artery stenosis, and 62% had a PDA. In 49% of cases, both branch pulmonary artery stenosis and PDA were present, whereas isolated branch pulmonary artery stenosis and isolated PDA were found in 29 and 13% of cases, respectively. Of the 12 patients in the 10 studies with echocardiographic data, PDA was more common than branch pulmonary artery stenosis, but this finding is greatly limited by the small numbers of patients and limitations of echocardiography. Although published studies of CVMs in CRS have in general reported PDA as the CVM phenotype most commonly associated with CRS, among CRS cases evaluated by catheterization, branch pulmonary artery stenosis was actually more common than PDA. Moreover, although the combination of branch pulmonary artery stenosis and PDA was more common than either branch pulmonary artery stenosis or PDA alone, isolated branch pulmonary artery stenosis was twice as common as isolated PDA.


CONCLUSION
Among children with suspected CRS, clinical evaluations for the presence of CVMs should include examinations for both branch pulmonary artery stenosis and PDA.

Matthew E. Oster

Tiffany Riehle-Colarusso

Adolfo Correa

Birth Defect Res A

An update on cardiovascular malformations in congenital rubella syndrome

先天性风疹综合征中心血管畸形的最新进展

The teratogenic effect of influenza viruses is currently being debated, and we examined the large population‐based data set of the Hungarian Case‐Control Surveillance of Congenital Abnormalities (HCCSCA) to study the possible association between maternal influenza and various congenital abnormalities (CAs).
The 1980–1996 HCCSCA includes 22,843 newborns or fetuses with CAs, and 38,151 matched controls (newborn infants without any abnormalities).
In the case group, 1328 (5.8%) mothers had influenza at some time during their pregnancies compared to 1838 (4.8%) mothers in the control group (adjusted prevalence odds ratios [PORs], 1.3; 95% confidence interval [CI], 1.2–1.4). In the calculation of the adjusted PORs, the use of antifever drugs and maternal employment status were considered. When cases and their matched controls were compared, there was a higher prevalence of maternal influenza during the second and/or third month of pregnancy for the group of newborns with cleft lip ± palate (adjusted POR, 3.2; 95% CI, 2.0–5.3), neural‐tube defects (adjusted POR, 1.9; 95% CI, 1.1–3.3), and cardiovascular malformations (adjusted POR, 1.7; 95% CI, 1.3–2.3). However, a direct teratogenic effect from influenza viruses appears to be unlikely, and we suggest that the higher prevalence of the CAs indicated above can be explained mainly by fever, because this risk was reduced by the use of antifever drugs. Periconceptional folic acid supplementation also showed some preventive effect for these CAs.
The indirect teratogenic effect of maternal influenza during pregnancy may be restricted by appropriate medical treatment (e.g., antifever drugs) and periconceptional folic acid supplementation. Birth Defects Research (Part A), 2005. © 2005 Wiley‐Liss, Inc.

NÁndor ács

Ferenc Bánhidy

Erzsébet Puhó

Andrew E. Czeizel

Maternal influenza during pregnancy and risk of congenital abnormalities in offspring

妊娠期母亲流感与后代先天性异常风险

BACKGROUND
The prevalence of ventricular septal defects (VSDs), a birth defect in which there is an opening in the wall that separates the left and right ventricles of the heart, seemed to be substantially higher in Delaware compared with the National Birth Defects Prevention Network (NBDPN). The Delaware Birth Defects Registry (BDR) noted their high prevalence of VSDs in comparison with other states.


METHODS
A subset of children with a VSD born in 2007 through 2010 was identified from the complete reportable statewide defect list that the BDR creates each year. VSDs were categorized by type of VSD (muscular, perimembranous, conotruncal, or atrioventricular septal defect), by either isolated or complex, and then by spontaneously closed, surgically closed, open but clinically insignificant, lost to follow-up, fetal or neonatal death.


RESULTS
The BDR team found a prevalence of VSD of 83.4 per 10,000 including fetal/neonatal deaths. Excluding fetal and neonatal deaths the prevalence was 78.7 per 10,000 live births. Excluding small muscular VSDs, the prevalence in Delaware falls to 25.7 per 10,000.


CONCLUSION
The BDR team chose to include all babies with all types of VSDs. Using these criteria Delaware's prevalence of 78.7 was higher than that reported by other states (whose prevalence ranges from 1.6 to 70.0 per 10,000 live births) (National Birth Defects Prevention Network, ). Delaware's prevalence is similar to other states when small muscular VSDs are excluded. Birth Defects Research (Part A) 106:888-893, 2016. © 2016 Wiley Periodicals, Inc.

Amy Acheson

Anika Vaidy

Kathleen Stomieroski

Dana R. Thompson

Kristin M. Maiden

Deborah B. Ehrenthal

Samir Yezdani

Abdul Majeed Bhat

Robert Locke

Louis E. Bartoshesky

Surveillance of ventricular septal defects in Delaware

特拉华州室间隔缺损的监测

BACKGROUND
Congenital heart defects (CHDs) are among the most prevalent and serious birth defects, occurring in 8 to 10 of every 1000 live births in the United States. Epidemiologic studies have reported an association between CHDs and maternal smoking, but it remains unknown how genes impact the susceptibility of offspring to CHDs in the presence of maternal tobacco use.


METHODS
Using data from 403 case- and 219 control-parental triads enrolled in the National Birth Defects Prevention Study between 1998 and 2008, we investigated the association between CHDs and maternal and infant genetic variants involved in the tobacco metabolism and DNA repair pathways among mothers who smoked prenatally.


RESULTS
The maternal genotypes of single nucleotide polymorphisms in the excision repair cross-complementation group 1 (ERCC1), poly (ADP-ribose) polymerase 2 (PARP2), and ERCC5 genes were identified to be significantly associated with the occurrence of CHDs in the presence of maternal tobacco use. Our analysis also revealed a moderate association between the infant genotypes of polymorphisms in the O-sialoglycoprotein endopeptidase (OSGEP) gene and increased risk of CHDs among mothers who smoked.


CONCLUSION
Our study provides evidence that maternal and infant polymorphisms within the ERCC1, PARP2, ERCC5, and OSGEP genes are associated with CHD risk in the presence of maternal tobacco use. These results may provide insight into the susceptibility of having a pregnancy affected by CHDs among women who smoke.

Xinyu Tang

Charlotte A. Hobbs

Mario A. Cleves

Stephen W. Erickson

Stewart L. MacLeod

Sadia Malik

the National Birth Defects Prevention Study

Genetic variation affects congenital heart defect susceptibility in offspring exposed to maternal tobacco use

遗传变异影响暴露于母亲吸烟的子代先天性心脏病易感性

BACKGROUND
There is evidence in experimental model systems that exposure to polycyclic aromatic hydrocarbons (PAHs) results in congenital heart defects (CHDs); however, to our knowledge, this relationship has not been examined in humans. Therefore, we conducted a case-control study assessing the association between estimated maternal occupational exposure to PAHs and CHDs in offspring.


METHODS
Data on CHD cases and control infants were obtained from the National Birth Defects Prevention Study for the period of 1997 to 2002. Exposure to PAHs was assigned by industrial hygienist consensus, based on self-reported maternal occupational histories from 1 month before conception through the third month of pregnancy. Logistic regression was used to evaluate the association between maternal occupational PAH exposure and specific CHD phenotypic subtypes among offspring.


RESULTS
The prevalence of occupational PAH exposure was 4.0% in CHD case mothers (76/1907) and 3.6% in control mothers (104/2853). After adjusting for maternal age, race or ethnicity, education, smoking, folic acid supplementation, and study center, exposure was not associated with conotruncal defects (adjusted odds ratio [AOR], 0.98; 95% confidence interval [CI], 0.58-1.67), septal defects (AOR, 1.28; 95% CI, 0.86-1.90), or with any isolated CHD subtype.


CONCLUSIONS
Our findings do not support an association between potential maternal occupational exposure to PAHs and various CHDs in a large, population-based study. For CHD phenotypic subtypes in which modest nonsignificant associations were observed, future investigations could be improved by studying populations with a higher prevalence of PAH exposure and by incorporating information on maternal and fetal genotypes related to PAH metabolism. Birth Defects Research (Part A), 2012.

Philip J. Lupo

Elaine Symanski

Peter H. Langlois

Christina C. Lawson

Suzanne M. Gilboa

Laura J. Lee

A. J. Agopian

Tania A. Desrosiers

Martha A. Waters

Paul A. Romitti

Gary M. Shaw

Laura E. Mitchell

Maternal occupational exposure to polycyclic aromatic hydrocarbons and congenital heart defects among offspring in the national birth defects prevention study

母亲职业暴露于多环芳烃与国家出生缺陷预防研究中后代先天性心脏缺陷的关系

出版信息	出版商: Wiley-Liss Inc.，出版周期: ，期刊类型: journal，开源期刊: 否
基本数据	创刊年份: 2003，原创研究文献占比: 0.00%，自引率:N.A.， Gold OA占比: 0.00%

Birth Defects Research Part A - Clinical and Molecular Teratology

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Expression and mutation analyses implicate ARHGAP29 as the etiologic gene for the cleft lip with or without cleft palate locus identified by genome‐wide association on chromosome 1p22

Further evidence suggesting a role for variation in ARHGAP29 variants in nonsyndromic cleft lip/palate

Association between maternal age and birth defects of unknown etiology ― United States, 1997-2007

An update on cardiovascular malformations in congenital rubella syndrome

Maternal influenza during pregnancy and risk of congenital abnormalities in offspring

Surveillance of ventricular septal defects in Delaware

Genetic variation affects congenital heart defect susceptibility in offspring exposed to maternal tobacco use

Further evidence suggesting a role for variation in ARHGAP29 variants in nonsyndromic cleft lip/palate

Expression and mutation analyses implicate ARHGAP29 as the etiologic gene for the cleft lip with or without cleft palate locus identified by genome‐wide association on chromosome 1p22

Maternal occupational exposure to polycyclic aromatic hydrocarbons and congenital heart defects among offspring in the national birth defects prevention study