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1.  Evaluating rare coding variants as contributing causes to nonsyndromic cleft lip and palate 
Clinical genetics  2012;84(5):496-500.
Rare coding variants are a current focus in studies of complex disease. Previously, at least 68 rare coding variants were reported from candidate gene sequencing studies in nonsyndromic cleft lip and palate (NSCL/P), a common birth defect. Advances in sequencing technology have now resulted in thousands of sequenced exomes, providing a large resource for comparative genetic studies. We collated rare coding variants reported to contribute to NSCL/P and compared them to variants identified from control exome databases to determine if some might be rare but benign variants. 71% of the variants described as etiologic for NSCL/P were not present in the exome data, suggesting that many likely contribute to disease. Our results strongly support a role for rare variants previously reported in the majority of NSCL/P candidate genes but diminish support for variants in others. However, because clefting is a complex trait it is not possible to be definitive about the role of any particular variant for its risk for NSCL/P.
doi:10.1111/cge.12018
PMCID: PMC3788862  PMID: 22978696
cleft lip; cleft palate; candidate gene; sequencing
2.  A Proposed Method to Predict Preterm Birth Using Clinical Data, Standard Maternal Serum Screening, and Cholesterol 
Objective
To create a predictive model for preterm birth (PTB) from available clinical data and serum analytes.
Study Design
Serum analytes, routine pregnancy screening plus cholesterol and corresponding health information were linked to birth certificate data for a cohort of 2699 Iowa women with serum sampled in the first and second trimester. Stepwise logistic regression was used to select the best predictive model for PTB.
Results
Serum screening markers remained significant predictors of PTB even after controlling for maternal characteristics. The best predictive model included maternal characteristics, first trimester total cholesterol (TC), TC change between trimesters and second trimester alpha-fetoprotein and inhibin A. The model showed better discriminatory ability than PTB history alone and performed similarly in subgroups of women without past PTB.
Conclusions
Using clinical and serum screening data a potentially useful predictor of PTB was constructed. Validation and replication in other populations, and incorporation of other measures that identify PTB risk, like cervical length, can be a step towards identifying additional women who may benefit from new or currently available interventions.
doi:10.1016/j.ajog.2013.03.005
PMCID: PMC3765002  PMID: 23500456
cholesterol; prediction; preterm birth; serum screening
3.  Search for Genetic Modifiers of IRF6 and Genotype-Phenotype Correlations in Van der Woude and Popliteal Pterygium Syndromes 
Van der Woude syndrome is the most common form of syndromic orofacial clefting, accounting for 1-2% of all patients with cleft lip and/or cleft palate. Van der Woude and popliteal pterygium syndromes are caused by mutations in IRF6, but phenotypic variability within and among families with either syndrome suggests that other genetic factors contribute to the phenotypes. The aim of this study was to identify common variants acting as genetic modifiers of IRF6 as well as genotype-phenotype correlations based on mutation type and location. We identified an association between mutations in the DNA-binding domain of IRF6 and limb defects (including pterygia). Although we did not detect formally significant associations with the genes tested, borderline associations suggest several genes that could modify the VWS phenotype, including FOXE1, TGFB3, and TFAP2A. Some of these genes are hypothesized to be part of the IRF6 gene regulatory network and may suggest additional genes for future study when larger sample sizes are also available. We also show that families with the Van der Woude phenotype but in whom no mutations have been identified have a lower frequency of cleft lip, suggesting there may be locus and/or mutation class differences in Van der Woude syndrome.
doi:10.1002/ajmg.a.36133
PMCID: PMC3898350  PMID: 23949966
Modifier gene; Van der Woude; popliteal pterygium; cleft; lip pit
4.  Racial Gaps in Child Health Insurance Coverage in Four South American Countries: The Role of Wealth, Human Capital, and Other Household Characteristics 
Health Services Research  2011;46(6 Pt 2):2119-2138.
Objective
To evaluate the extent of racial gaps in child health insurance coverage in South America and study the contribution of wealth, human capital, and other household characteristics to accounting for racial disparities in insurance coverage.
Data Sources/Study Setting
Primary data collected between 2005 and 2006 in 30 pediatric practices in Argentina, Brazil, Ecuador, and Chile.
Design
Country-specific regression models are used to assess differences in insurance coverage by race. A decomposition model is used to quantify the extent to which wealth, human capital, and other household characteristics account for racial disparities in insurance coverage.
Data Collection/Extraction Methods
In-person interviews were conducted with the mothers of 2,365 children.
Principal Findings
The majority of children have no insurance coverage except in Chile. Large racial disparities in insurance coverage are observed. Household wealth is the single most important household-level factor accounting for racial disparities in coverage and is significantly and positively associated with coverage, followed by maternal education and employment/occupational status. Geographic differences account for the largest part of racial disparities in insurance coverage in Argentina and Ecuador.
Conclusions
Increasing the coverage of children in less affluent families is important for reducing racial gaps in health insurance coverage in the study countries.
doi:10.1111/j.1475-6773.2010.01225.x
PMCID: PMC3119768  PMID: 21210797
Health insurance; racial disparities; socioeconomic disparities; child health; South America
5.  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 
Background
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/or environmental factors. Genome wide association studies have successfully identified five novel loci associated with NSCL/P including a locus on 1p22.1 near the ABCA4 gene. Since neither expression analysis nor mutation screening support a role for ABCA4 in NSCL/P, we investigated the adjacent gene ARHGAP29.
Methods
Mutation screening for ARHGAP29 protein coding exons was conducted in 180 individuals with NSCL/P and controls from the US and the Philippines. Nine exons with variants in ARHGAP29 were then screened in an independent set of 872 cases and 802 controls. Arhgap29 expression was evaluated using in situ hybridization in murine embryos.
Results
Sequencing of ARHGAP29 revealed eight potentially deleterious variants in cases including a frameshift and a nonsense variant. Arhgap29 showed craniofacial expression and was reduced in a mouse deficient for Irf6, a gene previously shown to have a critical role in craniofacial development.
Conclusion
The combination of genome wide association, rare coding sequence variants, craniofacial specific expression and interactions with IRF6 support a role for ARHGAP29 in NSCL/P and as the etiologic gene at the 1p22 GWAS locus for NSCL/P. This work suggests a novel pathway in which the IRF6 gene regulatory network interacts with the Rho pathway via ARHGAP29.
doi:10.1002/bdra.23076
PMCID: PMC3501616  PMID: 23008150
ARHGAP29; cleft lip and palate; candidate gene; complex traits; Rho signaling
6.  Genetic Influences on Preterm Birth in Argentina 
Objective
To investigate genetic etiologies of preterm birth (PTB) in Argentina through evaluation of single-nucleotide polymorphisms (SNP) in candidate genes and population genetic admixture.
Study Design
Genotyping was performed in 389 families. Maternal, paternal, and fetal effects were studied separately. Mitochondrial DNA (mtDNA) was sequenced in 50 males and 50 females. Y-chromosome anthropological markers were evaluated in 50 males.
Results
Fetal association with PTB was found in the progesterone receptor (PGR, rs1942836; p= 0.004). Maternal association with PTB was found in small conductance calcium activated potassium channel isoform 3 (KCNN3, rs883319; p= 0.01). Gestational age associated with PTB in PGR rs1942836 at 32 –36 weeks (p= 0.0004). MtDNA sequencing determined 88 individuals had Amerindian consistent haplogroups. Two individuals had Amerindian Y-chromosome consistent haplotypes.
Conclusions
This study replicates single locus fetal associations with PTB in PGR, maternal association in KCNN3, and demonstrates possible effects for divergent racial admixture on PTB.
doi:10.1038/jp.2012.118
PMCID: PMC3719965  PMID: 23018797
Prematurity; genetic admixture
7.  Comparative analysis of IRF6 variants in families with Van der Woude syndrome and popliteal pterygium syndrome using public whole exome databases 
Purpose
IRF6 is a transcription factor that, when mutated, causes allelic autosomal dominant clefting syndromes, Van der Woude syndrome (VWS) and popliteal pterygium syndrome (PPS). We compared the distribution of IRF6 coding and splice site mutations from 549 VWS or PPS families to that of variants from the 1000 Genomes and NHLBI Exome Sequencing Projects.
Methods
We compiled all published pathogenic IRF6 mutations and performed direct sequencing of IRF6 in VWS/PPS families.
Results
While mutations causing VWS/PPS were non-randomly distributed with significantly increased frequencies in the DNA-binding domain (p=0.0001), variants found in controls were rare and evenly distributed in IRF6. Out of 194 different missense or nonsense variants described as potentially pathogenic, we identified only two in over 6000 controls. 5.9% of missense mutations in patients were reported by PolyPhen and SIFT as benign; suggesting that use of current in silico prediction models to determine function can have significant false negatives.
Conclusion
Mutation of IRF6 occurs infrequently in controls, suggesting that for IRF6 there is a high probability that disruption of the coding sequence, particularly the DNA-binding domain, will result in syndromic features. Prior associations of coding sequence variants in IRF6 with clefting syndromes have had few false positives.
doi:10.1038/gim.2012.141
PMCID: PMC3723330  PMID: 23154523
Van der Woude; exome; cleft; popliteal pterygium; mutation
8.  Candidate gene linkage approach to Identify DNA variants that predispose to preterm birth 
Pediatric research  2012;73(2):135-141.
Background
To identify genetic variants contributing to preterm birth using a linkage candidate gene approach.
Methods
We studied 99 single nucleotide polymorphisms for 33 genes in 257 families with preterm births segregating. Nonparametric and parametric analyses were used. Premature infants and mothers of premature infants were defined as affected cases in independent analyses.
Results
Analyses with the infant as the case identified two genes with evidence of linkage: CRHR1 (p=0.0012) and CYP2E1 (p=0.0011). Analyses with the mother as the case identified four genes with evidence of linkage: ENPP1 (p=0.003), IGFBP3 (p=0.006), DHCR7 (p=0.009), and TRAF2 (p=0.01). DNA sequence analysis of the coding exons and splice sites for CRHR1 and TRAF2 identified no new likely etiologic variants.
Conclusion
These findings suggest the involvement of six genes acting through the infant and/or the mother in the etiology of preterm birth.
doi:10.1038/pr.2012.166
PMCID: PMC3740714  PMID: 23168575
9.  No Observed Association for Mitochondrial SNPs with Preterm Delivery and Related Outcomes 
Pediatric research  2012;72(5):539-544.
Background
Preterm delivery (PTD) is the leading cause of neonatal morbidity and mortality. Epidemiologic studies indicate recurrence of PTD is maternally inherited creating a strong possibility that mitochondrial variants contribute to its etiology. This study examines the association between mitochondrial genotypes with PTD and related outcomes.
Methods
This study combined, through meta-analysis, two case-control, genome-wide association studies (GWAS); one from the Danish National Birth Cohort (DNBC) Study and one from the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health. The outcomes of PTD (≤36 weeks), very PTD (≤32 weeks) and preterm prelabor rupture of membranes (PPROM) were examined. 135 individual SNP associations were tested using the combined genome from mothers and neonates (case vs. control) in each population and then pooled via meta-analysis.
Results
After meta-analysis there were four SNPs for the outcome of PTD below p≤0.10, and two below p≤0.05. For the additional outcomes of very PTD and PPROM there were three and four SNPs respectively below p≤0.10.
Conclusion
Given the number of tests no single SNP reached study wide significance (p=0.0006). Our study does not support the hypothesis that mitochondrial genetics contributes to the maternal transmission of PTD and related outcomes.
doi:10.1038/pr.2012.112
PMCID: PMC3694399  PMID: 22902432
10.  Identification of Microdeletions in Candidate Genes for Cleft Lip and/or Palate 
BACKGROUND
Genome-wide association studies are now used routinely to identify genes implicated in complex traits. The panels used for such analyses can detect single nucleotide polymorphisms and copy number variants, both of which may help to identify small deleted regions of the genome that may contribute to a particular disease
METHODS
We performed a candidate gene analysis involving 1221 SNPs in 333 candidate genes for orofacial clefting using 2823 samples from 725 two- and three-generation families with a proband with clefts of the lip and/or palate. We used SNP genotyping, DNA sequencing, high-resolution DNA microarray analysis and long-range PCR to confirm and characterize the deletion events
RESULTS
This dataset had a high duplicate reproducibility rate (99.98%), high Mendelian consistency rate (99.93%), and low missing data rate (0.55%), which provided a powerful opportunity for deletion detection. Apparent Mendelian inconsistencies between parents and child suggested deletion events in 15 individuals in 11 genomic regions. We confirmed deletions involving CYP1B1, FGF10, SP8, SUMO1, TBX1, TFAP2A, and UGT7A1, including both de novo and familial cases. Deletions of SUMO1, TBX1, and TFAP2A are likely to be etiologic
CONCLUSIONS
These deletions suggest the potential roles of genes or regulatory elements contained within deleted regions in the etiology of clefting. Our analysis took advantage of genotypes from a candidate-gene-based SNP survey and proved to be an efficient analytical approach to interrogate genes potentially involved in clefting. This can serve as a model to find genes playing a role in complex traits in general.
doi:10.1002/bdra.20571
PMCID: PMC3682790  PMID: 19137569
cleft lip; cleft palate; microdeletion; SNPs; CNV; candidate genes
11.  Genetic Associations of Surfactant Protein D and Angiotensin-Converting Enzyme with Lung Disease in Preterm Neonates 
Journal of Perinatology  2011;32(5):349-355.
Objective
To replicate genetic associations with respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in genes related to surfactant deficiency, inflammation and infection and the renin-angiotensin system.
Study Design
We examined eight candidate genes for associations with RDS and BPD in 433 preterm (PTB - <37 weeks) infants (251 with RDS and 134 with BPD). Both case-control and family-based analyses were performed in preterm (<37 weeks) and very preterm (VPTB - <32 weeks) infants.
Results
We replicated a previous finding that rs1923537, a marker downstream of surfactant protein D (SFTPD) is associated with RDS in VPTB infants in that the T allele was over-transmitted from parents to offspring with RDS (p=8.4×10−3). We also observed the A allele of rs4351 in the angiotensin-converting enzyme (ACE) gene was over-transmitted from parents to VPTB offspring with BPD (p=9.8×10−3).
Conclusion
These results give further insight into the genetic risk factors for complex neonatal respiratory diseases and provide more evidence of the importance of SFTPD and ACE in the etiology of RDS and BPD, respectively.
doi:10.1038/jp.2011.104
PMCID: PMC3370386  PMID: 21960125
bronchopulmonary dysplasia; respiratory distress syndrome; single nucleotide polymorphism
12.  Oral Cleft Recurrence Risk and Subsequent Maternal Fertility Preferences and Behavior in Brazil 
Background
Oral clefts are among the most common birth defects with numerous impacts on affected individuals and families. However, little is known about how being at a greater risk of having an affected child affects subsequent maternal fertility decisions. We investigated differences in fertility preferences and behavior between mothers who are themselves affected with cleft lip with/without cleft palate but have had no affected children and unaffected mothers of an affected child. We also compared these outcomes between unaffected mothers of a first versus another affected child.
Methods
The sample included 1475 Brazilian women interviewed between 2004 and 2009. The outcomes were wanting more children, contraceptive use and type, and maternal age at first child. Comparisons between the various maternal groups were performed using regression analysis adjusting for conceptually relevant demographic, socioeconomic, and geographic factors.
Results
Affected mothers of unaffected children were less likely to use contraceptives than unaffected mothers of affected children by 31% [95% CI: 1–53%]. Among unaffected mothers, those who had a first affected child were 67% [95% CI: 15–144%] more likely to use contraceptives.
Conclusions
The results suggest that having an affected child represents a stronger signal of recurrence risk to the mother than her own cleft status, and that cleft status of the first child is especially important in influencing subsequent maternal fertility decisions in affected families. These findings highlight the importance of adequate counseling of at-risk women about recurrence risks and available care resources and policies that improve access to quality cleft care.
doi:10.1002/bdra.23214
PMCID: PMC4103876  PMID: 24382743
birth defects; oral clefts; fertility; contraception; family planning
13.  Genome-Wide Analysis of DNA Methylation in Human Amnion 
The Scientific World Journal  2013;2013:678156.
The amnion is a specialized tissue in contact with the amniotic fluid, which is in a constantly changing state. To investigate the importance of epigenetic events in this tissue in the physiology and pathophysiology of pregnancy, we performed genome-wide DNA methylation profiling of human amnion from term (with and without labor) and preterm deliveries. Using the Illumina Infinium HumanMethylation27 BeadChip, we identified genes exhibiting differential methylation associated with normal labor and preterm birth. Functional analysis of the differentially methylated genes revealed biologically relevant enriched gene sets. Bisulfite sequencing analysis of the promoter region of the oxytocin receptor (OXTR) gene detected two CpG dinucleotides showing significant methylation differences among the three groups of samples. Hypermethylation of the CpG island of the solute carrier family 30 member 3 (SLC30A3) gene in preterm amnion was confirmed by methylation-specific PCR. This work provides preliminary evidence that DNA methylation changes in the amnion may be at least partially involved in the physiological process of labor and the etiology of preterm birth and suggests that DNA methylation profiles, in combination with other biological data, may provide valuable insight into the mechanisms underlying normal and pathological pregnancies.
doi:10.1155/2013/678156
PMCID: PMC3590748  PMID: 23533356
14.  Genetics of Nonsyndromic Orofacial Clefts 
With an average worldwide prevalence of approximately 1.2/1000 live births, orofacial clefts are the most common craniofacial birth defects in humans. Like other complex disorders, these birth defects are thought to result from the complex interplay of multiple genes and environmental factors. Significant progress in the identification of underlying genes and pathways has benefited from large populations available for study, increased international collaboration, rapid advances in genotyping technology, and major improvements in analytic approaches. Here we review recent advances in genetic epidemiological approaches to complex traits and their applications to studies of nonsyndromic orofacial clefts. Our main aim is to bring together a discussion of new and previously identified candidate genes to create a more cohesive picture of interacting pathways that shape the human craniofacial region. In future directions, we highlight the need to search for copy number variants that affect gene dosage and rare variants that are possibly associated with a higher disease penetrance. In addition, sequencing of protein-coding regions in candidate genes and screening for genetic variation in non-coding regulatory elements will help advance this important area of research.
doi:10.1597/10-178
PMCID: PMC3437188  PMID: 21545302
Nonsyndromic orofacial clefts; candidate gene; sequencing; single nucleotide polymorphism; association study; genome-wide association study
15.  Candidate gene analysis: Severe intraventricular hemorrhage in inborn preterm neonates 
The Journal of pediatrics  2013;163(5):10.1016/j.jpeds.2013.06.025.
Intraventricular hemorrhage is a disorder of complex etiology. We analyzed genotypes for 7 genes from 224 inborn preterm neonates treated with antenatal steroids and Grade 3-4 intraventricular hemorrhage and 389 matched controls. Only methylenetetrahydrofolate reductase was more prevalent in cases of intraventricular hemorrhage, emphasizing the need for more comprehensive genetic strategies.
doi:10.1016/j.jpeds.2013.06.025
PMCID: PMC3812267  PMID: 23896193
16.  Replication of genetic associations in the inflammation, complement and coagulation pathways with intraventricular hemorrhage in low birth weight preterm neonates 
Pediatric research  2011;70(1):90-95.
Intraventricular hemorrhage (IVH) is a significant morbidity seen in very low birth weight infants. Genes related to the inflammation, infection, complement or coagulation pathways have been implicated as risk factors for IVH. We examined ten candidate genes for associations with IVH in 271 preterm infants (64 with IVH grade I-IV and 207 without IVH) weighing less than 1,500 grams. The heterozygous genotype (odds ratio (OR)=8.1, confidence interval (CI)=2.5–26.0, p=4×10−4) and the A allele (OR=7.3, CI=2.4–22.5, p=1×10−4) of the coagulation factor V (FV) Leiden mutation (rs6025) were associated with an increased risk of developing IVH grade I or II but not grades III or IV after correction for multiple testing with Bonferroni. Lack of association in the severe grades of IVH may be a result of lack of power to detect an effect given the small sample size (n=8). However, this result is consistent with previous research that demonstrates that the heterozygous genotype of the FV mutation is associated with increased risk for the development of IVH but a decreased risk for the progression or extension to more severe grades of IVH.
doi:10.1203/PDR.0b013e31821ceb63
PMCID: PMC3117229  PMID: 21659962
17.  The influence of maternal disease on metabolites measured as part of newborn screening 
Objective
Measurements of neonatal metabolites are commonly used in newborn screening programs to detect inborn errors of metabolism. Variation in these metabolites, particularly in infants born preterm (<37 weeks gestation), can result from multiple etiologies. We sought to evaluate the impact of maternal complications of pregnancy and environmental stressors on newborn screening metabolites.
Methods
We examined 49 metabolic biomarkers obtained from routine newborn screening in 452 infants born preterm for association with maternal environmental stressors and complications of pregnancy.
Results
Neonatal free carnitine (C0, P=1.4×10−7), acetylcarnitine (C2, P=2.7×10−7), octenotylcarnitine (C8:1, P=5.2×10−11) and linoleoylcarnitine (C18:2, P=9.1×10−7) were elevated in infants born to preeclamptic mothers. Similar elevations were observed in small for gestational age infants and in infants where labor was not initiated prior to delivery. When accounting for all three factors associations remained strongest between acylcarnitines and preeclampsia.
Conclusion
We observed that maternal conditions, particularly preeclampsia, influence newborn screening biomarkers. This is important for identifying maternal conditions that influence metabolites measured during routine newborn screening that are also markers of fetal growth and overall health.
doi:10.3109/14767058.2013.791267
PMCID: PMC3753672  PMID: 23550828
preeclampsia; newborn screening; metabolic profiles
18.  Identification of a 7q33-q35 microdeletion disrupting the CNTNAP2 gene in a Brazilian Stuttering case 
Speech and language disorders are some of the most common referral reasons to child development centers accounting for approximately 40% of cases. Stuttering is a disorder in which involuntary repetition, prolongation or cessation of the sound precludes the flow of speech. About 5% of individuals in the general population have a stuttering problem, and about 80% of the affected children recover naturally. The causal factors of stuttering remain uncertain in most cases; studies suggest that genetic factors are responsible for 70% of the variance in liability for stuttering, whereas the remaining 30% is due to environmental effects supporting a complex cause of the disorder. The use of high-resolution genome wide array comparative genomic hybridization (array-CGH) has proven to be a powerful strategy to narrow down candidate regions for complex disorders. We report on a case with a complex set of speech and language difficulties including stuttering who presented with a 10 Mb deletion of chromosome region 7q33-35 causing the deletion of several genes and the disruption of CNTNAP2 by deleting the first 3 exons of the gene. CNTNAP2 is known to be involved in the cause of language and speech disorders and Autism Spectrum Disorder (ASD) and is in the same pathway as FOXP2, another important language gene, which makes it a candidate gene for causal studies speech and language disorders such as stuttering.
doi:10.1002/ajmg.a.33749
PMCID: PMC3058358  PMID: 21108403
microdeletion; CNTNAP2; stuttering
19.  Maternal Coding Variants in Complement Receptor 1 and Spontaneous Idiopathic Preterm Birth 
Human genetics  2013;132(8):10.1007/s00439-013-1304-5.
Preterm birth (PTB) is a major global public health concern. However, little is known about the pathophysiology of spontaneous idiopathic PTB. We tested the hypothesis that rare variants in families would target specific genes and pathways that contribute to PTB risk in the general population. Whole-exome sequencing was performed on 10 PTB mothers from densely affected families including two mother-daughter pairs. We identified novel variants shared between the two mother-daughter pairs when compared to a 1000 Genomes Project background exome file and investigated these genes for pathway aggregation using the Kyoto Encyclopedia of Genes and Genomes (KEGG). Genes in enriched pathways were then surveyed in the other six PTB exomes and tested for association in a larger number of nuclear families. The KEGG complement and coagulation cascade was one of the most enriched pathways in our two mother-daughter pairs. When the six genes found in this pathway (CFH, CR1, F13B, F5, CR2, and C4BPA) were examined for novel missense variants, half of all the exomes harbored at least one. Association analysis of variants in these six gene regions in nuclear families from Finland (237 cases and 328 controls) found statistically significant associations after multiple test corrections in three CR1 SNPs; the strongest in an exonic missense SNP, rs6691117, p-value = 6.91e-5, OR = 1.71. Our results demonstrate the importance of the complement and coagulation cascades in the pathophysiology of PTB, and suggest potential screening and intervention approaches to prevent prematurity that target this pathway.
doi:10.1007/s00439-013-1304-5
PMCID: PMC3868364  PMID: 23591632
CR1; Exome Sequencing; Association Study; Preterm Birth
20.  A case of 3q29 microdeletion syndrome involving oral cleft inherited from a non-affected mosaic parent: molecular analysis and ethical implications 
Objective
The objective of this study was to use array-CGH to detect causal microdeletions in samples of subjects with cleft lip and palate.
Subjects
We analyzed DNA samples from a male patient and parents that was seen during surgical screening for an Operation Smile medical mission in the Philippines.
Method
We used Affymetrix Genome Wide Human SNP Array 6.0 followed by sequencing and quantitative PCR using SYBR Green I dye.
Results
We report the second case of 3q29 microdeletion syndrome including cleft lip with or without cleft palate and the first case of this microdeletion syndrome inherited from a phenotypically normal mosaic parent.
Conclusions
Our findings confirm the utility of aCGH to detect causal microdeletions; indicate that parental somatic mosaicism should be considered in healthy parents for genetic counseling of the families and discuss important ethical implications of sharing health impact results from research studies with the participant families.
doi:10.1597/09-149
PMCID: PMC2964377  PMID: 20500065
microdeletion; cleft; 3q29; mosaicism; ethical
21.  Individual and Center-Level Factors Affecting Mortality Among Extremely Low Birth Weight Infants 
Pediatrics  2013;132(1):e175-e184.
OBJECTIVE:
To examine factors affecting center differences in mortality for extremely low birth weight (ELBW) infants.
METHODS:
We analyzed data for 5418 ELBW infants born at 16 Neonatal Research Network centers during 2006–2009. The primary outcomes of early mortality (≤12 hours after birth) and in-hospital mortality were assessed by using multilevel hierarchical models. Models were developed to investigate associations of center rates of selected interventions with mortality while adjusting for patient-level risk factors. These analyses were performed for all gestational ages (GAs) and separately for GAs <25 weeks and ≥25 weeks.
RESULTS:
Early and in-hospital mortality rates among centers were 5% to 36% and 11% to 53% for all GAs, 13% to 73% and 28% to 90% for GAs <25 weeks, and 1% to 11% and 7% to 26% for GAs ≥25 weeks, respectively. Center intervention rates significantly predicted both early and in-hospital mortality for infants <25 weeks. For infants ≥25 weeks, intervention rates did not predict mortality. The variance in mortality among centers was significant for all GAs and outcomes. Center use of interventions and patient risk factors explained some but not all of the center variation in mortality rates.
CONCLUSIONS:
Center intervention rates explain a portion of the center variation in mortality, especially for infants born at <25 weeks’ GA. This finding suggests that deaths may be prevented by standardizing care for very early GA infants. However, differences in patient characteristics and center intervention rates do not account for all of the observed variability in mortality; and for infants with GA ≥25 weeks these differences account for only a small part of the variation in mortality.
doi:10.1542/peds.2012-3707
PMCID: PMC3691533  PMID: 23753096
mortality rates; outcome; NICU; preterm infants; extremely preterm infants
22.  Ten-Year Review of Major Birth Defects in VLBW Infants 
Pediatrics  2013;132(1):49-61.
OBJECTIVE:
Birth defects (BDs) are an important cause of infant mortality and disproportionately occur among low birth weight infants. We determined the prevalence of BDs in a cohort of very low birth weight (VLBW) infants cared for at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers over a 10-year period and examined the relationship between anomalies, neonatal outcomes, and surgical care.
METHODS:
Infant and maternal data were collected prospectively for infants weighing 401 to 1500 g at NRN sites between January 1, 1998, and December 31, 2007. Poisson regression models were used to compare risk of outcomes for infants with versus without BDs while adjusting for gestational age and other characteristics.
RESULTS:
A BD was present in 1776 (4.8%) of the 37 262 infants in our VLBW cohort. Yearly prevalence of BDs increased from 4.0% of infants born in 1998 to 5.6% in 2007, P < .001. Mean gestational age overall was 28 weeks, and mean birth weight was 1007 g. Infants with BDs were more mature but more likely to be small for gestational age compared with infants without BDs. Chromosomal and cardiovascular anomalies were most frequent with each occurring in 20% of affected infants. Mortality was higher among infants with BDs (49% vs 18%; adjusted relative risk: 3.66 [95% confidence interval: 3.41–3.92]; P < .001) and varied by diagnosis. Among those surviving >3 days, more infants with BDs underwent major surgery (48% vs 13%, P < .001).
CONCLUSIONS:
Prevalence of BDs increased during the 10 years studied. BDs remain an important cause of neonatal morbidity and mortality among VLBW infants.
doi:10.1542/peds.2012-3111
PMCID: PMC3691532  PMID: 23733791
birth defects; prematurity; Neonatal Research Network; low birth weight
23.  Late-Onset Sepsis in Very Low Birth Weight Infants from Singleton and Multiple Gestation Births 
The Journal of pediatrics  2013;162(6):1120-1124.e1.
Objectives
To describe and compare incidence of late-onset sepsis (LOS) and demographic and clinical characteristics associated with LOS in very low birth weight (VLBW) infants from singleton and multiple births and to examine the heritability in susceptibility to LOS among VLBW twins by comparing same-sex with unlike-sex twin pairs.
Study design
We studied infants with birth weight 401–1500 grams cared for at clinical centers of the NICHD Neonatal Research Network 2002–2008. Only the first episode of LOS was examined. Stepwise logistic regression models were fitted separately for singleton and multiple pregnancies to examine the maternal and neonatal factors associated with LOS. LOS due to only gram-negative bacteria among singleton and multiple pregnancies was also examined in separate models. The heritability of LOS was estimated by examining concordance of LOS between twins from same-sex and unlike-sex pairs.
Results
LOS occurred in 25.0% (3797/15,178) of singleton and 22.6% (1196/5294) of multiple VLBW infants. Coagulase-negative staphylococci were the most common infecting organisms, accounting for 53.2% of all LOS episodes in singletons and 49.2% in multiples. E. coli and Klebsiella species were the most commonly isolated gram-negative organisms, and Candida albicans was the most commonly isolated fungus. Concordance of LOS was not significantly different between same-sex and unlike-sex twin pairs.
Conclusions
LOS remains a common problem in VLBW infants. The incidence of LOS is similar for singleton and multiple infants. Similar concordance of LOS in same-sex and unlike-sex twin pairs provided no evidence that susceptibility to LOS among VLBW infants is genetically determined.
doi:10.1016/j.jpeds.2012.11.089
PMCID: PMC3633723  PMID: 23324523
Heredity; preterm infants; twins
24.  Environmental risk factors and perinatal outcomes in preterm newborns, according to family recurrence of prematurity 
American journal of perinatology  2012;30(6):451-461.
Objetive
We analyzed the role of environmental risk factors, socio-demographic characteristics, clinical characteristics, and reproductive history in preterm births and their associated perinatal outcomes in families classified according to their histories of preterm recurrence among siblings.
Study Design
A retrospective study was conducted at “Nuestra Señora de la Merced” Maternity Hospital in the city of Tucumán, Argentina. A total of 348 preterm, non-malformed, singleton children born to multipara women were reviewed. The family history score described by Khoury was applied, and families were classified as having no, medium or high genetic aggregation.
Results
Families with no familial aggregation showed a higher rate of short length of cohabitation, maternal urinary tract infections during the current pregnancy and maternal history of miscarriage during the previous pregnancy. Families with a high level of aggregation had a significantly higher incidence of pregnancy complications, such as diabetes, hypertension and immunological disorders.
Conclusion
Reproductive histories clearly differed between the groups, suggesting both a different response to environmental challenges based on genetic susceptibility, and the activation of different pathophysiological pathways to determine the duration of pregnancy in each woman.
doi:10.1055/s-0032-1326990
PMCID: PMC3974336  PMID: 23132119
preterm birth; familial aggregation; pregnancy
25.  Public Perspectives on Biospecimen Procurement: What Biorepositories Should Consider 
Biopreservation and Biobanking  2013;11(3):137-143.
Purpose
Human biospecimens are central to biobanking efforts, yet how members of the public think about biobank procurement strategies is not well understood. This study aimed to explore public perspectives toward the procurement of residual clinical material versus “direct” procurement strategies such as the drawing of blood.
Methods
Members of the public residing in and beyond the biobank catchment area of the University of Iowa Hospitals and Clinics were randomly selected to participate in focus groups and a telephone survey.
Results
The majority of survey participants (75%, n=559) found both residual and direct procurement strategies equally workable. Small proportions preferred either residual (15%; n=117) or direct (5%; n=40) procurement. Focus group participants (n=48) could identify benefits to both procurement strategies, but raised concerns about possible donor inconvenience/discomfort and reduced biospecimen accrual in the case of direct procurement. Residual procurement raised concerns about lower-quality samples being procured without full donor awareness.
Conclusion
Biobanks should consider that members of the public in their research programs may be willing to make specimen donations regardless of whether a residual or direct procurement strategy is employed. Limiting patient discomfort and inconvenience may make direct procurement strategies more acceptable to some members of the public. Ensuring donor awareness through effective informed consent may allay public concerns about the indirectness of donating clinical biospecimens.
doi:10.1089/bio.2013.0001
PMCID: PMC4076971  PMID: 24850089

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