Targeted Sequencing of Candidate Regions Associated with Sagittal and Metopic Nonsyndromic Craniosynostosis

Craniosynostosis (CS) is a major birth defect in which one or more skull sutures fuse prematurely. We previously performed a genome-wide association study (GWAS) for sagittal nonsyndromic CS (sNCS), identifying associations downstream from BMP2 on 20p12.3 and intronic to BBS9 on 7p14.3; analyses of imputed variants in DLG1 on 3q29 were also genome-wide significant. We followed this work with a GWAS for metopic non-syndromic NCS (mNCS), discovering a significant association intronic to BMP7 on 20q13.31. In the current study, we sequenced the associated regions on 3q29, 7p14.3, and 20p12.3, including two candidate genes (BMP2 and BMPER) near some of these regions in 83 sNCS child-parent trios, and sequenced regions on 7p14.3 and 20q13.2-q13.32 in 80 mNCS child-parent trios. These child-parent trios were selected from the original GWAS co-horts if the probands carried at least one copy of the top associated GWAS variant (rs1884302 C allele for sNCS; rs6127972 T allele for mNCS). Many of the variants sequenced in these targeted regions are strongly predicted to be within binding sites for transcription factors involved in crani-ofacial development or bone morphogenesis. Variants enriched in more than one trio and predicted to be damaging to gene function are prioritized for functional studies

Understanding lactatemia in human sepsis potential impact for early management

Rationale: Hyperlactatemia in sepsis may derive from a prevalent impairment of oxygen supply/demand and/or oxygen use. Discriminating between these two mechanisms may be relevant for the early fluid resuscitation strategy. Objectives: To understand the relationship among central venous oxygen saturation (ScvO2), lactate, and base excess to better determine the origin of lactate. Methods: This was a post hoc analysis of baseline variables of 1,741 patients with sepsis enrolled in the multicenter trial ALBIOS (Albumin ItalianOutcome Sepsis). Variableswere analyzed as a function of sextiles of lactate concentration and sextiles of ScvO2.Wedefined the "alactic base excess," as the sum of lactate and standard base excess. Measurements and Main Results: Organ dysfunction severity scores, physiologic variables of hepatic, metabolic, cardiac, and renal function, and 90-day mortality were measured. ScvO2 was lower than 70% only in 35% of patients. Mortality, organ dysfunction scores, and lactate were highest in the first and sixth sextiles of ScvO2. Although lactate level related strongly to mortality, it was associated with acidemia only when kidney function was impaired (creatinine >2 mg/dl), as rapidly detected by a negative alactic base excess. In contrast, positive values of alactic base excess were associated with a relative reduction of fluid balance. Conclusions: Hyperlactatemia is powerfully correlated with severity of sepsis and, in established sepsis, is caused more frequently by impaired tissue oxygen use, rather than by impaired oxygen transport. Concomitant acidemia was only observed in the presence of renal dysfunction, as rapidly detected by alactic base excess. The current strategy of fluid resuscitation could be modified according to the origin of excess lactate

Factors affecting maternal participation in the genetic component of the National Birth Defects Prevention Study—United States, 1997–2007

As epidemiological studies expand to examine gene–environment interaction effects, it is important to identify factors associated with participation in genetic studies. The National Birth Defects Prevention Study is a multisite case–control study designed to investigate environmental and genetic risk factors for major birth defects. The National Birth Defects Prevention Study includes maternal telephone interviews and mailed buccal cell self-collection kits. Because subjects can participate in the interview, independent of buccal cell collection, detailed analysis of factors associated with participation in buccal cell collection was possible

Maternal underweight and obesity and risk of orofacial clefts in a large international consortium of population-based studies

Background: Evidence on association of maternal pre-pregnancy weight with risk of orofacial clefts is inconsistent

Bayesian Methods for Correcting Misclassification: An Example from Birth Defects Epidemiology

Cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) are common congenital malformations. Numerous epidemiologic studies have shown an increased risk for orofacial clefts among children whose mothers smoked during early pregnancy; however, there is concern that the results of these studies may have been biased because of exposure misclassification. The purpose of this study is to use previous research on the reliability of self-reported cigarette smoking to produce corrected point estimates (and associated credible intervals) of the effect of maternal smoking on children’s risk of clefts

Instability of short arm of acrocentric chromosomes : Lesson from non-acrocentric satellited chromosomes. Report of 24 unrelated cases

Satellited non-acrocentric autosomal chromosomes (ps-qs-chromosomes) are the result of an interchange between sub- or telomeric regions of autosomes and the p arm of acrocentrics. The sequence homology at the rearrangement breakpoints appears to be, among others, the most frequent mechanism generating these variant chromosomes. The unbalanced carriers of this type of translocation may or may not display phenotypic abnormalities. With the aim to understand the causative mechanism, we revised all the ps-qs-chromosomes identified in five medical genetics laboratories, which used the same procedures for karyotype analysis, reporting 24 unrelated cases involving eight chromosomes. In conclusion, we observed three different scenarios: true translocation, benign variant and complex rearrangement. The detection of translocation partners is essential to evaluate possible euchromatic unbalances and to infer their effect on phenotype. Moreover, we emphasize the importance to perform both, molecular and conventional cytogenetics methods, to better understand the behavior of our genome

A Genome-Wide association Study of Obstructive Heart Defects among Participants in the National Birth Defects Prevention Study

Obstructive heart defects (OHDs) share common structural lesions in arteries and cardiac valves, accounting for ~25% of all congenital heart defects. OHDs are highly heritable, resulting from interplay among maternal exposures, genetic susceptibilities, and epigenetic phenomena. A genome-wide association study was conducted in National Birth Defects Prevention Study participants (

Shared genetic risk between major orofacial cleft phenotypes in an African population

Nonsyndromic orofacial clefts (NSOFCs) represent a large proportion (70%–80%) of all OFCs. They can be broadly categorized into nonsyndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO). Although NSCL/P and NSCPO are considered etiologically distinct, recent evidence suggests the presence of shared genetic risks. Thus, we investigated the genetic overlap between NSCL/P and NSCPO using African genome-wide association study (GWAS) data on NSOFCs. These data consist of 814 NSCL/P, 205 NSCPO cases, and 2159 unrelated controls. We generated common single-nucleotide variants (SNVs) association summary statistics separately for each phenotype (NSCL/P and NSCPO) under an additive genetic model. Subsequently, we employed the pleiotropic analysis under the composite null (PLACO) method to test for genetic overlap. Our analysis identified two loci with genome-wide significance (rs181737795 [p = 2.58E−08] and rs2221169 [p = 4.5E−08]) and one locus with marginal significance (rs187523265 [p = 5.22E−08]). Using mouse transcriptomics data and information from genetic phenotype databases, we identified MDN1, MAP3k7, KMT2A, ARCN1, and VADC2 as top candidate genes for the associated SNVs. These findings enhance our understanding of genetic variants associated with NSOFCs and identify potential candidate genes for further exploration.</p

Maternal Occupational Exposure to Polycyclic Aromatic Hydrocarbons: Effects on Gastroschisis among Offspring in the National Birth Defects Prevention Study

Background: Exposure to polycyclic aromatic hydrocarbons (PAHs) occurs in many occupational settings. There is evidence in animal models that maternal exposure to PAHs during pregnancy is associated with gastroschisis in offspring; however, to our knowledge, no human studies examining this association have been conducted