Expanded carrier screening for reproductive risk assessment: An evidence-based practice guideline from the National Society of Genetic Counselors.

Expanded carrier screening (ECS) intends to broadly screen healthy individuals to determine their reproductive chance for autosomal recessive (AR) and X-linked (XL) conditions with infantile or early-childhood onset, which may impact reproductive management (Committee Opinion 690, Obstetrics and Gynecology, 2017, 129, e35). Compared to ethnicity-based screening, which requires accurate knowledge of ancestry for optimal test selection and appropriate risk assessment, ECS panels consist of tens to hundreds of AR and XL conditions that may be individually rare in various ancestries but offer a comprehensive approach to inherited disease screening. As such, the term "equitable carrier screening" may be preferable. This practice guideline provides evidence-based recommendations for ECS using the GRADE Evidence to Decision framework (Guyatt et al., BMJ, 2008, 336, 995; Guyatt et al., BMJ, 2008, 336, 924). We used evidence from a recent systematic evidence review (Ramdaney et al., Genetics in Medicine, 2022, 20, 374) and compiled data from peer-reviewed literature, scientific meetings, and clinical experience. We defined and prioritized the outcomes of informed consent, change in reproductive plans, yield in identification of at-risk carrier pairs/pregnancies, perceived barriers to ECS, amount of provider time spent, healthcare costs, frequency of severely/profoundly affected offspring, incidental findings, uncertain findings, patient satisfaction, and provider attitudes. Despite the recognized barriers to implementation and change in management strategies, this analysis supported implementation of ECS for these outcomes. Based upon the current level of evidence, we recommend ECS be made available for all individuals considering reproduction and all pregnant reproductive pairs, as ECS presents an ethnicity-based carrier screening alternative which does not rely on race-based medicine. The final decision to pursue carrier screening should be directed by shared decision-making, which takes into account specific features of patients as well as their preferences and values. As a periconceptional reproductive risk assessment tool, ECS is superior compared to ethnicity-based carrier screening in that it both identifies more carriers of AR and XL conditions as well as eliminates a single race-based medical practice. ECS should be offered to all who are currently pregnant, considering pregnancy, or might otherwise biologically contribute to pregnancy. Barriers to the broad implementation of and access to ECS should be identified and addressed so that test performance for carrier screening will not depend on social constructs such as race.

The impact of HBB-related hemoglobinopathies carrier status on fetal fraction in noninvasive prenatal screening.

OBJECTIVE: We evaluated whether there is an association between ß-globin (HBB) pathogenic variants and fetal fraction (FF), and whether the association has a clinically relevant impact on non-invasive prenatal screening (NIPS). METHOD: A whole-genome sequencing NIPS laboratory database was retrospectively queried for women who underwent NIPS and carrier screening of both HBB and the α-globin genes (HBA1/HBA2). Women affected with either condition were excluded from the study, yielding a cohort size of 15,853. A "corrected FF" was obtained via multivariable linear regression adjusted for the systematic impacts of maternal age, gestational age and BMI. Corrected FF distributions of HBB and HBA1/HBA2 carriers were each compared to non-carriers using the Kolmogorov-Smirnov test. RESULTS: In this cohort, 291 women were carriers for HBB alone, and 1016 were carriers for HBA1/HBA2 alone. The HBB carriers had a lower corrected FF when compared to non-carriers (p < 0.0001). There was no difference in corrected FF among carriers and non-carriers of HBA1/HBA2. CONCLUSION: Carriers of pathogenic variants in the HBB gene, but not the HBA1/HBA2 genes, are more likely to have lower FF when compared to women with structurally normal hemoglobin. This decrease in FF could result in an elevated test-failure rate if FF thresholds were used.

Flavonoid-based inhibitors of the Phi-class glutathione transferase from black-grass to combat multiple herbicide resistance.

The evolution and growth of multiple-herbicide resistance (MHR) in grass weeds continues to threaten global cereal production. While various processes can contribute to resistance, earlier work has identified the phi class glutathione-S-transferase (AmGSTF1) as a functional biomarker of MHR in black-grass (Alopecurus myosuroides). This study provides further insights into the role of AmGSTF1 in MHR using a combination of chemical and structural biology. Crystal structures of wild-type AmGSTF1, together with two specifically designed variants that allowed the co-crystal structure determination with glutathione and a glutathione adduct of the AmGSTF1 inhibitor 4-chloro-7-nitro-benzofurazan (NBD-Cl) were obtained. These studies demonstrated that the inhibitory activity of NBD-Cl was associated with the occlusion of the active site and the impediment of substrate binding. A search for other selective inhibitors of AmGSTF1, using ligand-fishing experiments, identified a number of flavonoids as potential ligands. Subsequent experiments using black-grass extracts discovered a specific flavonoid as a natural ligand of the recombinant enzyme. A series of related synthetic flavonoids was prepared and their binding to AmGSTF1 was investigated showing a high affinity for derivatives bearing a O-5-decyl-α-carboxylate. Molecular modelling based on high-resolution crystal structures allowed a binding pose to be defined which explained flavonoid binding specificity. Crucially, high binding affinity was linked to a reversal of the herbicide resistance phenotype in MHR black-grass. Collectively, these results present a nature-inspired new lead for the development of herbicide synergists to counteract MHR in weeds.

Chemically induced herbicide tolerance in rice by the safener metcamifen is associated with a phased stress response.

The closely related sulphonamide safeners, metcamifen and cyprosulfamide, were tested for their ability to protect rice from clodinafop-propargyl, a herbicide normally used in wheat. While demonstrating that both compounds were equally bioavailable in planta, only metcamifen prevented clodinafop from damaging seedlings, and this was associated with the enhanced detoxification of the herbicide. Transcriptome studies in rice cultures demonstrated that whereas cyprosulfamide had a negligible effect on gene expression over a 4 h exposure, metcamifen perturbed the abundance of 590 transcripts. Changes in gene expression with metcamifen could be divided into three phases, corresponding to inductions occurring over 30 min, 1.5 h and 4 h. The first phase of gene induction was dominated by transcription factors and proteins of unknown function, the second by genes involved in herbicide detoxification, while the third was linked to cellular homeostasis. Analysis of the inducible genes suggested that safening elicited similar gene families to those associated with specific biotic and abiotic stresses, notably those elicited by abscisic acid, salicylic acid, and methyl jasmonate. Subsequent experiments with safener biomarker genes induced in phase 1 and 2 in rice cell cultures provided further evidence of similarities in signalling processes elicited by metcamifen and salicylic acid.

Homozygous TANGO2 Single Nucleotide Variants Presenting with Additional Manifestations Resembling Alternating Hemiplegia of Childhood-Expanding the Phenotype of a Recently Reported Condition.

CASE: We report a 15-year-old Indian girl born to a consanguineous couple, who presented with epilepsy, developmental delay, neuroregression, and episodes of alternating hemiparesis. In addition, she had one episode of rhabdomyolysis at the age of 7 years. Extensive genetic and metabolic work up through the years was unrevealing. Eventually a trio whole exome sequencing (WES) revealed homozygous single nucleotide variants in TANGO2 gene. DISCUSSION: TANGO2 related recurrent metabolic crises with encephalomyopathy and cardiac arrhythmias were described very recently and only 15 cases were reported in literature at the time of writing. Alternating hemiplegia of childhood which was seen in our patient, has not been described in previous patients with TANGO2 mutation, and thereby expands the emerging phenotypic spectrum of this novel entity. This report also reiterates the utility of WES in diagnosing newly recognized neurogenetic conditions.

Substrate specificity and safener inducibility of the plant UDP-glucose-dependent family 1 glycosyltransferase super-family.

Plants contain large numbers of family 1 UDP-glucose-dependent glycosyltransferases (UGTs), including members that conjugate xenobiotics. Arabidopsis contains 107 UGT genes with 99 family members successfully expressed as glutathione transferase (GST)-fusion proteins in E. coli. A high-throughput catalytic screen was developed based on quantification of the fusion by measuring GST activity. UGT activity using UDP-glucose as donor was then determined using 11 synthetic acceptors bearing hydroxyl, amino and thiol groups that had been shown to undergo conjugation in plant extracts. In total, 44 UGTs, largely members of the D and E groups, were active towards xenobiotics, glucosylating phenol and thiol acceptors. In contrast, N-glucosyltransferase (NGT) activity was almost exclusively restricted to a single enzyme, UGT72B1. Using DNA microarrays, the induction of UGT transcripts following treatment with the herbicide safener fenclorim was compared in Arabidopsis and rice. D and L group members were the most safener-inducible UGTs in both species. The respective Arabidopsis enzymes showed low conjugating activity towards xenobiotics. Using Genevestigator, a small group of safened D and L UGTs were consistently induced in response to biotic and abiotic stress suggestive of protective activities beyond xenobiotic detoxification in both species. The induction of other detoxifying gene families following treatment with fenclorim, namely cytochromes P450 and glutathione transferases, further confirmed the selective enhancement of related subfamily members in the two species giving new insight into the safening response in cereals, where herbicide tolerance is enhanced compared with dicots, which are unresponsive to these treatments.

Genetic Counselors' and Genetic Counseling Students' Attitudes Around the Clinical Doctorate and Other Advanced Educational Options for Genetic Counselors: A Report from the Genetic Counseling Advanced Degree Task Force.

Since its establishment over 40 years ago, the genetic counseling profession has grown to an estimated ~4,000 professionals in North America. While the profession has maintained the Master's degree as the entry-level and terminal degree, many other allied health professions have added advanced training pathways, such as the clinical doctorate (ClinD) either as an optional post-professional degree or required entry-level degree. Discussions regarding advanced degrees have also occurred within the genetic counseling profession, dating back to as early as the 1980s. In 2011, the Genetic Counseling Advanced Degree Task Force (GCADTF) was convened to explore the issue again, with the goal of "[engaging] all of the professional leadership organizations in the field of genetic counseling in a decision-making process about whether the profession should move to a Clinical Doctorate". As part of their work, the GCADTF surveyed practicing genetic counselors (n = 4,321) and genetic counseling students (n = 522) in the US and Canada regarding their interest in moving to the ClinD as the entry-level degree. This survey also included questions about other options for advanced training to generate data to inform future discussions around this very important professional issue. Herein, we describe the results of the survey, with particular attention to genetic counselor preferences for additional advanced education/certification opportunities and recommendations for future discussion.

Successes and Challenges in Patient Care Transition Programming: One Hospital's Journey.

The 2013 addition of the Care Transition Measures to the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey; enactment of the Patient Protection and Affordable Care Act (2010); and a greater focus on population health have brought a heightened awareness and need for action with patient transitions. Data are emerging from the additional Care Transition Measures and benchmarks have been developed. This article briefly describes the context of care transition. We describe the journey of Indiana University Health North Hospital to overcome patient care transition obstacles, ultimately achieving designation as a top performer. We will discuss our efforts to personalize patient outcomes and transition through activation and improve transitions for vulnerable populations, specifically in the bariatric and orthopedic patient populations. The article concludes with discussion of overcoming obstacles and future directions with continued focus on collaboration and improvement.

Discovery of active mouse, plant and fungal cytochrome P450s in endogenous proteomes and upon expression in planta.

Eukaryotes produce a large number of cytochrome P450s that mediate the synthesis and degradation of diverse endogenous and exogenous metabolites. Yet, most of these P450s are uncharacterized and global tools to study these challenging, membrane-resident enzymes remain to be exploited. Here, we applied activity profiling of plant, mouse and fungal P450s with chemical probes that become reactive when oxidized by P450 enzymes. Identification by mass spectrometry revealed labeling of a wide range of active P450s, including six plant P450s, 40 mouse P450s and 13 P450s of the fungal wheat pathogen Zymoseptoria tritici. We next used transient expression of GFP-tagged P450s by agroinfiltration to show ER-targeting and NADPH-dependent, activity-based labeling of plant, mouse and fungal P450s. Both global profiling and transient expression can be used to detect a broad range of active P450s to study e.g. their regulation and discover selective inhibitors.

Metabolic engineering of the flavone-C-glycoside pathway using polyprotein technology.

C-Glycosylated flavonoids are biologically active plant natural products linked to dietary health benefits. We have used polyprotein expression technology to reconstruct part of the respective biosynthetic pathway in tobacco and yeast, such that dihydrochalcone and flavanone precursors are directly converted to C-glycosides. The polyprotein system developed facilitated the simple and efficient co-expression of pathway enzymes requiring different sub-cellular localization in both plants and yeast. The pathway to flavone-C-glucosides comprised a flavanone 2-hydroxylase (F2H), co-expressed with a C-glucosyltransferase (CGT). While pathway engineering in tobacco resulted in only minor C-glycoside formation, when fed with the flavanone naringenin, yeast transformed with the F2H-CGT polyprotein construct produced high concentrations of 2-hydroxynaringenin-C-glucoside in the medium. These fermentation products could then be readily chemically converted to the respective flavone-C-glucosides. The efficiency of the biosynthesis was optimal when both the F2H and CGT were obtained from the same species (rice). These results confirm the coupled roles of the F2H and CGT in producing C-glucosides in vivo, with the use of the polyprotein expression system in yeast offering a useful system to optimize the synthesis of these natural products in quantities suitable for dietary studies.

Protective responses induced by herbicide safeners in wheat.

Safeners are agrochemicals which enhance tolerance to herbicides in cereals including wheat (Triticum aestivum L.) by elevating the expression of xenobiotic detoxifying enzymes, such as glutathione transferases (GSTs). When wheat plants were spray-treated with three safener chemistries, namely cloquintocet mexyl, mefenpyr diethyl and fenchlorazole ethyl, an apparently identical subset of GSTs derived from the tau, phi and lambda classes accumulated in the foliage. Treatment with the closely related mefenpyr diethyl and fenchlorazole ethyl enhanced seedling shoot growth, but this effect was not determined with the chemically unrelated cloquintocet mexyl. Focussing on cloquintocet mexyl, treatments were found to only give a transient induction of GSTs, with the period of elevation being dose dependent. Examining the role of safener metabolism in controlling these responses, it was determined that cloquintocet mexyl was rapidly hydrolysed to the respective carboxylic acid. Studies with cloquintocet showed that the acid was equally effective at inducing GSTs as the ester and appeared to be the active safener. Studies on the tissue induction of GSTs showed that whilst phi and tau class enzymes were induced in all tissues, the induction of the lambda enzymes was restricted to the meristems. To test the potential protective effects of cloquintocet mexyl in wheat on chemicals other than herbicides, seeds were pre-soaked in safeners prior to sowing on soil containing oil and a range of heavy metals. Whilst untreated seeds were unable to germinate on the contaminated soil, safener treatments resulted in seedlings briefly growing before succumbing to the pollutants. Our results show that safeners exert a range of protective and growth promoting activities in wheat that extend beyond enhancing tolerance to herbicides.

Prenatal Lethal Diagnosis of 8p23.1 Duplication Syndrome Associated with Omphalocele and Encephalocele.

Despite increased prenatal and postnatal use of array comparative genomic hybridization (aCGH), isolated 8p23.1 duplication remains rare and has been associated with a widely variable phenotype. Here, we report an isolated 8p23.1 duplication in a fetus with an omphalocele and encephalocele that were incompatible with life. Prenatal aCGH demonstrated a 3.75 Mb de novo duplication of 8p23.1. This region encompassed 54 genes, 21 of which are described in OMIM, including SOX7 and GATA4. The summarized case demonstrates phenotypic features not previously described in 8p23.1 duplication syndrome and is reported in order to enhance understanding of the phenotypic variation.

A Diagnosis of Maternal 22q Duplication and Mosaic Deletion following Prenatal Cell-Free DNA Screening.

Concurrent microduplication and microdeletion of the chromosome 22q11.2 region are a rarely reported phenomenon. We describe a case of germline 22q11.21 microduplication syndrome with concurrent mosaic 22q11.2 deletion in a pregnant patient, identified by chromosomal microarray and FISH after noninvasive prenatal genetic screening (cfDNA) results discordant with family history. The patient was referred to maternal-fetal medicine (MFM) at 14 weeks' gestation secondary to an SNP-based cfDNA result of a suspected maternal 22q11.2 deletion and a fetal risk of 1 in 2 for 22q11.2 deletion syndrome. The patient reported a similar cfDNA result in a previous pregnancy; however postnatal chromosomal microarray on that child identified an atypical 22q11.21 microduplication. We report the maternal chromosomal microarray findings of a germline 726 kb 22q11.21 duplication and a mosaic 1.33 Mb 22q11.2 deletion and highlight the copy number variant data generated by cfDNA in this unique case. This family adds to the limited literature of concurrent 22q11.2 microduplication and microdeletion carriers.

Xenobiotic responsiveness of Arabidopsis thaliana to a chemical series derived from a herbicide safener.

Plants respond to synthetic chemicals by eliciting a xenobiotic response (XR) that enhances the expression of detoxifying enzymes such as glutathione transferases (GSTs). In agrochemistry, the ability of safeners to induce an XR is used to increase herbicide detoxification in cereal crops. Based on the responsiveness of the model plant Arabidopsis thaliana to the rice safener fenclorim (4,6-dichloro-2-phenylpyrimidine), a series of related derivatives was prepared and tested for the ability to induce GSTs in cell suspension cultures. The XR in Arabidopsis could be divided into rapid and slow types depending on subtle variations in the reactivity (electrophilicity) and chemical structure of the derivatives. In a comparative microarray study, Arabidopsis cultures were treated with closely related compounds that elicited rapid (fenclorim) and slow (4-chloro-6-methyl-2-phenylpyrimidine) XRs. Both chemicals induced major changes in gene expression, including a coordinated suppression in cell wall biosynthesis and an up-regulation in detoxification pathways, whereas only fenclorim selectively induced sulfur and phenolic metabolism. These transcriptome studies suggested several linkages between the XR and oxidative and oxylipin signaling. Confirming links with abiotic stress signaling, suppression of glutathione content enhanced GST induction by fenclorim, whereas fatty acid desaturase mutants, which were unable to synthesize oxylipins, showed an attenuated XR. Examining the significance of these studies to agrochemistry, only those fenclorim derivatives that elicited a rapid XR proved effective in increasing herbicide tolerance (safening) in rice.

Molecular diagnostics for real-time determination of herbicide resistance in wild grasses.

The growth of resistance to multiple herbicides in grass weeds is a major threat to global cereal production and in the UK, is epitomized by the loss of control of blackgrass (Alopecurus myosuroides), causing losses in winter wheat production equating to 5% of national consumption. With an urgent need to develop new black-grass management tools, we have developed a lateral flow assay (LFA) that can predict resistance to multiple herbicides within 10 min.

Characterization of Cytochrome P450s with Key Roles in Determining Herbicide Selectivity in Maize.

Safeners such as metcamifen and benoxacor are widely used in maize to enhance the selectivity of herbicides through the induction of key detoxifying enzymes, notably cytochrome P450 monooxygenases (CYPs). Using a combination of transcriptomics, proteomics, and functional assays, the safener-inducible CYPs responsible for herbicide metabolism in this globally important crop have been identified. A total of 18 CYPs belonging to clans 71, 72, 74, and 86 were safener-induced, with the respective enzymes expressed in yeast and screened for activity toward thiadiazine (bentazon), sulfonylurea (nicosulfuron), and triketone (mesotrione and tembotrione) chemistries. Herbicide metabolism was largely restricted to family CYP81A members from clan 71, notably CYP81A9, CYP81A16, and CYP81A2. Quantitative transcriptomics and proteomics showed that CYP81A9/CYP81A16 were dominant enzymes in safener-treated field maize, whereas only CYP81A9 was determined in sweet corn. The relationship between CYP81A sequence and activities were investigated by splicing CYP81A2 and CP81A9 together as a series of recombinant chimeras. CYP81A9 showed wide ranging activities toward the three herbicide chemistries, while CYP81A2 uniquely hydroxylated bentazon in multiple positions. The plasticity in substrate specificity of CYP81A9 toward multiple herbicides resided in the second quartile of its N terminal half. Further phylogenetic analysis of CYP81A9 showed that the maize enzyme was related to other CYP81As linked to agrochemical metabolism in cereals and wild grasses, suggesting this clan 71 CYP has a unique function in determining herbicide selectivity in arable crops.

The Burnout Dyad: A Collaborative Approach for Including Patients in a Model of Provider Burnout.

ABSTRACT: Both patients and providers in the United States (US) suffer from burnout, which can impact the clinical relationship and quality of care. Among providers, burnout is a state of exhaustion including heightened depersonalization; among patients, burnout can negatively affect clinical outcomes. More than half of clinical providers in the United States suffer from burnout; less is known about the magnitude and prevalence among patients. Understanding patient burnout will improve our recognition of treatment barriers, understanding of patient-provider communication, and perceived quality of care. The purpose of the 2019 Stanford University MedicineX Burnout Workgroup was to use a collaborative approach to expand on the National Academy of Medicine (NAM) Wellness and Resilience Model, which does not currently include the patient as an influential member of the care team potentially experiencing burnout. This collaboration among patients, physicians, students, caregivers, technologists, and researchers used a convenience sample of conference attendees, broken into three focus groups to (1) provide an expanded definition of burnout that includes patients' perspectives, (2) analyze the NAM burnout model for inclusion of the patient experience, and (3) define a care experience that includes both patients and providers. The design of this workgroup was informed by Everyone Included, a model that recognizes and rejects hierarchical traditions in clinical practice. This approach allowed for the creation of a safe space for the exchange of knowledge between the various stakeholders. The resulting inclusive conceptual model, The Burnout Dyad, describes a cocreated care experience informed by both patient and provider characteristics.

Non-target Site Herbicide Resistance Is Conferred by Two Distinct Mechanisms in Black-Grass (Alopecurus myosuroides).

Non-target site resistance (NTSR) to herbicides in black-grass (Alopecurus myosuroides) results in enhanced tolerance to multiple chemistries and is widespread in Northern Europe. To help define the underpinning mechanisms of resistance, global transcriptome and biochemical analysis have been used to phenotype three NTSR black-grass populations. These comprised NTSR1 black-grass from the classic Peldon field population, which shows broad-ranging resistance to post-emergence herbicides; NTSR2 derived from herbicide-sensitive (HS) plants repeatedly selected for tolerance to pendimethalin; and NTSR3 selected from HS plants for resistance to fenoxaprop-P-ethyl. NTSR in weeds is commonly associated with enhanced herbicide metabolism catalyzed by glutathione transferases (GSTs) and cytochromes P450 (CYPs). As such, the NTSR populations were assessed for their ability to detoxify chlorotoluron, which is detoxified by CYPs and fenoxaprop-P-ethyl, which is acted on by GSTs. As compared with HS plants, enhanced metabolism toward both herbicides was determined in the NTSR1 and NTSR2 populations. In contrast, the NTSR3 plants showed no increased detoxification capacity, demonstrating that resistance in this population was not due to enhanced metabolism. All resistant populations showed increased levels of AmGSTF1, a protein functionally linked to NTSR and enhanced herbicide metabolism. Enhanced AmGSTF1 was associated with increased levels of the associated transcripts in the NTSR1 and NTSR2 plants, but not in NTSR3, suggestive of both pre- and post-transcriptional regulation. The related HS, NTSR2, and NTSR3 plants were subject to global transcriptome sequencing and weighted gene co-expression network analysis to identify modules of genes with coupled regulatory functions. In the NTSR2 plants, modules linked to detoxification were identified, with many similarities to the transcriptome of NTSR1 black-grass. Critical detoxification genes included members of the CYP81A family and tau and phi class GSTs. The NTSR2 transcriptome also showed network similarities to other (a)biotic stresses of plants and multidrug resistance in humans. In contrast, completely different gene networks were activated in the NTSR3 plants, showing similarity to the responses to cold, osmotic shock and fungal infection determined in cereals. Our results demonstrate that NTSR in black-grass can arise from at least two distinct mechanisms, each involving complex changes in gene regulatory networks.

The association of HBB-related significant hemoglobinopathies and low fetal fraction on noninvasive prenatal screening for fetal aneuploidy.

OBJECTIVES: HBB-related significant hemoglobinopathies have been anecdotally associated with low fetal fraction on noninvasive prenatal screening (NIPS). We sought to compare the difference in fetal fraction using NIPS in women with HBB-related significant hemoglobinopathies (HSH) and women with normal hemoglobin. STUDY DESIGN: This is a retrospective case-control study. Cases were women with a diagnosis of HSH using NIPS from a commercial laboratory. The comparison group was women with hemoglobin AA from a tertiary care center database. We tested for differences in median fetal fraction using quantile regression analysis, adjusting for maternal body weight and gestational age. RESULTS: This study includes 35 women with clinically significant HSH and a comparison group of 636 women with hemoglobin AA. Adjusting for gestational age and body weight, the median fetal fraction was 4.1 point lower in the HSH than in the comparison group (ß - 4.1; 95% -5.7 to -2.5, p < .05). The rate of no-calls due to low fetal fraction was significantly higher in the clinically significant HSH group than in the comparison group [HSH: n = 9/35, 25.7% versus comparison: n = 32/636, 5.0% (p < .001)]. CONCLUSION: Women with HSH were more likely to have a lower fetal fraction and ultimately a five-fold higher no-call rate. What's already known about this topic?Low fetal fraction is one of the most common causes of no-call result in noninvasive prenatal screeningHigh maternal weight, early gestational age and fetal aneuploidies are associated with low fetal fraction What does this study add?HBB-related significant hemoglobinopathies are associated with low fetal fractionReduction in fetal fraction due to HBB-related significant hemoglobinopathies may also result in higher no-call rate.

The C-glycosylation of flavonoids in cereals.

Flavonoids normally accumulate in plants as O-glycosylated derivatives, but several species, including major cereal crops, predominantly synthesize flavone-C-glycosides, which are stable to hydrolysis and are biologically active both in planta and as dietary components. An enzyme (OsCGT) catalyzing the UDP-glucose-dependent C-glucosylation of 2-hydroxyflavanone precursors of flavonoids has been identified and cloned from rice (Oryza sativa ssp. indica), with a similar protein characterized in wheat (Triticum aestivum L.). OsCGT is a 49-kDa family 1 glycosyltransferase related to known O-glucosyltransferases. The recombinant enzyme C-glucosylated 2-hydroxyflavanones but had negligible O-glucosyltransferase activity with flavonoid acceptors. Enzyme chemistry studies suggested that OsCGT preferentially C-glucosylated the dibenzoylmethane tautomers formed in equilibrium with 2-hydroxyflavanones. The resulting 2-hydroxyflavanone-C-glucosides were unstable and spontaneously dehydrated in vitro to yield a mixture of 6C- and 8C-glucosyl derivatives of the respective flavones. In contrast, in planta, only the respective 6C-glucosides accumulated. Consistent with this selectivity in glycosylation product, a dehydratase activity that preferentially converted 2-hydroxyflavanone-C-glucosides to the corresponding flavone-6C-glucosides was identified in both rice and wheat. Our results demonstrate that cereal crops synthesize C-glucosylated flavones through the concerted action of a CGT and dehydratase acting on activated 2-hydroxyflavanones, as an alternative means of generating flavonoid metabolites.