Background
Individuals with intellectual and developmental disabilities may face barriers in accessing healthcare, including cancer screening and detection services. We sought to assess the ...association of intellectual and developmental disabilities (IDD) with breast cancer screening rates.
Methods
Data from 2018 to 2020 was used to identify screening-eligible individuals from Medicare Standard Analytic Files. Adults aged 65–79 years who did not have a previous diagnosis of breast cancer were included. Multivariable regression was used to analyze the differences in breast cancer screening rates among individuals with and without IDD.
Results
Among 9,383,349 Medicare beneficiaries, 11,265 (0.1%) individuals met the criteria for IDD. Of note, individuals with IDD were more likely to be non-Hispanic White (90.5% vs. 87.3%), have a Charlson Comorbidity Index score ≤ 2 (66.2% vs. 85.5%), and reside in a low social vulnerability index neighborhood (35.7% vs. 34.4%). IDD was associated with reduced odds of undergoing breast cancer screening (odds ratio (OR) 0.77, 95% confidence interval (CI) 0.74–0.80;
p
< 0.001). Breast cancer screening rates in individuals with IDD were further influenced by social vulnerability and belonging to a racial/ethnic minority.
Conclusions
Individuals with IDD may face additional barriers to breast cancer screening. The combination of IDD and social vulnerability placed patients at particularly high risk of not being screened for breast cancer.
De novo mutations in protein-coding genes are a well-established cause of developmental disorders
. However, genes known to be associated with developmental disorders account for only a minority of ...the observed excess of such de novo mutations
. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent-offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders.
Summary Background Human genome sequencing has transformed our understanding of genomic variation and its relevance to health and disease, and is now starting to enter clinical practice for the ...diagnosis of rare diseases. The question of whether and how some categories of genomic findings should be shared with individual research participants is currently a topic of international debate, and development of robust analytical workflows to identify and communicate clinically relevant variants is paramount. Methods The Deciphering Developmental Disorders (DDD) study has developed a UK-wide patient recruitment network involving over 180 clinicians across all 24 regional genetics services, and has performed genome-wide microarray and whole exome sequencing on children with undiagnosed developmental disorders and their parents. After data analysis, pertinent genomic variants were returned to individual research participants via their local clinical genetics team. Findings Around 80 000 genomic variants were identified from exome sequencing and microarray analysis in each individual, of which on average 400 were rare and predicted to be protein altering. By focusing only on de novo and segregating variants in known developmental disorder genes, we achieved a diagnostic yield of 27% among 1133 previously investigated yet undiagnosed children with developmental disorders, whilst minimising incidental findings. In families with developmentally normal parents, whole exome sequencing of the child and both parents resulted in a 10-fold reduction in the number of potential causal variants that needed clinical evaluation compared to sequencing only the child. Most diagnostic variants identified in known genes were novel and not present in current databases of known disease variation. Interpretation Implementation of a robust translational genomics workflow is achievable within a large-scale rare disease research study to allow feedback of potentially diagnostic findings to clinicians and research participants. Systematic recording of relevant clinical data, curation of a gene–phenotype knowledge base, and development of clinical decision support software are needed in addition to automated exclusion of almost all variants, which is crucial for scalable prioritisation and review of possible diagnostic variants. However, the resource requirements of development and maintenance of a clinical reporting system within a research setting are substantial. Funding Health Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust and the UK Department of Health.
Although previous studies demonstrate associations between adverse perinatal outcomes and developmental disabilities (DDs), study of population impacts is limited.
We computed relative risks adjusted ...(aRRs) for sociodemographic factors and component and summary population attributable fractions (PAFs) for associations between very low birth weight (VLBW, all preterm births), moderately low birth weight (MLBW) + Preterm, MLBW at term, and normal birth weight (NBW) + Preterm and seven DDs (cerebral palsy CP, autism spectrum disorder ASD, intellectual disability ID, behavioral-conduct disorders, attention-deficit-hyperactivity disorder ADHD, learning disability LD, and other developmental delay) among children aged 3–17 years in the 2011–2012 National Survey of Children's Health.
VLBW-Preterm, MLBW-Preterm and NBW-Preterm were strongly to moderately associated with CP (aRRs: 43.5, 10.1, and 2.2, respectively; all significant) and also associated with ID, ASD, LD, and other developmental delay (aRR ranges: VLBW-Preterm 2.8–5.3; MLBW-Preterm 1.9–2.8; and NBW-Preterm 1.6–2.3). Summary PAFs for preterm birth and/or LBW were 55% for CP, 10%–20% for ASD, ID, LD, and other developmental delay, and less than 5% for ADHD and behavioral-conduct disorders. Findings were similar whether we assessed DDs as independent outcomes or within mutually exclusive categories accounting for DD co-occurrence.
Preterm birth has a sizable impact on child neurodevelopment. However, relative associations and population impacts vary widely by DD type.
ABSTRACT Background Two reports by the U.S. surgeon general noted the disproportionate impact of oral disease on and lack of oral health information regarding people with disabilities. Methods In ...this retrospective study, the authors used clinical and demographic data (from April 1, 2009, through March 31, 2010) from electronic dental records of 4,732 adults with intellectual and developmental disabilities (IDDs) who were receiving dental care through a state-supported system of dental clinics. The authors used these data to investigate the oral health status of, and associated risk factors for, adults with IDD. Results The prevalence of untreated caries in the study population was 32.2 percent, of periodontitis was 80.3 percent and of edentulism was 10.9 percent. The mean (standard deviation) numbers of decayed teeth; missing teeth; and decayed, missing and filled teeth were 1.0 (2.2), 6.7 (7.0) and 13.9 (7.7), respectively. Conclusions Management of oral health presents significant challenges in adults with IDD. Age, ability to cooperate with dental treatment and type of residence are important considerations in identifying preventive strategies. Clinical Implications The study population demonstrated a high burden of dental disease. Further research is required to identify effective interventions to improve oral health in adults with IDD.
Given the rapid pace of discovery in rare disease genomics, it is likely that improvements in diagnostic yield can be made by systematically reanalyzing previously generated genomic sequence data in ...light of new knowledge.
We tested this hypothesis in the United Kingdom-wide Deciphering Developmental Disorders study, where in 2014 we reported a diagnostic yield of 27% through whole-exome sequencing of 1,133 children with severe developmental disorders and their parents. We reanalyzed existing data using improved variant calling methodologies, novel variant detection algorithms, updated variant annotation, evidence-based filtering strategies, and newly discovered disease-associated genes.
We are now able to diagnose an additional 182 individuals, taking our overall diagnostic yield to 454/1,133 (40%), and another 43 (4%) have a finding of uncertain clinical significance. The majority of these new diagnoses are due to novel developmental disorder-associated genes discovered since our original publication.
This study highlights the importance of coupling large-scale research with clinical practice, and of discussing the possibility of iterative reanalysis and recontact with patients and health professionals at an early stage. We estimate that implementing parent-offspring whole-exome sequencing as a first-line diagnostic test for developmental disorders would diagnose >50% of patients.
Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic ...neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were heterozygous for a previously reported variant (c.1969G>A p.Ala657Thr). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.
Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as ...hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype-phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype-phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.
The goal of this study was to describe the typical longitudinal developmental trajectories of social and communication functioning in children with autism and to determine the correlates of these ...trajectories.
Children with autism who were born in California from 1992 through 2001 and enrolled with the California Department of Developmental Services were identified. Subjects with <4 evaluations present in the database were excluded, resulting in a sample of 6975 children aged 2 to 14 years. Score sequences were constructed based on 9 evaluative items for social, communication, and repetitive behavior functioning. Typical trajectories were identified by using group-based latent trajectory modeling, and multinomial logistic regression models were used to determine the odds of classification within each trajectory varied by individual and family-level factors.
Six typical patterns of social, communication, and repetitive behavior functioning were identified. These trajectories displayed significant heterogeneity in developmental pathways, and children whose symptoms were least severe at first diagnosis tended to improve more rapidly than those severely affected. One group of ∼10% of children experienced rapid gains, moving from severely affected to high functioning. Socioeconomic factors were correlated with trajectory outcomes; children with non-Hispanic, white, well-educated mothers were more likely to be high functioning, and minority children with less-educated mothers or intellectual disabilities were very unlikely to experience rapid gains.
Children with autism have heterogeneous developmental pathways. One group of children evidenced remarkable developmental change over time. Understanding what drives these outcomes is thus critical.
Zebrafish have several advantages compared to other vertebrate models used in modeling human diseases, particularly for large-scale genetic mutant and therapeutic compound screenings, and other ...biomedical research applications. With the impactful developments of CRISPR and next-generation sequencing technology, disease modeling in zebrafish is accelerating the understanding of the molecular mechanisms of human genetic diseases. These efforts are fundamental for the future of precision medicine because they provide new diagnostic and therapeutic solutions. This review focuses on zebrafish disease models for biomedical research, mainly in developmental disorders, mental disorders, and metabolic diseases.
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