Search

A 20-year-old woman was referred to the diabetes clinic with type 2 diabetes diagnosed at the age of 19. Her body mass index was 31.4 kg/m2, HbA1C was 76 mmol/mol, GAD antibodies were negative with a detectable C-peptide. She had a characteristic facial appearance with widespread eyes, posterior hairline suggesting a facial gestalt and abnormal dentition. She also had hypothyroidism, mild intellectual disability, primary amenorrhoea and patent ductus arteriosus. Karyotyping reported normal 46XX karyotype. Genetic testing revealed a pathogenic variant in the gene encoding the HIST1H1E protein which confirmed her diagnosis of HIST1H1E syndrome. Type 2 diabetes has not been reported in previous cases of HIST1H1E and so this is the first reported case of type 2 diabetes with HIST1H1E syndrome.

The Mendelian inheritance pattern of acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria is autosomal dominant, but the clinical phenotype is heterogeneous. Within the general population, penetrance is low, but among first-degree relatives of a symptomatic proband, penetrance is higher. These observations suggest that genetic factors, in addition to mutation of the specific enzyme of the biosynthetic pathway of heme, contribute to the clinical phenotype. Recent studies by others suggested that the genotype of the transporter protein ABCB6 contribute to the porphyria phenotype. Identifying the molecule(s) that are transported by ABCB6 has been problematic and has led to uncertainty with respect to how or if variants/mutants contribute to phenotypic heterogeneity. Knockout mouse models of Abcb6 have not provided a direction for investigation as homozygous knockout animals do not have a discrete phenotype. To address the proposed link between ABC6 genotype and porphyria phenotype, a large cohort of patients with acute hepatic porphyria and erythropoietic protoporphyria was analyzed. Our studies showed that ABCB6 genotype did not correlate with disease severity. Therefore, genotyping of ABCB6 in patients with acute hepatic porphyria and erythropoietic protoporphyria is not warranted.

Escamoles are the larvae of the ant Liometopum apiculatum and have been consumed in Mexico since pre-Hispanic times. Currently, they are one of the most consumed insects in Mexico because of their organoleptic and nutritional characteristics. Escamoles are rich in protein, unsaturated fatty acids, including oleic, linoleic, linolenic, and arachidic acid, as well as vitamin A, thiamine, riboflavin, and niacin. Escamoles, however, have a shelf life of five days at 4 °C. Canning is an alternative process for increasing their shelf life and creating new products. Therefore, the objective of this study was to include traditional Mexican food ingredients for creating new canned escamoles products, as well as to determine and validate the canning time. Four canned escamoles products were obtained according to an official Mexican regulation using the following ingredients: mole, adobo, butter, Mexican mix, and tamarind sauce. Cylindrical cans with a diameter of 68 mm and height of 76 mm were used in all experiments. The sterilisation process was performed with saturated steam at 121 °C. The process time was calculated with a graphic method and validated by a microbiological test. Additionally, thermophysical properties, chemical composition, lipid oxidation, structural changes, and sensory evaluation were determined after the canning process. The process time (P

Purpose To assess the efficacy of tasimelteon to improve sleep in Smith–Magenis syndrome (SMS). Methods A 9-week, double-blind, randomized, two-period crossover study was conducted at four US clinical centers. Genetically confirmed patients with SMS, aged 3 to 39, with sleep complaints participated in the study. Patients were assigned to treatment with tasimelteon or placebo in a 4-week crossover study with a 1-week washout between treatments. Eligible patients participated in an open-label study and were followed for >3 months. Results Improvement of sleep quality (DDSQ50) and total sleep time (DDTST50) on the worst 50% of nights were primary endpoints. Secondary measures included actigraphy and behavioral parameters. Over three years, 52 patients were screened, and 25 patients completed the randomized portion of the study. DDSQ50 significantly improved over placebo (0.4, p = 0.0139), and DDTST50 also improved (18.5 minutes, p = 0.0556). Average sleep quality (0.3, p = 0.0155) and actigraphy-based total sleep time (21.1 minutes, p = 0.0134) improved significantly, consistent with the primary outcomes. Patients treated for ≥90 days in the open-label study showed persistent efficacy. Adverse events were similar between placebo and tasimelteon. Conclusion Tasimelteon safely and effectively improved sleep in SMS.

Summary Organic agriculture is a food production system that sustains the health of people, soils and ecosystems with no adverse consequences, combining tradition, innovation and science. The development of such type of agricultural production, from its beginnings to the present day, has encompassed a number of specific stages both in Serbia and worldwide. Accordingly, the purpose of this survey study is to present the developmental course of organic agricultural production in Serbia and worldwide. The paper also summarises the state of organic plant production across different regions of Serbia, arguing that the Serbian organic production has been increasing since the 1990s. Following the political changes in Serbia in 2000, foreign donations, investments and organisations have significantly enhanced the country’s organic production sector as a whole. The largest number of organic producers (1/3) and the largest areas devoted to organic farming are concentrated in Vojvodina.

A recent report by Majethia and Girisha described a patient with biallelic pathogenic variants in POLR3A and Wiedemann-Rautenstrauch syndrome. In this correspondence, we compare the features of this patient to that of a cohort of patients with severe POLR3-related leukodystrophy and a similar genotype and clinical course. We comment on the phenotyping and classification of POLR3-related disorders.

Lissencephaly represents a spectrum of rare malformations of cortical development including agyria, pachygyria and subcortical band heterotopia. The progress in molecular genetics has led to identification of 31 lissencephaly-associated genes with the overall diagnostic yield over 80%. In this review, we focus on clinical and molecular diagnosis of lissencephaly and summarize the current knowledge on histopathological changes and their correlation with the MRI imaging. Additionally we provide the overview of clinical follow-up recommendations and available data on epilepsy management in patients with lissencephaly.

PURPOSE: Despite widespread provision of Lynch syndrome (LS) screening programs, questions remain about the most effective and efficient protocol for LS case finding. The purpose of this study was to explore the performance of the two protocols widely shown to be the most efficient and effective, respectively: immunohistochemical (IHC) staining of tumor and direct-to-sequencing (DtS) in endometrial cancer populations. METHODS: Simulation models were developed to explore performance of the IHC and DtS protocols, updated to reflect current evidence. Analyses explicitly account for protocol complexity and failure points, as well as decreased sequencing costs. Key outcomes are percent of LS cases identified, total protocol costs and efficiency, and break-even analyses of sequencing costs. All costs are in 2020 US dollars (USD). RESULTS: Under plausible conditions, the IHC protocol is expected to identify 40%-78% of LS cases and DtS protocol from 49% to 97%. When the key variable success in proceeding to sequencing is fixed for both protocols at 50%, 75%, and 100%, the DtS protocol is 9%, 12%, and 16% better at case finding, respectively, than the IHC protocol. The break-even cost of sequencing is about $488 USD when the outcome is total direct testing protocol costs; it is about $670 USD when the outcome is cost per LS case detected. CONCLUSION: This study quantifies the plausible differences in the clinical effectiveness and cost-effectiveness of the two LS case-finding protocols. We demonstrate the large influence of success in proceeding to sequencing and potential impact of decreasing sequencing prices.

Variants of uncertain significance (VUS) are frequently reclassified but recontacting patients with updated results poses significant resource challenges. We aimed to characterize public and patient preferences for being recontacted with updated results. A discrete choice experiment (DCE) was administered to representative samples of the Canadian public and cancer patients. DCE attributes were uncertainty, cost, recontact modality, choice of results, and actionability. DCE data were analyzed using a mixed logit model and by calculating willingness to pay (WTP) for types of recontact. Qualitative interviews exploring recontact preferences were analyzed thematically. DCE response rate was 60% (n = 1003, 50% cancer patient participants). 31 participants were interviewed (11 cancer patients). Interviews revealed that participants expected to be recontacted. Quantitatively, preferences for how to be recontacted varied based on certainty of results. For certain results, WTP was highest for being recontacted by a doctor with updates ($1075, 95% CI: $845, $1305) and for contacting a doctor to request updates ($1038, 95% CI: $820, $1256). For VUS results, WTP was highest for an online database ($1735, 95% CI: $1224, $2247) and for contacting a doctor ($1705, 95% CI: $1102, $2307). Qualitative data revealed that preferences for provider-mediated recontact were influenced by trust in healthcare providers. Preferences for a database were influenced by lack of trust in providers and desire for control. Patients and public participants support an online database (e.g. patient portal) to recontact for VUS, improving feasibility, and provider-mediated recontact for certain results, consistent with usual care.

Background Current preimplantation genetic testing (PGT) technologies enable embryo genotyping across the whole genome. This has led to the development of polygenic risk scoring of human embryos (PGT-P). Recent implementation of PGT-P, including screening for intelligence, has been extensively covered by media reports, raising major controversy. Considering the increasing demand for assisted reproduction, we evaluated how information about PGT-P is communicated in press media and explored the diversity of ethical themes present in the public debate. Methods LexisNexis Academic database and Google News were searched to identify articles about polygenic embryo screening. This led to 535 news articles. 59 original articles met the inclusion criteria. Inductive content analysis was used to analyse these articles. Results 8.8% of articles gave embryo polygenic scoring a positive portrayal, while 36.8% expressed a negative attitude. 54.4% were neutral, mostly highlighting limited practical value of the technology in in vitro fertilization settings. We identified five main ethical themes that are also present in academic literature and the broader debate on reproductive technologies: a slippery slope towards designer babies, well-being of the child and parents, impact on society, deliberate choice and societal readiness. Conclusions Implementation of embryo polygenic profiling engenders a need for specific recommendations. Current media analysis discloses important ethical themes to consider when creating future guidelines for PGT-P.

International audience; The BCAP31 gene, located at Xq28, encodes BAP31, which plays a role in ER-to-Golgi anterograde transport. To date, BCAP31 pathogenic variants have been reported in 12 male cases from seven families (six loss of function (LoF) and one missense). Patients had severe intellectual disability (ID), dystonia, deafness, and central hypomyelination, delineating a so-called deafness, dystonia and cerebral hypomyelination syndrome (DDCH). Female carriers are mostly asymptomatic but may present with deafness. BCAP31 is flanked by the SLC6A8 and ABCD1 genes. Contiguous deletions of BCAP31 and ABCD1 and/or SLC6A8 have been described in 12 patients. Patients with deletions including BCAP31 and SLC6A8 have the same phenotype as BCAP31 patients. Patients with deletions of BCAP31 and ABCD1 have contiguous ABCD1 and DXS1375E/BCAP31 deletion syndrome (CADDS), and demonstrate a more severe neurological phenotype with cholestatic liver disease and early death. We report 17 novel families, 14 with intragenic BCAP31 variants (LoF and missense) and three with a deletion of BCAP31 and adjacent genes (comprising two CADDS patients, one male and one symptomatic female). Our study confirms the phenotype reported in males with intragenic LoF variants and shows that males with missense variants exhibit a milder phenotype. Most patients with a LoF pathogenic BCAP31 variant have permanent or transient liver enzyme elevation. We further demonstrate that carrier females (n = 10) may have a phenotype comprising LD, ID, and/or deafness. The male with CADDS had a severe neurological phenotype, but no cholestatic liver disease, and the symptomatic female had moderate ID and cholestatic liver disease.

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is predominantly caused by desmosomal genetic variants, and clinical hallmarks include arrhythmias and systolic dysfunction. We aimed at studying the impact of the implicated gene(s) on the disease course.MethodsThe Nordic ARVC Registry holds data on a multinational cohort of ARVC families. The effects of genotype on electrocardiographic features, imaging findings and clinical events were analysed.ResultsWe evaluated 419 patients (55% men), with a mean follow-up of 11.2±7.4 years. A pathogenic desmosomal variant was identified in 62% of the 230 families: PKP2 in 41%, DSG2 in 13%, DSP in 7% and DSC2 in 3%. Reduced left ventricular ejection fraction (LVEF) ≤45% on cardiac MRI was more frequent among patients with DSC2/DSG2/DSP than PKP2 ARVC (27% vs 4%, pPKP2 than DSC2/DSG2/DSP carriers: HR 0.25 (0.10–0.68, pDSC2/DSG2/DSP carriers. Male sex was a risk factor for both arrhythmias and reduced LVEF across all genotype groups (pConclusionIn this large cohort of ARVC families with long-term follow-up, we found PKP2 genotype to be more arrhythmic than DSC2/DSG2/DSP or gene-negative carrier status, whereas reduced LVEF was mostly seen among DSC2/DSG2/DSP carriers. Male sex was associated with a more severe phenotype.

Objective:To describe a postnatal series of patients with arthrogryposis multiplex congenita by the causal mechanisms involved.Methods:In this single-center study, the local data warehouse was used to identify patients with arthrogryposis multiplex congenita. Patients were classified into different etiologic groups.Results:Of 82 patients included, the most frequent cause of arthrogryposis multiplex congenita was a neuromuscular disorder (39%), including skeletal muscle (n = 19), neuromuscular junction (n = 3), and peripheral nerve (n = 11) involvement. In other subgroups, 19 patients (23%) were classified by disorders in the central nervous system, 5 (6%) in connective tissue, 7 (8.5%) had mixed mechanisms, and 18 (22%) could not be classified. Contractures topography was not associated with a causal mechanism. Cerebral magnetic resonance imaging (MRI), electroneuromyography, and muscle biopsy were the most conclusive investigations. Metabolic investigations were normal in all the patients tested. Targeted or whole exome sequencing diagnostic rates were 51% and 71%, respectively. Thirty-three percent of patients died (early death occurred in patients with polyhydramnios, prematurity, and ventilatory dependency).Discussion:The benefits of a precise diagnosis in the neonatal period include more tailored management of arthrogryposis multiplex congenita and better genetic information.

Exome sequencing and genome sequencing have the potential to improve clinical utility for patients undergoing genetic investigations. However, evidence of clinical utility is limited to pediatric populations; we aimed to fill this gap by conducting a systematic review of the literature on the clinical utility of exome/genome sequencing across disease indications in pediatric and adult populations. MEDLINE, EMBASE and Cochrane Library were searched between 2016 and 2020. Quantitative studies evaluating diagnostic yield were included; other measures of clinical utility such as changes to clinical management were documented if reported. Two reviewers screened, extracted data, and appraised risk of bias. Fifty studies met our inclusion criteria. All studies reported diagnostic yield, which ranged from 3 to 70%, with higher range of yields reported for neurological indications and acute illness ranging from 22 to 68% and 37–70%, respectively. Diagnoses triggered a range of clinical management changes including surveillance, reproductive-risk counseling, and identifying at-risk relatives in 4–100% of patients, with higher frequencies reported for acute illness ranging from 67 to 95%. The frequency of variants of uncertain significance ranged from 5 to 85% across studies with a potential trend of decreasing frequency over time and higher rates identified in patients of non-European ancestry. This review provides evidence for a higher range of diagnostic yield of exome/genome sequencing compared to standard genetic tests, particularly in neurological and acute indications. However, we identified significant heterogeneity in study procedures and outcomes, precluding a meaningful meta-analysis and certainty in the evidence available for decision-making. Future research that incorporates a comprehensive and consistent approach in capturing clinical utility of exome/genome sequencing across broader ancestral groups is necessary to improve diagnostic accuracy and yield and allow for analysis of trends over time. Prospero registration CRD42019094101.

Osteogenesis Imperfecta (OI) comprises a heterogeneous group of patients who share bone fragility and deformities as the main characteristics, albeit with different degrees of severity. Phenotypic variation also exists in other connective tissue aspects of the disease, complicating disease classification and disease course prediction. Although collagen type I defects are long established as the primary cause of the bone pathology, we are still far from comprehending the complete mechanism. In the last years, the advent of next generation sequencing has triggered the discovery of many new genetic causes for OI, helping to draw its molecular landscape. It has become clear that, in addition to collagen type I genes, OI can be caused by multiple proteins connected to different parts of collagen biosynthesis. The production of collagen entails a complex process, starting from the production of the collagen Iα1 and collagen Iα2 chains in the endoplasmic reticulum, during and after which procollagen is subjected to a plethora of posttranslational modifications by chaperones. After reaching the Golgi organelle, procollagen is destined to the extracellular matrix where it forms collagen fibrils. Recently discovered mutations in components of the retrograde transport of chaperones highlight its emerging role as critical contributor of OI development. This review offers an overview of collagen regulation in the context of recent gene discoveries, emphasizing the significance of transport disruptions in the OI mechanism. We aim to motivate exploration of skeletal fragility in OI from the perspective of these pathways to identify regulatory points which can hint to therapeutic targets.

ObjectiveTo assess cost-effectiveness of newborn screening (NBS) for spinal muscular atrophy (SMA) and early treatment with nusinersen or onasemnogene abeparvovec (gene therapy), compared with nusinersen without SMA screening.MethodsInformed by an Australian state-wide SMA NBS programme, a decision analytical model nested with Markov models was constructed to evaluate costs and quality-adjusted life-years (QALYs) from a societal perspective with sensitivity analyses.ResultsBy treating one presymptomatic SMA infant with nusinersen or gene therapy, an additional 9.93 QALYs were gained over 60 years compared with late treatment in clinically diagnosed SMA. The societal cost was $9.8 million for early nusinersen treatment, $4.4 million for early gene therapy and $4.8 million for late nusinersen treatment. Compared with late nusinersen treatment, early gene therapy would be dominant, gaining 9.93 QALYs while saving $360 000; whereas early nusinersen treatment would result in a discounted incremental cost-effectiveness ratio (ICER) of $507 000/QALY.At a population level, compared with no screening and late treatment with nusinersen, NBS and early gene therapy resulted in 0.00085 QALY gained over 60 years and saving $24 per infant screened (85 QALYs gained and $2.4 million saving per 100 000 infants screened). More than three quarters of simulated ICERs by probability sensitivity analyses showed NBS and gene therapy would be dominant or less than $50 000/QALY, compared with no screening and late nusinersen treatment.ConclusionNBS coupled with gene therapy improves the quality and length of life for infants with SMA and would be considered value-for-money from an Australian clinical and policy context.

Rare diseases affect an estimated 300 million individuals worldwide, and ∼30 million Americans. One of these diseases, FOXG1 syndrome, is a severe neurological condition that causes medical complications and developmental delays. The majority of those diagnosed with the genetic condition are children, making parenting a challenging experience. The purpose of this investigation was to explore the relationship between anxiety, coping, and stress among parents of children with FOXG1 syndrome, ( N = 84). The objective was to identify how these constructs relate and contribute to one another to best treat parents who are seeking counseling services. Results indicated significant relationships between these constructs. Study implications, limitations, and areas for future research are discussed.

Background Clinical genomic professionals are increasingly facing decisions about returning incidental findings (IFs) from genetic research. Although previous studies have shown that research participants are interested in receiving IFs, yet there has been an argument about the extent of researcher obligation to return IFs. We aimed in this study to explore the perspectives of clinical genomics professionals toward returning incidental findings from genomic research. Methods We conducted a national survey of a sample (n = 113) of clinical genomic professionals using a convenient sampling. A self-administered questionnaire was used to explore their attitudes toward disclosure of IFs, their perception of the duties to return IFs and identifying the barriers for disclosure of IFs. A descriptive analysis was employed to describe participants' responses. Results Sixty-five (57.5%) respondents had faced IFs in their practice and 31 (27.4%) were not comfortable in discussing IFs with their research subjects. Less than one-third of the respondents reported the availability of guidelines governing IFs. The majority 84 (80%) and 69 (62.7%) of the study participants indicated they would return the IFs if the risk of disease threat ≥ 50% and 6–49%, respectively and 36 (31.9%) reported they have no obligation to return IFs. Conclusion Clinical genomics professionals have positive attitudes and perceptions toward the returning IFs from genomic research, yet some revealed no duty to do so. Detailed guidelines must be established to provide insights into how genomics professionals should be handled IFs.

Preconception expanded carrier screening (ECS) enables prospective parents to assess their risk of having a child with an autosomal recessive disorder. Knowledge on motivations, feelings, and considerations people have towards the offer and use of ECS is limited. To enrich the public and professional discussion on ECS implementation, this study explored the perspectives towards various aspects of ECS in seven focus groups compromising first- and second-degree relatives of MPS III patients (N=9, N=4, N=5, N=5) and members of the general Dutch population (N=6, N=7, N=5). The focus groups were audio recorded and the transcripts were qualitatively analyzed to identify themes. Both relatives of MPS III patients and participants from the general population supported offering ECS, in particular for severe, childhood-onset disorders. Important barriers identified for ECS were a lack of genetic knowledge and a perceived lack of personal relevance and awareness, as well as out-of-pocket costs of testing. The majority of participants would prefer full disclosure of individual test results instead of couple-based test results. Moreover, offering people a choice for the way of reporting was proposed. All participants agreed that more efforts, for example by governmental campaigns, should be made to increase awareness on the availability, potentials, and limitations of ECS. Educating prospective parents about ECS is essential for increasing awareness and informed decision making. This study provides valuable insights that can be used by governments and public health authorities when considering implementation of preconception ECS.

Objective This study aimed to determine whether Japanese cancer patients share test results of germline pathogenic variants of hereditary cancer with their relatives. Methods This single-center cross-sectional study enrolled 21 Japanese patients who received results of germline pathogenic variants of hereditary cancer at least 6 months prior. Results All patients shared their test results with at least one relative, with the following sharing rates: 85.7% for first-degree relatives, 10% for second-degree relatives and 8.3% for third-degree relatives. Patients most commonly shared the information with their children aged >18 years (86.7%), followed by their siblings (73.6%), spouses (64.7%) and parents (54.5%). Three categories were extracted from qualitative analysis: ‘characteristics of my cancer’, ‘knowledge and caution about inheritability’ and ‘utilization of medical care.’ Conclusions The rate of test result sharing with first-degree relatives was comparable with those in Europe and the USA. Patients with germline pathogenic variants also tended to share their test results more with their children and siblings than with their parents. Informing their relatives of the results was suggestive of the motivation to influence their relatives’ health outcome and contribute to the well-being of their children and siblings., Japanese patients with germline pathogenic variants of hereditary cancers disclosed their test results to at least one relative, mostly first-degree relatives, including the patients’ adult children, siblings, spouses and parents.

Tannins are a large group of polyphenolic compounds and natural protective substances for plant survival. The differentially expressed genes (DEGs) of Micromelalopha troglodyta (Graeser) under tannin stress were studied by Solexa sequencing technology. A total of 51,797,038–54,991,822 and 51,674,478–52,307,172 clean reads were obtained from the tannin treatment (TT) library and the control (CK) library transcriptomes, respectively, and assembled into 21,236 nonredundant consensus sequences. The expression of 1,627 unigenes in the TT library was remarkably different from that of the CK library; 885 genes were upregulated, and 742 genes were downregulated (P ≤ 0.001). The expression of 18 DEGs was detected by real-time fluorescent quantitative PCR, and the trend of gene expression was consistent with that of transcriptome data. In the biological process category, the DEGs were primarily related to cellular processes, metabolic processes, and single-organism processes. In the molecular function category, the DEGs were mainly involved in binding and catalytic activity, and in the cellular component category, the DEGs were mainly related to the cell, cell part, and organelle. Pathway enrichment analysis indicated that drug metabolism-cytochrome P450 and glutathione metabolism may be associated with detoxification-related processes under tannin stress, and glutathione S-transferases and other detoxification enzyme genes play an important role in detoxifying tannins in M. troglodyta larvae. This study also provides important resources for further study of the genes related to pesticide targets and metabolic processes in M. troglodyta.

Whilst informed consent is a key component of considering whether individual genomic research results could or should be fed back to research participants, little is known about the views of Africa...

Genetic testing plays an increasingly important role in the diagnosis and potential treatment of inherited and rare conditions, such as aniridia—a disease that leads to abnormal eye development, as well as in health research on these conditions. As genetic testing is increasingly sought for accurate and early diagnosis of rare genetic disorders and in the context of direct‐to‐consumer genomics, it is critical to examine the public‐facing information about access to these services and reimbursement policies. We conducted a targeted policy and public‐facing resource search. Our analysis of resources available for the patient community revealed that there is very little practical guidance available about access and reimbursement for genetic testing for rare diseases. Greater clarity in public‐facing resources about genetic testing would be beneficial to the patient community as it would promote informed choices about the procedure, mitigate potential harms associated with lack of information and enable patient engagement in their own health care., Key points Genetic testing is crucial for diagnosis and treatment of inherited and rare conditions.Information about access to genetic testing and reimbursement for it is not easily available in public‐facing resources.The patient community would benefit from greater clarity in available information about genetic testing, because it would facilitate informed decision‐making and promote patient engagement in their care.

Next-generation sequencing technology has afforded the discovery of many novel variants that are of significance to inheritable pharmacogenomics (PGx) traits but a large proportion of them have unknown consequences. These include missense variants resulting in single amino acid substitutions in cytochrome P450 (CYP) proteins that can impair enzyme function, leading to altered drug efficacy and toxicity. While most unknown variants are rare, an overlooked minority are variants that are collectively rare but enriched in specific populations. Here, we analyzed sequence variation data in 141,456 individuals from across eight study populations in gnomAD for 38 CYP genes to identify such variants in addition to common variants. By further comparison with data from two PGx-specific databases (PharmVar and PharmGKB) and ClinVar, we identified 234 missense variants in 35 CYP genes, of which 107 were unknown to these databases. Most unknown variants (n = 83) were population-specific common variants and several (n = 7) were found in important CYP pharmacogenes (CYP2D6, CYP4F2, and CYP2C19). Overall, 29% (n = 31) of 107 unknown variants were predicted to affect CYP enzyme function although further biochemical characterization is necessary. These variants may elucidate part of the unexplained interpopulation differences observed in drug response.

Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are biomarkers for liver health. Here we report the largest genome‐wide association analysis to date of serum ALT and AST levels in over 388k people of European ancestry from UK biobank and DiscovEHR. Eleven million imputed markers with a minor allele frequency (MAF) ≥ 0.5% were analyzed. Overall, 300 ALT and 336 AST independent genome‐wide significant associations were identified. Among them, 81 ALT and 61 AST associations are reported for the first time. Genome‐wide interaction study identified 9 ALT and 12 AST independent associations significantly modified by body mass index (BMI), including several previously reported potential liver disease therapeutic targets, for example, PNPLA3, HSD17B13, and MARC1. While further work is necessary to understand the effect of ALT and AST‐associated variants on liver disease, the weighted burden of significant BMI‐modified signals is significantly associated with liver disease outcomes. In summary, this study identifies genetic associations which offer an important step forward in understanding the genetic architecture of serum ALT and AST levels. Significant interactions between BMI and genetic loci not only highlight the important role of adiposity in liver damage but also shed light on the genetic etiology of liver disease in obese individuals.

BACKGROUND. Genetic defects of innate immunity impairing intestinal bacterial sensing are linked to the development of Inflammatory Bowel Disease (IBD). Although much evidence supports a role of the intestinal virome in gut homeostasis, most studies focus on intestinal viral composition rather than on host intestinal viral sensitivity. AIM. To demonstrate the association between the development of Very Early Onset IBD (VEOIBD) and variants in the IFIH1 gene which encodes MDA5, a key cytosolic sensor for viral nucleic acids. METHODS. Whole exome sequencing (WES) was performed in two independent cohorts of children with VEOIBD enrolled in Italy (n=18) and USA (n=24). Luciferase reporter assays were employed to assess MDA5 activity. An enrichment analysis was performed on IFIH1 comparing 42 VEOIBD probands with 1527 unrelated individuals without gastrointestinal or immunological issues. RESULTS. We identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD from a combined cohort of 42 children. One subject, carrying a homozygous truncating variant resulting in complete LoF, experienced neonatal-onset, pan-gastrointestinal, IBD-like enteropathy plus multiple infectious episodes. The remaining seven subjects, affected by VEOIBD without immunodeficiency, were carriers of one LoF variant in IFIH1. Among these, two patients also carried a second hypomorphic variant, with partial function apparent when MDA5 was weakly stimulated. Furthermore, IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p=0.007). CONCLUSIONS. Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis.

Demographic and clinical information from de-identified individuals utilizing a single DNA banking service over a 22-year period was assessed using descriptive statistics. The socioeconomic characteristics of the study population were estimated using a zip code–level analysis of US Census data and compared to national US Metrics for 2016. Samples from 4,874 individuals were deposited to a single commercial DNA bank from 1997 to 2019. Samples originated from 31 countries across 6 continents, with the majority of samples originating from the United States (US; 97.37%; n = 4,746). A higher proportion of individuals identifying as females (55.58%; n = 2,709) utilized the service compared to males (41.18%; n = 2,007). The age distribution was bimodal, peaking around 5 years of age and again around 65 years of age. Whole blood was the preferred specimen for submission. Sample deposits peaked in 2015 with 559 annual deposits. Clinical genetic counselors were the most common referral source (41.73%; n = 2,034). Individuals utilizing DNA banking services are estimated to reside in wealthier, more educated and less racially diverse zip codes compared to national metrics. Although direct to consumer DNA banking is being utilized by the general public and clinical genetic counselors in the US, it is not widespread. Supplementary Information The online version contains supplementary material available at 10.1007/s12687-021-00533-4.

To evaluate the outcome of first trimester intervention by intrafetal laser (IFL) in pregnancies complicated by twin reversed arterial perfusion (TRAP). For a 10-year study period, all patients with TRAP diagnosed 14.0 weeks of gestation were retrospectively analyzed for intrauterine course and outcome. Monoamniotic pregnancies were excluded. Patients were offered either intervention by IFL in the first trimester, expectant management, or termination of pregnancy (TOP). Adverse outcome was defined as either intrauterine death (IUD), neonatal death, or preterm birth. In 45 cases TRAP was diagnosed. 17 monoamniotics were excluded. The cohort was divided into two groups according to management. Group A: 24 cases underwent IFL and group B: 4 cases were managed expectantly. No patient opted for TOP. In group A, 70.8 % of pump twins were born alive, including one preterm delivery, and 29.2 % died within four days after the intervention. All 4 expectantly managed cases in group B had an adverse outcome (1 preterm delivery, 3 IUDs 15.0 weeks). There were no neonatal deaths. In cases treated by IFL, a comparison of survivors and non-survivors identified no significant differences in gestational age at IFL or any of the assessed biometrical and functional parameters. There was a trend towards better outcome in the second half of the study period. IFL in first trimester TRAP sequence is technically feasible but is associated with significant mortality, albeit less than previously reported. No risk stratification is possible using the investigated parameters. However, there seems to be a learning curve.ZIEL: Evaluation des Outcomes von Schwangerschaften mit Twin Reverse Arterial Perfusion (TRAP) nach intrafetaler Laserung (IFL) im 1. Trimester. Innerhalb einer 10-jährigen Studienperiode wurden alle TRAP-Sequenzen, diagnostiziert vor 14 + 0 SSW, hinsichtlich des intrauterinen Verlaufs und Outcomes retrospektiv evaluiert. Monoamniote Schwangerschaften wurden ausgeschlossen. Primäre Endpunkte waren intrauteriner Fruchttod (IUD), perinatale Mortalität und SSW bei Geburt. 45 TRAP-Sequenzen wurden diagnostiziert. 17 Monoamniote wurden ausgeschlossen. Die übrigen 28 Fälle wurden je nach Vorgehen in 2 Gruppen eingeteilt. Gruppe A: 24 Fälle mit IFL im 1. Trimester und Gruppe B: 4 Fälle mit exspektativem Management. Es erfolgte kein Schwangerschaftsabbruch (TOP). In Gruppe A wurden 70,8 % der Zwillinge lebend geboren (eine Frühgeburt), 29,2 % starben innerhalb von 4 Tagen nach Intervention. In Gruppe B hatten alle ein ungünstiges Outcome (1 Frühgeburt, 3 spontane IUD 15 + 0 SSW). Es gab keine neonatalen Todesfälle. Ein Vergleich Überlebender und Verstorbener bezüglich SSW bei Intervention sowie biometrischer und funktioneller Parameter ergab keine signifikanten Unterschiede. Lediglich die Analyse des Überlebens in Gruppe A, stratifiziert nach dem Jahr der Intervention, ergab einen Trend Richtung eines besseren Outcomes in der zweiten Hälfte des Studienzeitraums. IFL bei TRAP-Sequenz im 1. Trimester ist sinnvoll, aber mit einer signifikanten Mortalität behaftet, wenn auch geringer als vorbeschrieben. Eine Risikostratifikation anhand der untersuchten Parameter ist nicht möglich. Allerdings scheint es eine Lernkurve zu geben.

Regional human brain volumes including total area, average thickness, and total volume are heritable and associated with neurological disorders. However, the genetic architecture of brain structure and function is still largely unknown and worthy of exploring. The Pediatric Imaging, Neurocognition, and Genetics (PING) dataset provides an excellent resource with genome-wide genetic data and the related neuroimaging data. In this study, we perform genome-wide association studies (GWAS) of 315 brain volumetric phenotypes from the PING dataset including 1,036 samples with 539,865 single-nucleotide polymorphisms (SNPs). We introduce a nonparametric test based on K-sample Ball Divergence (KBD) to identify genetic risk variants that influence regional brain volumes. We carry out simulations to demonstrate that KBD is a powerful test for identifying significant SNPs associated with multivariate phenotypes while controlling the type I error rate. We successfully identify 9 SNPs below a significance level of 5 * 10(−5) for the PING data. Among the nine identified genetic variants, two SNPs rs486179 and rs562110 are located in the ADRA1A gene that is a well-known risk factor of mental illness, such as schizophrenia and attention deficit hyperactivity disorder (ADHD). Our study suggests that the nonparametric test KBD is an effective method for identifying genetic variants associated with complex diseases in large-scale GWAS of multiple phenotypes.

Familial mitral valve prolapse in human beings has been associated with several genetic variants; however, in most cases, a known variant has not been identified. Dogs also have a naturally occurring form of familial mitral valve disease (MMVD) with similarities to the human disease. A shared genetic background and clinical phenotype of this disease in some dog breeds has indicated that the disease may share a common genetic cause. We evaluated DNA from 50 affected dogs from five different dog breeds in a whole genome sequencing approach to identify shared variants across and within breeds that could be associated with MMVD. No single causative genetic mutation was found from the 50 dogs with MMVD. Ten variants were identified in 37/50 dogs around and within the MED13L gene. These variants were no longer associated with MMVD when evaluated with a larger cohort including both affected and unaffected dogs. No high/moderate impact variants were identified in 10/10 miniature poodles, one was identified in 10/10 Yorkshire Terriers and 10/10 dachshunds, respectively, 14 were identified in 10/10 Miniature schnauzers, and 19 in 10/10 CKCS. Only one of these could be associated with the cardiac valve (Chr12:36801705, COL12A1; CKCS) but when evaluated in an additional 100 affected CKCS the variant was only identified in 84/100 affected dogs, perhaps indicating genetic heterogeneity in this disease. Our findings indicate that development of MMVD in the dog may be related to a combination of genetic and environmental factors that impact specific molecular pathways rather than a single shared genetic variant across or within breeds.

In the analysis of gene expression data, when there are two or more disease conditions/groups (e.g., diseased and normal, responder and nonresponder, and multiple stages/subtypes), differential analysis has been extensively conducted to identify key differences and has important implications. Network analysis takes a system perspective and can be more informative than that limited to simple statistics such as mean and variance. In differential network analysis, a common practice is to first estimate a gene expression network for each condition/group, and then spectral clustering can be applied to the network difference(s) to identify key genes and biological mechanisms that lead to the differences. Compared to "simple" analysis such as regression, differential network analysis can be more challenging with the significantly larger number of parameters. In this study, taking advantage of the increasing popularity of multidimensional profiling data, we develop an assisted analysis strategy and propose incorporating regulator information to improve the identification of key genes (that lead to the differences in gene expression networks). An effective computational algorithm is developed. Comprehensive simulation is conducted, showing that the proposed approach can outperform the benchmark alternatives in identification accuracy. With the The Cancer Genome Atlas lung adenocarcinoma data, we analyze the expressions of genes in the KEGG cell cycle pathway, assisted by copy number variation data. The proposed assisted analysis leads to identification results similar to the alternatives but different estimations. Overall, this study can deliver an efficient and cost-effective way of improving differential network analysis.

A non-negligible proportion of human pathogenic variants are known to be present as wild type in at least some non-human mammalian species. The standard explanation for this finding is that molecular mechanisms of compensatory epistasis can alleviate the mutations' otherwise pathogenic effects. Examples of compensated variants have been described in the literature but the interacting residue(s) postulated to play a compensatory role have rarely been ascertained. In this study, the examination of five human X-chromosomally encoded proteins (FIX, GLA, HPRT1, NDP and OTC) allowed us to identify several candidate compensated variants. Strong evidence for a compensated/compensatory pair of amino acids in the coagulation FIXa protein (involving residues 270 and 271) was found in a variety of mammalian species. Both amino acid residues are located within the 60-loop, spatially close to the 39-loop that performs a key role in coagulation serine proteases. To understand the nature of the underlying interactions, molecular dynamics simulations were performed. The predicted conformational change in the 39-loop consequent to the Glu270Lys substitution (associated with hemophilia B) appears to impair the protein's interaction with its substrate but, importantly, such steric hindrance is largely mitigated in those proteins that carry the compensatory residue (Pro271) at the neighboring amino acid position.

David Herman MacLennan, one of Canada's foremost biomedical scientists, was known internationally for his research on the molecular mechanism of muscle contraction in human health and disease. David was born on 3 July 1937 in Swan River, Manitoba, and grew up in farm country. After obtaining a BS (Agriculture) in plant science from the University of Manitoba in 1959, David completed his MSc (1961) and PhD (1963) in biology at Purdue. A post-doctoral fellowship at the Enzyme Institute at the University of Wisconsin followed, where he was appointed as an assistant professor (1964–1968). At Wisconsin David published a series of elegant papers on the isolation and characterization of the mitochondrial ATPase and protein components of the electron transfer system. In 1969 he was recruited back to Canada as an associate professor in the Banting and Best Department of Medical Research at the University of Toronto, where he spent the rest of his illustrious career. Here, David shifted his focus to determine how calcium regulates muscle contraction, with a focus on the role of the sarcoplasmic reticulum (SR). David was a scientist who knew where a field was going and he often got there first, incorporating new technologies along the way. His early discovery of the Ca 2+ ATPase pump that controls calcium uptake into the SR was the key to muscle relaxation. His lab systematically characterized the components of the SR, including the ryanodine receptor which acts as a calcium release channel to allow muscle contraction. David's discoveries of these molecular mechanisms and their application to debilitating muscle disease are an inspiring scientific legacy. Although David published hundreds of papers, many cited hundreds of times, gave hundreds of invited seminars and won many prestigious awards, including Fellow of the Royal Society of London in 1994, his greatest legacy is the people he trained, many of whom went on to leadership positions in research and at universities around the world.

SARS‐CoV‐2 mortality has been extensively studied in relation to host susceptibility. How sequence variations in the SARS‐CoV‐2 genome affect pathogenicity is poorly understood. Starting in October 2020, using the methodology of genome‐wide association studies (GWAS), we looked at the association between whole‐genome sequencing (WGS) data of the virus and COVID‐19 mortality as a potential method of early identification of highly pathogenic strains to target for containment. Although continuously updating our analysis, in December 2020, we analyzed 7548 single‐stranded SARS‐CoV‐2 genomes of COVID‐19 patients in the GISAID database and associated variants with mortality using a logistic regression. In total, evaluating 29,891 sequenced loci of the viral genome for association with patient/host mortality, two loci, at 12,053 and 25,088 bp, achieved genome‐wide significance (p values of 4.09e−09 and 4.41e−23, respectively), though only 25,088 bp remained significant in follow‐up analyses. Our association findings were exclusively driven by the samples that were submitted from Brazil (p value of 4.90e−13 for 25,088 bp). The mutation frequency of 25,088 bp in the Brazilian samples on GISAID has rapidly increased from about 0.4 in October/December 2020 to 0.77 in March 2021. Although GWAS methodology is suitable for samples in which mutation frequencies varies between geographical regions, it cannot account for mutation frequencies that change rapidly overtime, rendering a GWAS follow‐up analysis of the GISAID samples that have been submitted after December 2020 as invalid. The locus at 25,088 bp is located in the P.1 strain, which later (April 2021) became one of the distinguishing loci (precisely, substitution V1176F) of the Brazilian strain as defined by the Centers for Disease Control. Specifically, the mutations at 25,088 bp occur in the S2 subunit of the SARS‐CoV‐2 spike protein, which plays a key role in viral entry of target host cells. Since the mutations alter amino acid coding sequences, they potentially imposing structural changes that could enhance viral infectivity and symptom severity. Our analysis suggests that GWAS methodology can provide suitable analysis tools for the real‐time detection of new more transmissible and pathogenic viral strains in databases such as GISAID, though new approaches are needed to accommodate rapidly changing mutation frequencies over time, in the presence of simultaneously changing case/control ratios. Improvements of the associated metadata/patient information in terms of quality and availability will also be important to fully utilize the potential of GWAS methodology in this field.

Among the myriad causes of intellectual disability (ID), Fragile X Syndrome (FXS) is the leading genetic cause. Yet, little is known of how people affected by this condition make sense of it. The present study aimed to investigate the explanatory models for the causes of FXS in an extended family mainly affected by this condition and members of the village from which they originated in Cameroon. Using an ethnographic approach, 92 participants were interviewed (59 females and 33 males) through 10 focus group discussions and 23 in-depth interviews between April 2018 and February 2020. Data analysis revealed four explanatory models regarding the etiologies of FXS in the community. Firstly, the curse model described a curse from the chief because of the belief that his wives did not mourn his intellectually disabled servant. Secondly, the spiritual model relates FXS to a punishment from God. Thirdly, the socioeconomic model attributes FXS to events in the prenatal and perinatal periods. Finally, the genetic model describes the pattern of inheritance of the disease in the family. This paper helps to understand the explanatory disease models that exist for FXS in rural Cameroon and could inform genetic counseling practices, community genetic education, and policymakers when drafting protocols for public engagement activities.

The psychosocial sequelae of caregiving in Huntington’s disease (HD) have been shown to be extensive, even in comparison with other progressive neurological disorders. Based on observed clinical need, this investigation aimed to identify psychoeducational and emotional support needs of male HD caregivers and to explore the feasibility and utility of a carer support group. Six male caregivers completed quantitative measures assessing depression, anxiety, carer burden, and carer support needs. The men participated in two education and support group sessions, four weeks apart, which were developed with consideration of male support preferences. Qualitative themes arising in these sessions were documented. Questionnaire results showed overall low levels of psychological distress and carer burden. Despite this, the group sessions facilitated disclosure of significant emotional, practical, and relationship challenges arising from HD. Further, a range of psychoeducational and emotional support needs were identified on quantitative and qualitative assessments. Participants strongly endorsed the format of the group and the benefits of participation, highlighting in particular the importance of meeting other men who understood the experience of living with a spouse with HD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12687-021-00535-2.

PCDH19 is a nonclustered protocadherin molecule involved in axon bundling, synapse function, and transcriptional coregulation. Pathogenic variants in PCDH19 cause infantile-onset epilepsy known as PCDH19-clustering epilepsy or PCDH19-CE. Recent advances in DNA-sequencing technologies have led to a significant increase in the number of reported PCDH19-CE variants, many of uncertain significance. We aimed to determine the best approaches for assessing the disease relevance of missense variants in PCDH19. The application of the American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) guidelines was only 50% accurate. Using a training set of 322 known benign or pathogenic missense variants, we identified MutPred2, MutationAssessor, and GPP as the best performing in silico tools. We generated a protein structural model of the extracellular domain and assessed 24 missense variants. We also assessed 24 variants using an in vitro reporter assay. A combination of these tools was 93% accurate in assessing known pathogenic and benign PCDH19 variants. We increased the accuracy of the ACMG-AMP classification of 45 PCDH19 variants from 50% to 94%, using these tools. In summary, we have developed a robust toolbox for the assessment of PCDH19 variant pathogenicity to improve the accuracy of PCDH19-CE variant classification. Refereed/Peer-reviewed

Mutations in ALDH3A2 cause Sjogren-Larsson Syndrome (SLS), a neuro-ichthyotic condition that is caused by deficiency of fatty aldehyde dehydrogenase (FALDH). We screened for novel mutations causing SLS among Indian ethnicity, characterized the identified mutations in silico and in vitro; and retrospectively evaluated their role in phenotypic heterogeneity. Interestingly, asymmetric distribution of non-classical traits was observed in our cases. Nerve conduction studies suggested intrinsic-minus-claw hands in two siblings, a novel neurological phenotype to SLS. Genetic testing revealed 5 novel homozygous ALDH3A2 mutations in six cases: Case-1-NM_000382.2:c.50C>A, NP_000373.1:p.(Ser17Ter); Case-2-NM_000382.2:c.199G>T, NP_000373.1:p.(Glu67Ter); Case-3-NM_000382.2:c.1208G>A, NP_000373.1:p.(Gly403Asp); Case-4-NM_000382.2:c.1325C>T, NP_000373.1:p.(Pro442Leu); Case-5&6-NM_000382.2:c.1349G>A, NP_000373.1:p.(Trp450Ter). The mutations identified were predicted to be pathogenic and disrupts the functional domains of the FALDH. p.(Pro442Leu) at the C-terminal α-helix, might impair substrate gating process. Mammalian expression studies with exon-9 mutants confirmed the profound reduction in the enzyme activity. Diminished aldehyde oxidizing activity was observed with cases-2&3. Cases-2 & 3 showed epidermal hyperplasia with mild intracellular edema, spongiosis, hypergranulosis, and perivascular-interstitial lymphocytic infiltrate and a leaky eosinophilic epidermis. The presence of keratin-milia like lipid vacuoles implies defective lamellar secretion with p.(Gly403Asp). This study improves our understanding of the clinical and mutational diversity in SLS, which might help to fast-track diagnostic and therapeutic interventions of this debilitating disorder. This article is protected by copyright. All rights reserved.

Omics studies frequently use samples collected during cohort studies. Conditioning on sample availability can cause selection bias if sample availability is nonrandom. Inverse probability weighting (IPW) is purported to reduce this bias. We evaluated IPW in an epigenome-wide analysis testing the association between DNA methylation (261,435 probes) and age in healthy adolescent subjects (n = 114). We simulated age and sex to be correlated with sample selection and then evaluated four conditions: complete population/no selection bias (all subjects), naïve selection bias (no adjustment), and IPW selection bias (selection bias with IPW adjustment). Assuming the complete population condition represented the "truth," we compared each condition to the complete population condition. Bias or difference in associations between age and methylation was reduced in the IPW condition versus the naïve condition. However, genomic inflation and type 1 error were higher in the IPW condition relative to the naïve condition. Postadjustment using bacon, type 1 error and inflation were similar across all conditions. Power was higher under the IPW condition compared with the naïve condition before and after inflation adjustment. IPW methods can reduce bias in genome-wide analyses. Genomic inflation is a potential concern that can be minimized using methods that adjust for inflation.

The government-funded ‘Punjab Thalassaemia Prevention Project’ (PTPP) in Pakistan includes cascade screening for biological relatives of children with beta-Thalassaemia Major (β-TM). However, there is low uptake of cascade screening. This paper presents the (i) development of a paper-based ‘decision support intervention for relatives’ (DeSIRe) to enable PTPP Field Officers to facilitate informed decision making about carrier testing, and (ii) assessment of the feasibility and acceptability of the DeSIRe. The intervention was developed using the International Patient Decision Aids Standards quality criteria and Ottawa Decision Support Framework. Twelve focus groups were conducted (September and October 2020) to explore the views of healthcare professionals (HCPs) and relatives of children with β-TM, in six cities. The focus groups were attended by 117 participants (60 HCPs and 57 relatives). Thematic analysis showed that the DeSIRe was considered acceptable for supporting relatives to make informed decisions about cascade screening, and potentially feasible for use in clinical practice. Suggestions for changing some words, the structure and adding information about how carrier testing relates to consanguineous marriages will enable further development of the DeSIRe. Participants generally welcomed the DeSIRe; however, they highlighted the perceived need to use more directive language, hence showed a cultural preference for directive genetic counselling. The findings highlight challenges for researchers using western theories, frameworks, policies and clinical guidelines to develop decision support interventions for implementation more globally. Future research is needed to evaluate the use of the DeSIRe in routine practice and whether it enables relatives to make informed decisions.

Femoral-facial syndrome (FFS) is an exceedingly rare congenital disorder of unknown etiology related to maternal diabetes during pregnancy. It is characterized by variations of bilateral femoral hypoplasia and facial anomalies. We discuss an interesting case of a 3-year-old girl with FFS with an extensive surgical history who presented to a pediatric orthopaedic clinic with ankle pains and absent femurs. As this disease process is not frequently encountered, it is imperative for the practicing clinician to be aware of the various presentations. In this study, we discuss the different orthopaedic presentations in the literature and discuss various management recommendations.

DNA methylation, chromatin-binding proteins, and DNA looping are common components regulating genomic imprinting which leads to parent-specific monoallelic gene expression. Loss of methylation (LOM) at the human imprinting center 2 (IC2) on chromosome 11p15 is the most common cause of the imprinting overgrowth disorder Beckwith-Wiedemann Syndrome (BWS). Here, we report a familial transmission of a 7.6 kB deletion that ablates the core promoter of KCNQ1. This structural alteration leads to IC2 LOM and causes recurrent BWS. We find that occupancy of the chromatin organizer CTCF is disrupted proximal to the deletion, which causes chromatin architecture changes both in cis and in trans. We also profile the chromatin architecture of IC2 in patients with sporadic BWS caused by isolated LOM to identify conserved features of IC2 regulatory disruption. A strong interaction between CTCF sites around KCNQ1 and CDKN1C likely drive their expression on the maternal allele, while a weaker interaction involving the imprinting control region element may impede this connection and mediate gene silencing on the paternal allele. We present an imprinting model in which KCNQ1 transcription is necessary for appropriate CTCF binding and a novel chromatin conformation to drive allele-specific gene expression.

Genome-wide association studies (GWASs) have successfully identified a large amount of single-nucleotide polymorphisms associated with many complex phenotypes in diverse populations. However, a comprehensive understanding of the genetic correlation of associated loci of phenotypes across populations remains lacking and the extent to which associations discovered in one population can be generalized to other populations or can be utilized for trans-ethnic genetic prediction is also unclear. By leveraging summary statistics, we proposed MAGIC to evaluate the trans-ethnic marginal genetic correlation (rm) of per-allele effect sizes for associated SNPs (P

Objective The study aimed to evaluate the association between hemoglobin A1c values and likelihood of fetal anomalies in women with pregestational diabetes.Study Design Women with pregestational diabetes who delivered at a single institution that serves a nonreferred population from May 1, 2009 to December 31, 2018 were ascertained. Hemoglobin A1c values were obtained at the first prenatal visit. Women who delivered a singleton live- or stillborn infant with a major malformation as defined by European Surveillance of Congenital Anomalies criteria were identified. In infants with multiple system anomalies, each malformation was considered separately. Hemoglobin A1c values were analyzed categorically by using Mantel–Haenszel method and continuously with linear regression for trend for fetal anomalies.Results A total of 1,676 deliveries to women with pregestational diabetes were delivered at our institution, and hemoglobin A1c was assessed in 1,573 deliveries (94%). There were 129 deliveries of an infant with at least one major malformation, an overall anomaly rate of approximately 8%. Mean hemoglobin A1c concentration was significantly higher in pregnancies with anomalous infants, 9.3 ± 2.1% versus 8.0 ± 2.1%, and p Conclusion In women with pregestational diabetes, hemoglobin A1c is strongly associated with fetal anomaly risk. Data from a contemporary cohort may facilitate counseling and also highlight the need for preconceptual care and glycemic optimization prior to entry to obstetric care.Key Points

Interest in analyzing X chromosome single nucleotide polymorphisms (SNPs) is growing and several approaches have been proposed. Prior studies have compared power of different approaches, but bias and interpretation of coefficients have received less attention. We performed simulations to demonstrate the impact of X chromosome model assumptions on effect estimates. We investigated the coefficient biases of SNP and sex effects with commonly used models for X chromosome SNPs, including models with and without assumptions of X chromosome inactivation (XCI), and with and without SNP–sex interaction terms. Sex and SNP coefficient biases were observed when assumptions made about XCI and sex differences in SNP effect in the analysis model were inconsistent with the data‐generating model. However, including a SNP–sex interaction term often eliminated these biases. To illustrate these findings, estimates under different genetic model assumptions are compared and interpreted in a real data example. Models to analyze X chromosome SNPs make assumptions beyond those made in autosomal variant analysis. Assumptions made about X chromosome SNP effects should be stated clearly when reporting and interpreting X chromosome associations. Fitting models with SNP × Sex interaction terms can avoid reliance on assumptions, eliminating coefficient bias even in the absence of sex differences in SNP effect.

Multitrait tests can improve power to detect associations between individual single-nucleotide polymorphisms (SNPs) and several related traits. Here, we develop methods for multi-SNP transcriptome-wide association (TWAS) tests to test the association between predicted gene expression levels and multiple phenotypes. We show that the correlation in TWAS test statistics for multiple phenotypes has the same form as multitrait statistics for the single-SNP setting. Thus, established methods for combining single-SNP test statistics across multiple traits can be extended directly to the TWAS setting. We performed an extensive evaluation across eight multitrait methods in simulations that varied gene-phenotype effect sizes in addition to the underlying covariance structure among the phenotypes. We found that all multitrait TWAS tests have well-calibrated Type I error (except ASSET, which can have a slightly elevated or depressed Type I error rate). Our results show that multitrait TWAS can improve statistical power compared with multiple single-trait TWAS followed by Bonferroni correction. To illustrate our approach to real data, we conducted a multitrait TWAS of four circulating lipid traits from the Global Lipids Genetics Consortium. We found that our multitrait Wald TWAS approach identified 506 genes associated with lipid levels compared with 87 identified through Bonferroni-corrected single-trait TWAS. Overall, we find that our proposed multitrait TWAS framework outperforms single-trait approaches to identify new genetic associations, especially for functionally correlated phenotypes and phenotypes with overlapping genome-wide association studies samples, leading to insights into the genetic architecture of multiple phenotypes.

Contains fulltext : 237830.pdf (Publisher’s version ) (Open Access) Genome-wide association studies (GWAS) have generated unprecedented insights into the genetic etiology of orofacial clefting (OFC). The moderate effect sizes of associated noncoding risk variants and limited access to disease-relevant tissue represent considerable challenges for biological interpretation of genetic findings. As rare variants with stronger effect sizes are likely to also contribute to OFC, an alternative approach to delineate pathogenic mechanisms is to identify private mutations and/or an increased burden of rare variants in associated regions. This report describes a framework for targeted resequencing at selected noncoding risk loci contributing to nonsyndromic cleft lip with/without cleft palate (nsCL/P), the most frequent OFC subtype. Based on GWAS data, we selected three risk loci and identified candidate regulatory regions (CRRs) through the integration of credible SNP information, epigenetic data from relevant cells/tissues, and conservation scores. The CRRs (total 57 kb) were resequenced in a multiethnic study population (1061 patients; 1591 controls), using single-molecule molecular inversion probe technology. Combining evidence from in silico variant annotation, pedigree- and burden analyses, we identified 16 likely deleterious rare variants that represent new candidates for functional studies in nsCL/P. Our framework is scalable and represents a promising approach to the investigation of additional congenital malformations with multifactorial etiology.

Genome‐wide association studies have identified SNPs associated with glioma risk on 9p21.3, but biological mechanisms underlying this association are unknown. We tested the hypothesis that a functional SNP on 9p21.3 affects activity of an enhancer, causing altered expression of nearby genes. We considered all SNPs in linkage disequilibrium with the 9p21.3 sentinel SNP rs634537 that mapped to putative enhancers. An enhancer containing rs1537372 exhibited allele‐specific effects on luciferase activity. Deletion of this enhancer in GBM cell lines correlated with decreased expression of CDKN2B‐AS1. Expression quantitative trait loci analysis using non‐diseased brain samples showed rs1537372 to be a consistently significant eQTL for CDKN2B‐AS1. Additionally, our analysis of Hi‐C data generated in neural progenitor cells showed that the bait region containing rs1537372 interacted with the CDKN2B‐AS1 promoter. These data suggest rs1537372, a SNP at the 9p21.3 risk locus, is a functional variant that modulates expression of CDKN2B‐AS1.

Correction: A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis. Eur J Hum Genet. 2021 Sep;29(9):1470-1471. doi: 10.1038/s41431-021-00937-3. The genetic etiology of intellectual disability remains elusive in almost half of all affected individuals. Within the Solve-RD consortium, systematic re-analysis of whole exome sequencing (WES) data from unresolved cases with (syndromic) intellectual disability (n = 1,472 probands) was performed. This re-analysis included variant calling of mitochondrial DNA (mtDNA) variants, although mtDNA is not specifically targeted in WES. We identified a functionally relevant mtDNA variant in MT-TL1 (NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C), at a heteroplasmy level of 22% in whole blood, in a 23-year-old male with severe intellectual disability, epilepsy, episodic headaches with emesis, spastic tetraparesis, brain abnormalities, and feeding difficulties. Targeted validation in blood and urine supported pathogenicity, with heteroplasmy levels of 23% and 58% in index, and 4% and 17% in mother, respectively. Interestingly, not all phenotypic features observed in the index have been previously linked to this MT-TL1 variant, suggesting either broadening of the m.3291T > C-associated phenotype, or presence of a co-occurring disorder. Hence, our case highlights the importance of underappreciated mtDNA variants identifiable from WES data, especially for cases with atypical mitochondrial phenotypes and their relatives in the maternal line. This work was financially supported by Aspasia grants of the Dutch Research Council (015.014.036 to TK and 015.014.066 to LELMV), the European Research Council (ERC to RH), the Well come Investigator Award (109915/Z/15/Z to RH), the Medical Research Council UK (MR/N025431/1 to RH), the Newton Fund (MR/N027302/1 to RH), the Lily Foundation (RH), and the Evelyn Trust (RH). The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 779257. Sí

In children with developmental delay (DD) and neurologic impairment, diagnosis can be challenging because of the wide spectrum of causes. Since the last decade, the use of array comparative genomic hybridization (CGH) offered a great contribution to get a diagnosis in complex phenotypes. The chromosome 7 is subject of interest in medical genetics because of its frequent association with chromosome aberrations, rearrangements, and deletions involving clinical manifestations. We hereby reported a 3-year-old male child patient with severe neuro-DD, craniofacial dysmorphisms, and pulmonary stenosis, whose array CGH analysis disclosed a duplication of 14.4 Mb on chromosome 7 (7q21.3-7q31.1). By reviewing the current literature to date, we first reported on neurologic and dysmorphic anomalies related to this rearrangement which was not previously reported.