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Numerous observational studies have attempted to identify risk factors for infection with SARS-CoV-2 and COVID-19 disease outcomes. Studies have used datasets sampled from patients admitted to hospital, people tested for active infection, or people who volunteered to participate. Here, we highlight the challenge of interpreting observational evidence from such non-representative samples. Collider bias can induce associations between two or more variables which affect the likelihood of an individual being sampled, distorting associations between these variables in the sample. Analysing UK Biobank data, compared to the wider cohort the participants tested for COVID-19 were highly selected for a range of genetic, behavioural, cardiovascular, demographic, and anthropometric traits. We discuss the mechanisms inducing these problems, and approaches that could help mitigate them. While collider bias should be explored in existing studies, the optimal way to mitigate the problem is to use appropriate sampling strategies at the study design stage. Many published studies of the current SARS-CoV-2 pandemic have analysed data from non-representative samples from populations. Here, using UK BioBank samples, Gibran Hemani and colleagues discuss the potential for such studies to suffer from collider bias, and provide suggestions for optimising study design to account for this.

There are over 1,000,000 publications on diet and health and over 480,000 references on inflammation in the National Library of Medicine database. In addition, there have now been over 30,000 peer-reviewed articles published on the relationship between diet, inflammation, and health outcomes. Based on this voluminous literature, it is now recognized that low-grade, chronic systemic inflammation is associated with most non-communicable diseases (NCDs), including diabetes, obesity, cardiovascular disease, cancers, respiratory and musculoskeletal disorders, as well as impaired neurodevelopment and adverse mental health outcomes. Dietary components modulate inflammatory status. In recent years, the Dietary Inflammatory Index (DII®), a literature-derived dietary index, was developed to characterize the inflammatory potential of habitual diet. Subsequently, a large and rapidly growing body of research investigating associations between dietary inflammatory potential, determined by the DII, and risk of a wide range of NCDs has emerged. In this narrative review, we examine the current state of the science regarding relationships between the DII and cancer, cardiometabolic, respiratory and musculoskeletal diseases, neurodevelopment, and adverse mental health outcomes. We synthesize the findings from recent studies, discuss potential underlying mechanisms, and look to the future regarding novel applications of the adult and children’s DII (C-DII) scores and new avenues of investigation in this field of nutritional research.

Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve non-overlapping cohorts from ten independent longitudinal studies ( N  = 5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3 . Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX , MyD88 , and both UHRF1 and SDCCAG8 , respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring.

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta‐analyzed epigenome‐wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5–10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR < 0.05). Eight of these CpGs were located near/in the MTNR1B gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near MTNR1B, at which higher DNAm was associated with greater maternal age (PFDR = 6.92 × 10−8) in newborns. In childhood blood samples, these differences in blood DNAm of MTNR1B CpGs were nominally significant (p < 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in RTEL1‐TNFRSF6B at birth (PFDR < 0.05) and nominally in childhood (p < 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in YPEL3/BOLA2B in external data was associated with expression of ITGAL, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health. The study meta‐analyzed epigenome‐wide associations of parental age with offspring blood DNAm of newborns and children (5–10 years old) from cohorts in the Pregnancy and Childhood Epigenetics consortium. DNA was derived from newborn or childhood blood samples and analyzed using the 450K or EPIC microarrays. DNAm levels were associated with maternal age but not paternal age and potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health.

Endophytic bacteria are not known from woody plant seedlings. Endophytic and epiphytic bacteria were isolated from leaves, stems and roots of hybrid aspen (Populus tremula x Populus tremuloides) seedlings. The uncultured 16S rRNA rhizospheric bacterial community was cloned from pristine and polyaromatic hydrocarbon polluted rhizosphere soil. The isolates were subjected to restriction fragment length polymorphism analysis and partial 16S rRNA of selected strains was sequenced for phylogenetic identification. The bacteria could be classified into 16 different genera, showing that epiphytes from plant surfaces were most often Gammaproteobacteria, which composed 47% of the isolates. Endophytes from plant tissue were most frequently Betaproteobacteria (45%). Polyaromatic hydrocarbons caused a shift in the cultured bacterial community in the rhizosphere soil to a Betaproteobacteria dominated one. The root bacterial community showed a strong association of Burkholderia bacteria with hybrid aspen. Over 50% of all isolated strains grew on benzoic acid, but only 16% of benzoic acid degraders grew on m-toluate.

Background COVID‐19 outbreak prompted health centres to reorganize their clinical and surgical activity. In this paper, we show how medical genetics department's activity, in our tertiary pediatric hospital, has changed due to pandemic. Methods We stratified all our scheduled visits, from March 9th through April 30th, and assessed case‐by‐case which genetic consultations should be maintained as face‐to‐face visit, or postponed/switched to telemedicine. Results Out of 288 scheduled appointments, 60 were prenatal consultations and 228 were postnatal visits. We performed most of prenatal consultations as face‐to‐face visits, as women would have been present in the hospital to perform other procedures in addition to our consult. As for postnatal care, we suspended all outpatient first visits and opted for telemedicine for selected follow‐up consultations: interestingly, 75% of our patients’ parents revealed that they would have cancelled the appointment themselves for the fear to contract an infection. Conclusions Spread of COVID‐19 in Italy forced us to change our working habits. Given the necessity to optimize healthcare resources and minimize the risk of in‐hospital infections, we experienced the benefits of telegenetics. Current pandemic made us familiar with telemedicine, laying the foundations for its application to deal with the increasing number of requests in clinical genetics. In this paper, we show how medical genetics department's activity, in our tertiary pediatric hospital, has changed due to COVID‐19 pandemic. Given the necessity to optimize healthcare resources and minimize the risk of in‐hospital infections, we experienced the benefits of telegenetics. Current pandemic made us familiar with telemedicine, laying the foundations for its application to deal with the increasing number of requests in clinical genetics.

Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown. A total of 670 patients belonging to unrelated pedigrees with European and Chinese ancestry with CFM, are investigated. We identify 18 likely pathogenic variants in 21 probands (3.1%) in FOXI3 . Biochemical experiments on transcriptional activity and subcellular localization of the likely pathogenic FOXI3 variants, and knock-in mouse studies strongly support the involvement of FOXI3 in CFM. Our findings indicate autosomal dominant inheritance with reduced penetrance, and/or autosomal recessive inheritance. The phenotypic expression of the FOXI3 variants is variable. The penetrance of the likely pathogenic variants in the seemingly dominant form is reduced, since a considerable number of such variants in affected individuals were inherited from non-affected parents. Here we provide suggestive evidence that common variation in the FOXI3 allele in trans with the pathogenic variant could modify the phenotypic severity and accounts for the incomplete penetrance. Most cases of craniofacial microsomia are sporadic but familial cases have been reported. Here the authors report that variants in FOXI3 can cause a small fraction of cases with different modes of inheritance including autosomal dominant with reduced penetrance.

This is the first case of NBAS disease detected by NBS for primary immunodeficiency. NBS with KRECs is revealing unknown potentialities detecting conditions that benefit from early recognition like NBAS deficiency. Immune phenotyping should be mandatory in patients with NBAS deficiency since they can exhibit severe immunodeficiency with hypogammaglobulinemia as the most frequent finding. Fever during infections is a known trigger of acute liver failure in this syndrome, so immune dysfunction, should never go unnoticed in NBAS deficiency in order to start adequate therapy and prophylaxis.

Abstract Disclosure: G. Del Medico: None. E. Andreucci: None. S. Bargiacchi: None. G. Gori: None. G. Mancano: None. G. Traficante: None. F. Girolami: None. S. Favilli: None. A. Peron: None. I. Olivotto: None. M. Tartaglia: None. S. Stagi: None. Background: Noonan syndrome (NS) is a congenital genetic condition with an estimated incidence of 1 in 1,000-2,500 live births. Typical clinical features include congenital heart defects, short stature, distinctive facial characteristics, chest anomalies, and varying degrees of cognitive impairment. NS is caused by pathogenic variants in genes involved in the RAS/MAPK signaling cascade, resulting in significant clinical and genetic variability. Aims: To analyze the prevalence of specific genetic mutations and their correlation to clinical features in NS. Methods: This retrospective observational study included 111 individuals with genetically confirmed NS. Data collected comprised genotype, cardiac abnormalities, and anthropometric measurements (birth weight, birth length, height, and weight at the latest clinical visit). Standard deviation (SD) scores were determined using Italian population growth references. Results: Complete data were available for 60 NS patients (38% male). The most prevalent mutations were identified in PTPN11 (60%) and SOS1 (10%), with additional variants detected in LZTR1, RAF1, RIT1, CBL, KRAS, SOS2, BRAF, and MAP2K1. Cardiovascular abnormalities were present in 62% of the cohort, with PTPN11 and RIT1 mutations predominantly linked to pulmonary valve stenosis, while RAF1 mutations were associated with hypertrophic cardiomyopathy. Less frequent heart defects, such as atrial and ventricular septal defects and abnormalities of the mitral or aortic valves, showed no clear genotype correlation. Small for gestational age (SGA) was identified in 5% of individuals, all carrying PTPN11 mutations. At an average age of 9.8 ± 5.9 years, mean height and weight were -1.8 ± 1.18 SD and -1.5 ± 1.40 SD, respectively. Short stature was present in 42% of patients, with an average height of -2.84 SD. Growth hormone treatment was administered to 37% of patients, the significant majority of whom carried PTPN11 mutations (74%, p<0.05). Among those born SGA, two-thirds developed short stature. Interestingly, individuals with CBL, SOS2, or MAP2K1 mutations did not exhibit short stature. In 28% of the cohort, both short stature and heart defects coexisted, though no significant genotype association was observed for this combination. Conclusion: This study underscores the high frequency of cardiac defects and short stature in NS, with distinct genotype-phenotype correlation for cardiovascular abnormalities. While being born SGA was relatively rare, it was strongly associated with the PTPN11 genotype. Conversely, genotype-growth correlations were less evident, though some mutations appeared to reduce the likelihood of short stature. These findings highlight the genetic and clinical variability of NS and emphasize the necessity for larger studies to enhance our understanding of genotype-phenotype correlations. Presentation: Saturday, July 12, 2025