Genetic Testing Integration Panels (GTIPs): A Novel Approach for Considering Integration of Direct‐To‐Consumer and Other New Genetic Tests into Patient Care

There has been a dramatic increase in the number of genetic tests available but few tests have practice guidelines. In addition, many tests have become available outside of clinical settings through direct‐to‐consumer (DTC) companies and several offer tests not considered standard of care. To address several practical challenges associated with the rapid introduction of clinical and DTC genetic tests, we propose that genetic counselors and geneticists organize expert panels in their institutions to discuss the integration of new tests into patient care. We propose the establishment of Genetic Testing Integration Panels (GTIPs) to bring together local experts in medical genetics, genetic counseling, bioethics and law, health communication and clinical laboratory genetics. We describe key features of this approach and consider some of the potential advantages and limitations of using a GTIP to address the many clinical challenges raised by rapidly emerging clinical and DTC genetic tests.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147023/1/jgc40374.pd

Genetic associations with childhood brain growth, defined in two longitudinal cohorts

Genome-wide association studies (GWASs) are unraveling the genetics of adult brain neuroanatomy as measured by cross-sectional anatomic magnetic resonance imaging (aMRI). However, the genetic mechanisms that shape childhood brain development are, as yet, largely unexplored. In this study we identify common genetic variants associated with childhood brain development as defined by longitudinal aMRI. Genome-wide single nucleotide polymorphism (SNP) data were determined in two cohorts: one enriched for attention-deficit/hyperactivity disorder (ADHD) (LONG cohort: 458 participants; 119 with ADHD) and the other from a population-based cohort (Generation R: 257 participants). The growth of the brain's major regions (cerebral cortex, white matter, basal ganglia, and cerebellum) and one region of interest (the right lateral prefrontal cortex) were defined on all individuals from two aMRIs, and a GWAS and a pathway analysis were performed. In addition, association between polygenic risk for ADHD and brain growth was determined for the LONG cohort. For white matter growth, GWAS meta-analysis identified a genome-wide significant intergenic SNP (rs12386571, P = 9.09 × 10-9 ), near AKR1B10. This gene is part of the aldo-keto reductase superfamily and shows neural expression. No enrichment of neural pathways was detected and polygenic risk for ADHD was not associated with the brain growth phenotypes in the LONG cohort that was enriched for the diagnosis of ADHD. The study illustrates the use of a novel brain growth phenotype defined in vivo for further study

The long-term impact of folic acid in pregnancy on offspring DNA methylation : follow-up of the Aberdeen folic acid supplementation trial (AFAST)

Funding This work was supported by the NIHR Bristol Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. R.C.R., G.C.S., N.K., T.G., G.D.S. and C.L.R. work in a unit that receives funds from the University of Bristol and the UK Medical Research Council (MC_UU_12013/1, MC_UU_12013/2 and MC_UU_12013/8). This work was also supported by CRUK (grant number C18281/A19169) and the ESRC (grant number ES/N000498/1). C.M.T. is supported by a Wellcome Trust Career Re-entry Fellowship (grant number 104077/Z/14/Z).Peer reviewedPublisher PD

γδ T cell–induced hyaluronan production by epithelial cells regulates inflammation

Nonhealing wounds are a major complication of diseases such as diabetes and rheumatoid arthritis. For efficient tissue repair, inflammatory cells must infiltrate into the damaged tissue to orchestrate wound closure. Hyaluronan is involved in the inflammation associated with wound repair and binds the surface of leukocytes infiltrating damaged sites. Skin γδ T cells play specialized roles in keratinocyte proliferation during wound repair. Here, we show that γδ T cells are required for hyaluronan deposition in the extracellular matrix (ECM) and subsequent macrophage infiltration into wound sites. We describe a novel mechanism of control in which γδ T cell–derived keratinocyte growth factors induce epithelial cell production of hyaluronan. In turn, hyaluronan recruits macrophages to the site of damage. These results demonstrate a novel function for skin γδ T cells in inflammation and provide a new perspective on T cell regulation of ECM molecules

Genetic variation in male sexual behaviour in a population of white-footed mice in relation to photoperiod

In natural populations, genetic variation in seasonal male sexual behaviour could affect behavioural ecology and evolution. In a wild-source population of white-footed mice, Peromyscus leucopus, from Virginia, U.S.A., males experiencing short photoperiod show high levels of genetic variation in reproductive organ mass and neuroendocrine traits related to fertility. We tested whether males from two divergent selection lines, one that strongly suppresses fertility under short photoperiod (responder) and one that weakly suppresses fertility under short photoperiod (nonresponder), also differ in photoperiod-dependent sexual behaviour and responses to female olfactory cues. Under short, but not long, photoperiod, there were significant differences between responder and nonresponder males in sexual behaviour and likelihood of inseminating a female. Males that were severely oligospermic or azoospermic under short photoperiod failed to display sexual behaviour in response to an ovariectomized and hormonally primed receptive female. However, on the day following testing, females were positive for spermatozoa only when paired with a male having a sperm count in the normal range for males under long photoperiod. Males from the nonresponder line showed accelerated reproductive development under short photoperiod in response to urine-soiled bedding from females, but males from the responder line did not. The results indicate genetic variation in sexual behaviour that is expressed under short, but not long, photoperiod, and indicate a potential link between heritable neuroendocrine variation and male sexual behaviour. In winter in a natural population, this heritable behavioural variation could affect fitness, seasonal life history trade-offs and population growth. (C) 2015 The Association for the Study of Animal Behaviour. Published by Elsevier Ltd. All rights reserved

Time Trend and Factors Associated with Late Enrollment in Early Intervention among Children with Permanent Hearing Loss in Louisiana 2008-2013

This study aimed to identify the time trend of and factors associated with late enrollment in early intervention (EI) services among children with permanent hearing loss (HL) born between 2008 and 2013 in Louisiana. 2008-2013 linked Louisiana Early Hearing Detection and Intervention, birth records, EarlySteps (IDEA, Part C), Parent-Pupil Education Program, and Medicaid data were analyzed. Logistic regression models were used to evaluate the trend and associations of mother and child’s demographic and hearing loss characteristics with late EI enrollment. Results of data analyses did not show any trend of late enrollment in EI services from 2008 to 2013. Delayed diagnosis and mild or unilateral HL were strongly associated with late enrollment. Appropriate strategies to resolve problems relating to missed diagnosis during newborn hearing screening and to convince parents of children with HL to enroll soon after diagnosis of HL will contribute to success of early EI enrollment in the state

Time Trend and Factors Associated with Late Enrollment in Early Intervention among Children with Permanent Hearing Loss in Louisiana 2008-2013

This study aimed to identify the time trend of and factors associated with late enrollment in early intervention (EI) services among children with permanent hearing loss (HL) born between 2008 and 2013 in Louisiana. 2008-2013 linked Louisiana Early Hearing Detection and Intervention, birth records, EarlySteps (IDEA, Part C), Parent-Pupil Education Program, and Medicaid data were analyzed. Logistic regression models were used to evaluate the trend and associations of mother and child’s demographic and hearing loss characteristics with late EI enrollment. Results of data analyses did not show any trend of late enrollment in EI services from 2008 to 2013. Delayed diagnosis and mild or unilateral HL were strongly associated with late enrollment. Appropriate strategies to resolve problems relating to missed diagnosis during newborn hearing screening and to convince parents of children with HL to enroll soon after diagnosis of HL will contribute to success of early EI enrollment in the state

Randomised controlled trial of a theory-based behavioural intervention to reduce formula milk intake

Objective: To assess the efficacy of a theory-based behavioural intervention to prevent rapidweight gain in formula-milk fed infants.  Design: In this single (assessor) blind, randomised controlled trial, 669 healthy full-terminfants receiving formula-milk within 14 weeks of birth were individually-randomised tointervention (n=340) or attention-matched control (n=329) groups. The intervention aimed toreduce formula-milk intakes, and promote responsive feeding and growth monitoring toprevent rapid weight gain (>+ 0.67 standard deviation scores [SDS]). It was delivered tomothers by trained facilitators up to infant age 6 months through 3 face-to-face contacts, 2telephone contacts, and written materials.  Results: Retention was 93% (622) at 6 months, 88% (586) at 12 months, and 94% attended >4/5 sessions. The intervention strengthened maternal attitudes to following infant feedingrecommendations, reduced reported milk intakes at ages 3 (-14%; intervention vs controlinfants), 4 (-12%), 5 (-9%), and 6 (-7%) months, slowed initial infant weight gain frombaseline to 6 months (mean change 0.32 vs 0.42 SDS, baseline-adjusted difference(intervention vs control) -0.08 [95% CI; -0.17, -0.004] SDS), but had no effect on the primaryoutcome of weight gain to 12 months (baseline-adjusted difference -0.04 [-0.17, 0.10] SDS).By 12 months, 40.3% of infants in the intervention group and 45.9% in the control groupshowed rapid weight gain (OR: 0.84 [95% CI; 0.59, 1.17]).  Conclusions: Despite reducing milk intakes and initial weight gain, the intervention did notalter the high prevalence of rapid weight gain to age 12 months suggesting the need forsustained intervention

Distinct DNA methylation profiles in subtypes of orofacial cleft

Abstract Background Epigenetic data could help identify risk factors for orofacial clefts, either by revealing a causal role for epigenetic mechanisms in causing clefts or by capturing information about causal genetic or environmental factors. Given the evidence that different subtypes of orofacial cleft have distinct aetiologies, we explored whether children with different cleft subtypes showed distinct epigenetic profiles. Methods In whole-blood samples from 150 children from the Cleft Collective cohort study, we measured DNA methylation at over 450,000 sites on the genome. We then carried out epigenome-wide association studies (EWAS) to test the association between methylation at each site and cleft subtype (cleft lip only (CLO) n = 50; cleft palate only (CPO) n = 50; cleft lip and palate (CLP) n = 50). We also compared methylation in the blood to methylation in the lip or palate tissue using genome-wide data from the same 150 children and conducted an EWAS of CLO compared to CLP in lip tissue. Results We found four genomic regions in blood differentially methylated in CLO compared to CLP, 17 in CPO compared to CLP and 294 in CPO compared to CLO. Several regions mapped to genes that have previously been implicated in the development of orofacial clefts (for example, TBX1, COL11A2, HOXA2, PDGFRA), and over 250 associations were novel. Methylation in blood correlated with that in lip/palate at some regions. There were 14 regions differentially methylated in the lip tissue from children with CLO and CLP, with one region (near KIAA0415) showing up in both the blood and lip EWAS. Conclusions Our finding of distinct methylation profiles in different orofacial cleft (OFC) subtypes represents a promising first step in exploring the potential role of epigenetic modifications in the aetiology of OFCs and/or as clinically useful biomarkers of OFC subtypes

Tetrahydrofurandiols (THF-diols), Leukotoxindiols (LTX-diols), and Endocrine Disruption in Rats

BACKGROUND: Ground corncob animal bedding and corn food products contain substances that disrupt endocrine function in rats. The disruptors were identified as isomeric mixtures of tetrahydrofurandiols (THF-diols; 9,12-oxy-10,13-dihydroxyoctadecanoic acid and 10,13-oxy-9,12-dihydroxyoctadecanoic acid) and leukotoxindiols (LTX-diols; 9,10-dihydroxy-12-octadecenoic acid and 12,13-dihydroxy-9-octadecenoic acid). The authentic compounds blocked sexual behavior in male rats and estrous cyclicity in female rats at oral doses of 2 ppm. OBJECTIVES: To define the lowest observed adverse effect level (LOAEL) for the THF-diols and LTX-diols in rats, we examined the nature of their interaction (additive or synergistic) and quantified the concentration of THF-diols in rat tissues. METHODS: Adult male and female rats were provided drinking solutions containing various doses of THF-diols and/or LTX-diols, and we evaluated their effects on male sexual behavior and female estrous cyclicity. Tissues were collected for THF-diol determination by gas chromatography–mass spectrometry. RESULTS: The LOAEL for THF-diols and LTX-diols for blocking estrous cyclicity was 0.5–1.0 ppm and 0.2–0.5 ppm, respectively. Higher concentrations (1–2 ppm) of THF-diols were required to block male sexual behavior. Combination studies with subthreshold doses of 0.05 ppm THF-diols plus 0.05 ppm LTX-diols revealed that their effects on estrous cyclicity were not synergistic. We were unable to detect THF-diols in tissues from rats treated with 10 ppm of the compounds, suggesting that metabolism may be involved. DISCUSSION: THF-diols, LTX-diols, and/or their metabolites likely act additively to disrupt endocrine function in male and female rats at concentrations (0.5–1 ppm) that are 200-fold lower than those of classical phytoestrogen endocrine disruptors