Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders.

Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.

Supporting engagement and retention of online and blended-learning students: A qualitative study from an Australian University.

Enrolment numbers in online higher education courses have continued to increase over the last decade. The challenges brought about by the COVID-19 pandemic have further accelerated the growth in online and blended course offerings. The development of institutional support services, however, does not reflect this growth. Many students are not equipped with the skills or given adequate support to engage and succeed in their courses, leading to student disengagement and attrition. This study investigated the perceptions of students in online and blended subjects, regarding both the academic and institutional support they were provided. The research team collected interview data from 41 online and blended-learning students and then analysed these data using an iterative thematic analysis approach. This article introduces the key findings with two models: one presenting support strategies at multiple levels within this university; the other presenting three key elements of subject-level teacher support, which were identified by the interviewees as the most significant, effective, and relevant support mechanism in this context. The findings will inform higher education institutions who aim to engage and support online and blended students better, through an improved understanding of how support is perceived by this student cohort. This study was conducted at one Australian university; however, the findings are relevant to higher education institutions in other countries that strive to bring about positive experiences and enhance retention rates for online and blended students.

Clinical and Anthropometric Improvements with a Tailored Dietary Approach in Pediatric Crohn's Disease.

Pediatric Crohn's disease (CD) is more common today than in prior decades. Therapeutic goals in children with CD are to reduce symptomatology, promote normal growth, and avoid nutritional deficiencies. Diet plays a crucial role in the treatment of CD. However, there is a lack of comprehensive guidelines and individualized dietary approaches. A 12-and-a-half-year-old boy presented with chronic diarrhea, intermittent fever, abdominal pain, and a history of eczema. At the first visit, his body mass index (BMI) was 14.4, and his BMI-for-age was in the 1st percentile, classifying him as underweight. He received the diagnosis of Crohn's ileocolitis and gastritis and was unresponsive to treatment for 10.5 months. The patient was placed on a tailored dietary approach based on the in vitro leukocyte activation assay-MRT (LAA-MRT®), known as the Lifestyle Eating and Performance (LEAP) program. The LEAP program is an elimination diet built on the selection of less-immune-reactive foods and chemicals identified by the LAA-MRT® results. After 39 days of following the LEAP program, his fecal calprotectin levels decreased from >2000 µg/g to 185.9 µg/g. A repeat esophagogastroduodenoscopy (EGD) and colonoscopy with 10 biopsies showed complete histologic remission 1 year after beginning diet therapy. At that point, the patient discontinued his pharmacologic therapy and maintained clinical remission of CD after more than 3 years of follow-up. In addition, his anthropometric measurements and laboratory biomarkers were normalized. This case presents evidence supporting the use of the LEAP program in clinical practice as an adjunctive, tailored dietary option to manage pediatric CD.

A pilot evaluation of a social media literacy intervention to reduce risk factors for eating disorders.

OBJECTIVE: This pilot study investigated the effectiveness of a social media literacy intervention for adolescent girls on risk factors for eating disorders. METHOD: A quasi-experimental pre- to post-test design comparing intervention and control conditions was used. Participants were 101 adolescent girls (Mage = 13.13, SD = 0.33) who were allocated to receive three social media literacy intervention lessons (n = 64) or to receive classes as usual (n = 37). Self-report assessments of eating disorder risk factors were completed one week prior to, and one week following the intervention. RESULTS: Significant group by time interaction effects revealed improvements in the intervention condition relative to the control condition for body image (body esteem-weight; d = .19), disordered eating (dietary restraint; d = .26) and media literacy (realism scepticism; d = .32). DISCUSSION: The outcomes of this pilot study suggest that social media literacy is a potentially useful approach for prevention of risk for eating disorders in adolescent girls in the current social media environment of heightened vulnerability. Replication of this research with larger, randomized controlled trials, and longer follow-up is needed.

Photoshopping the selfie: Self photo editing and photo investment are associated with body dissatisfaction in adolescent girls.

OBJECTIVE: Social media engagement by adolescent girls is high. Despite its appeal, there are potential negative consequences for body dissatisfaction and disordered eating from social media use. This study aimed to examine, in a cross-sectional design, the relationship between social media use in general, and social media activities related to taking "selfies" and sharing specifically, with overvaluation of shape and weight, body dissatisfaction, and dietary restraint. METHOD: Participants were 101 grade seven girls (M(age) = 13.1, SD = 0.3), who completed self-report questionnaires of social media use and body-related and eating concerns measures. RESULTS: Results showed that girls who regularly shared self-images on social media, relative to those who did not, reported significantly higher overvaluation of shape and weight, body dissatisfaction, dietary restraint, and internalization of the thin ideal. In addition, among girls who shared photos of themselves on social media, higher engagement in manipulation of and investment in these photos, but not higher media exposure, were associated with greater body-related and eating concerns, including after accounting for media use and internalization of the thin ideal. DISCUSSION: Although cross-sectional, these findings suggest the importance of social media activities for body-related and eating concerns as well as potential avenues for targeted social-media-based intervention.

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A.

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods-recursive partitioning and regression-to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; P(combined) = 2.01 x 10(-19) and 2.35 x 10(-13), respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes.

The candidate genes TAF5L, TCF7, PDCD1, IL6 and ICAM1 cannot be excluded from having effects in type 1 diabetes.

BACKGROUND: As genes associated with immune-mediated diseases have an increased prior probability of being associated with other immune-mediated diseases, we tested three such genes, IL23R, IRF5 and CD40, for an association with type 1 diabetes. In addition, we tested seven genes, TAF5L, PDCD1, TCF7, IL12B, IL6, ICAM1 and TBX21, with published marginal or inconsistent evidence of an association with type 1 diabetes. METHODS: We genotyped reported polymorphisms of the ten genes, nonsynonymous SNPs (nsSNPs) and, for the IL12B and IL6 regions, tag SNPs in up to 7,888 case, 8,858 control and 3,142 parent-child trio samples. In addition, we analysed data from the Wellcome Trust Case Control Consortium genome-wide association study to determine whether there was any further evidence of an association in each gene region. RESULTS: We found some evidence of associations between type 1 diabetes and TAF5L, PDCD1, TCF7 and IL6 (ORs = 1.05 - 1.13; P = 0.0291 - 4.16 x 10-4). No evidence of an association was obtained for IL12B, IRF5, IL23R, ICAM1, TBX21 and CD40, although there was some evidence of an association (OR = 1.10; P = 0.0257) from the genome-wide association study for the ICAM1 region. CONCLUSION: We failed to exclude the possibility of some effect in type 1 diabetes for TAF5L, PDCD1, TCF7, IL6 and ICAM1. Additional studies, of these and other candidate genes, employing much larger sample sizes and analysis of additional polymorphisms in each gene and its flanking region will be required to ascertain their contributions to type 1 diabetes susceptibility.

Sequencing and association analysis of the type 1 diabetes-linked region on chromosome 10p12-q11.

BACKGROUND: In an effort to locate susceptibility genes for type 1 diabetes (T1D) several genome-wide linkage scans have been undertaken. A chromosomal region designated IDDM10 retained genome-wide significance in a combined analysis of the main linkage scans. Here, we studied sequence polymorphisms in 23 Mb on chromosome 10p12-q11, including the putative IDDM10 region, to identify genes associated with T1D. RESULTS: Initially, we resequenced the functional candidate genes, CREM and SDF1, located in this region, genotyped 13 tag single nucleotide polymorphisms (SNPs) and found no association with T1D. We then undertook analysis of the whole 23 Mb region. We constructed and sequenced a contig tile path from two bacterial artificial clone libraries. By comparison with a clone library from an unrelated person used in the Human Genome Project, we identified 12,058 SNPs. We genotyped 303 SNPs and 25 polymorphic microsatellite markers in 765 multiplex T1D families and followed up 22 associated polymorphisms in up to 2,857 families. We found nominal evidence of association in six loci (P = 0.05 - 0.0026), located near the PAPD1 gene. Therefore, we resequenced 38.8 kb in this region, found 147 SNPs and genotyped 84 of them in the T1D families. We also tested 13 polymorphisms in the PAPD1 gene and in five other loci in 1,612 T1D patients and 1,828 controls from the UK. Overall, only the D10S193 microsatellite marker located 28 kb downstream of PAPD1 showed nominal evidence of association in both T1D families and in the case-control sample (P = 0.037 and 0.03, respectively). CONCLUSION: We conclude that polymorphisms in the CREM and SDF1 genes have no major effect on T1D. The weak T1D association that we detected in the association scan near the PAPD1 gene may be either false or due to a small genuine effect, and cannot explain linkage at the IDDM10 region.

No evidence for association of the TATA-box binding protein glutamine repeat sequence or the flanking chromosome 6q27 region with type 1 diabetes.

Susceptibility to the autoimmune disease type 1 diabetes has been linked to human chromosome 6q27 and, moreover, recently associated with one of the genes in the region, TATA box-binding protein (TBP). Using a much larger sample of T1D families than those studied by others, and by extensive re-sequencing of nine other genes in the proximity, in which we identified 279 polymorphisms, 83 of which were genotyped in up to 725 T1D multiplex and simplex families, we obtained no evidence for association of the TBP CAG/CAA (glutamine) microsatellite repeat sequence with disease, or for nine other genes, PDCD2, PSMB1, KIAA1838, DLL1, dJ894D12.4, FLJ25454, FLJ13162, FLJ11152, PHF10 and CCR6. This study also provides an exon-based tag single nucleotide polymorphism map for these 10 genes that can be used for analysis of other diseases.

Haplotype structure, LD blocks, and uneven recombination within the LRP5 gene.

Patterns of linkage disequilibrium (LD) in the human genome are beginning to be characterized, with a paucity of haplotype diversity in "LD blocks," interspersed by apparent "hot spots" of recombination. Previously, we cloned and physically characterized the low-density lipoprotein-receptor-related protein 5 (LRP5) gene. Here, we have extensively analysed both LRP5 and its flanking three genes, spanning 269 kb, for single nucleotide polymorphisms (SNPs), and we present a comprehensive SNP map comprising 95 polymorphisms. Analysis revealed high levels of recombination across LRP5, including a hot-spot region from intron 1 to intron 7 of LRP5, where there are 109 recombinants/Mb (4882 meioses), in contrast to flanking regions of 14.6 recombinants/Mb. This region of high recombination could be delineated into three to four hot spots, one within a 601-bp interval. For LRP5, three haplotype blocks were identified, flanked by the hot spots. Each LD block comprised over 80% common haplotypes, concurring with a previous study of 14 genes that showed that common haplotypes account for at least 80% of all haplotypes. The identification of hot spots in between these LD blocks provides additional evidence that LD blocks are separated by areas of higher recombination.