Cornelis, Stéphanie S* Dotaz Zobrazit nápovědu
Importance: The mechanisms behind the phenotypic variability and reduced penetrance in autosomal recessive Stargardt disease (STGD1), often a blinding disease, are poorly understood. Identification of the unknown disease modifiers can improve patient and family counseling and provide valuable information for disease management. Objective: To assess the association of incompletely penetrant ABCA4 alleles with sex in STGD1. Design, Setting, and Participants: Genetic data for this cross-sectional study were obtained from 2 multicenter genetic studies of 1162 patients with clinically suspected STGD1. Unrelated patients with genetically confirmed STGD1 were selected. The data were collected from June 2016 to June 2019, and post hoc analysis was performed between July 2019 and January 2020. Main Outcomes and Measures: Penetrance of reported mild ABCA4 variants was calculated by comparing the allele frequencies in the general population (obtained from the Genome Aggregation Database) with the genotyping data in the patient population (obtained from the ABCA4 Leiden Open Variation Database). The sex ratio among patients with and patients without an ABCA4 allele with incomplete penetrance was assessed. Results: A total of 550 patients were included in the study, among which the mean (SD) age was 45.7 (18.0) years and most patients were women (311 [57%]). Five of the 5 mild ABCA4 alleles, including c.5603A>T and c.5882G>A, were calculated to have incomplete penetrance. The women to men ratio in the subgroup carrying c.5603A>T was 1.7 to 1; the proportion of women in this group was higher compared with the subgroup not carrying a mild allele (difference, 13%; 95% CI, 3%-23%; P = .02). The women to men ratio in the c.5882G>A subgroup was 2.1 to 1, and the women were overrepresented compared with the group carrying no mild allele (difference, 18%; 95% CI, 6%-30%; P = .005). Conclusions and Relevance: This study found an imbalance in observed sex ratio among patients harboring a mild ABCA4 allele, which concerns approximately 25% of all patients with STGD1, suggesting that STGD1 should be considered a polygenic or multifactorial disease rather than a disease caused by ABCA4 gene mutations alone. The findings suggest that sex should be considered as a potential disease-modifying variable in both basic research and clinical trials on STGD1.
- MeSH
- ABC transportéry genetika metabolismus MeSH
- alely MeSH
- DNA genetika MeSH
- frekvence genu MeSH
- genotyp MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace * MeSH
- mutační analýza DNA MeSH
- průřezové studie MeSH
- rozložení podle pohlaví MeSH
- sexuální faktory MeSH
- Stargardtova nemoc diagnóza genetika MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
The ABCA4 gene is the most frequently mutated Mendelian retinopathy-associated gene. Biallelic variants lead to a variety of phenotypes, however, for thousands of cases the underlying variants remain unknown. Here, we aim to shed further light on the missing heritability of ABCA4-associated retinopathy by analyzing a large cohort of macular dystrophy probands. A total of 858 probands were collected from 26 centers, of whom 722 carried no or one pathogenic ABCA4 variant, while 136 cases carried two ABCA4 alleles, one of which was a frequent mild variant, suggesting that deep-intronic variants (DIVs) or other cis-modifiers might have been missed. After single molecule molecular inversion probes (smMIPs)-based sequencing of the complete 128-kb ABCA4 locus, the effect of putative splice variants was assessed in vitro by midigene splice assays in HEK293T cells. The breakpoints of copy number variants (CNVs) were determined by junction PCR and Sanger sequencing. ABCA4 sequence analysis solved 207 of 520 (39.8%) naive or unsolved cases and 70 of 202 (34.7%) monoallelic cases, while additional causal variants were identified in 54 of 136 (39.7%) probands carrying two variants. Seven novel DIVs and six novel non-canonical splice site variants were detected in a total of 35 alleles and characterized, including the c.6283-321C>G variant leading to a complex splicing defect. Additionally, four novel CNVs were identified and characterized in five alleles. These results confirm that smMIPs-based sequencing of the complete ABCA4 gene provides a cost-effective method to genetically solve retinopathy cases and that several rare structural and splice altering defects remain undiscovered in Stargardt disease cases.
- MeSH
- ABC transportéry genetika MeSH
- HEK293 buňky MeSH
- lidé MeSH
- makulární degenerace * genetika MeSH
- mutace genetika MeSH
- retinální dystrofie * genetika MeSH
- sekvenční analýza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Gluten free products are essential for people who suffer from coeliac disease or have a more generic gluten intolerance. In both instances people are forced to resort to consuming gluten free (GF) foods. We carried out two online surveys to gauge the sentiments from people purchasing GF produce, and we carried out two retail observation studies. These studies were carried out in 2015 and repeated again 2019. Bread was the most commonly purchased GF product, but also the most complained about GF product, both from a quality and a price point of view. These sentiments did not change much from 2015 to 2019. One clear set of trends was that people purchased less specialty flour and raising agent when comparing 2019 to 2015, and they did less home-baking over the same period. Furthermore, the decrease in home-baking coincided with a relative increase in satisfaction in the quality of GF products. With regards to observations made across 11 supermarkets, we observed an overall increase in the number of GF line items, with the budget supermarkets offering a very small selection of produce labelled as GF in 2019 only. Our research shows that the relative cost of GF items increased from 2015 to 2019, with the average price ratio of GF food to non-GF foods rising from 3.2 to 4.1 across all UK supermarkets. Ultimately, GF produce cost significantly more compared to similar, gluten-containing foods, while many of the GF products, especially GF breads, still underperform when it comes to the perceived quality and value for money.
- MeSH
- bezlepková dieta * ekonomika MeSH
- celiakie dietoterapie ekonomika MeSH
- chléb ekonomika MeSH
- chování spotřebitelů * statistika a číselné údaje MeSH
- kvalita jídla MeSH
- lidé MeSH
- longitudinální studie MeSH
- mouka ekonomika MeSH
- postoj MeSH
- pozorovací studie jako téma MeSH
- statistika jako téma MeSH
- supermarkety MeSH
- vaření MeSH
- zásobování potravinami MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Spojené království MeSH
PURPOSE: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands. METHODS: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays. RESULTS: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. CONCLUSION: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases.
- MeSH
- ABC transportéry genetika MeSH
- genomika MeSH
- introny MeSH
- lidé MeSH
- makulární degenerace * genetika MeSH
- mutace MeSH
- rodokmen MeSH
- Stargardtova nemoc MeSH
- transkriptom * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Importance: The incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer. Observations: Within the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts. Conclusions and Relevance: The clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes.
