GATA3 is a transcription factor that is important during development and plays a role in differentiation and activity of immune cells, particularly T cells. Abnormal T cell function is found in ...autoimmune arthritis. We present the first known case of autoimmune arthritis associated with a novel GATA3 mutation.
Whole exome sequencing of the proband was performed on a clinical basis. Peripheral blood mononuclear cells (PBMCs) were collected from the proband, healthy sibling, and parent. cDNA prepared from RNA was analyzed with polymerase chain reaction and Sanger sequencing. Intracellular proteins were assessed by immunoblot of PBMC homogenates. GATA3 in vitro activity was measured in HeLa cell cultures expressing a mammalian expression vector containing GATA3 or mutants generated by site-directed mutagenesis. GATA3 transcriptional activity was examined using a luciferase reporter assay system. T helper cell ex vivo function was evaluated by stimulating PBMCs to differentiate into effector T cells along Th0, Th1, Th2, and Th17 lineages, and re-stimulating effector cells to secrete cytokines. Cytokine production was measured by enzyme-linked immunosorbent assay.
The proband is the first known case of autoimmune arthritis associated with a mutation in GATA3. The proband M401VfsX106 protein is expressed and has a dominant negative function on GATA3 transcriptional activity. The proband PBMCs have markedly increased differentiation along the Th1 and Th17 pathways, with decreased differentiation along the Th2 pathway. Unexpectedly, Th0 cells from the proband express high levels of IFNγ.
Our research presents the first known case of autoimmune arthritis associated with a mutation in GATA3. This work expands the phenotypic spectrum of GATA3 mutations. It reveals the novel insight that decreased and altered GATA3 activity coincides with autoimmune arthritis. This work suggests that modulation of GATA3 may be a therapeutic approach for patients with autoimmune arthritis.
OBJECTIVES/GOALS: Congenital anomalies (CA) are common, but the cause is often unknown. The interplay between known environmental teratogens, such as medication use in pregnancy, and genetic ...predisposition impacts CA risk, but such interactions are poorly understood. We test the hypothesis that pharmacogenomic (PGx) variation impacts CA risk. METHODS/STUDY POPULATION: We performed a drug absorption, distribution, metabolism, and excretion (ADME) gene-wide association study (GWAS), which tests for a possible association between ADME gene single nucleotide polymorphisms and individuals with CAs. This analysis was performed in BioVU and utilized billing codes to identify 5,845 cases, individuals with at least one CA, and 50,059 controls of genetically European ancestry. Using Plink software we analyzed 5,398 SNPs in 292 ADME genes across cases and controls. Results from this analysis drove us to further investigate the association between CA risk and SLC22A1-3. Next, we performed PrediXcan analyses to estimate the association between genetically predicted gene expression (GPGE) of SLC22A1-3 genes across all available tissues in the GTEx resource and CA risk. RESULTS/ANTICIPATED RESULTS: The ADME GWAS identified multiple variants on chromosome 6 in the region of SCL22A1-3 that were associated with the risk for CAs. The most significant variants were rs2048327, rs2292334, rs3088442, rs1810126, rs376563, and rs7758229, p DISCUSSION/SIGNIFICANCE: The combination of the known crucial pharmacological roles of OCT1-3 and the results of our ADME GWAS / PrediXcan analyses demonstrates that PGx burden, specifically variation in the SLC22A1-3 genes, influences the risk of developing CAs. This new understanding has the potential to personalize care for pregnant individuals to reduce the risk of CAs.
OBJECTIVES/GOALS: Congenital anomalies (CAs) affect 3% of live births, yet the cause of 80% of CAs is unknown and for the 20% with an identified cause, variability in penetrance suggests additional ...risk drivers exist. Our method for identifying and categorizing CAs in electronic health record (EHR) linked biobank databases can expand and improve CA etiologic research. METHODS/STUDY POPULATION: We identified individuals with CAs in three groups: 1. Those with at least one CA 2. Those with multiple CAs (MCA), those with two or more ‘major’ CAs, and 3. Those with CAs in a specific organ system. We also created a novel quantitative approach, using phenome-wide association studies (pheWAS), for determining CA-associated genetic disease billing codes in order to separate individuals that have a known genetic cause for their CAs from those with idiopathic CAs. We updated CA phecodes, aggregates of clinical billing codes, which we used to identify CA cases in Vanderbilt’s EHR-linked biobank database, BioVU. We create a new phecode, ‘All CAs’, for researchers to quickly identify all individuals with at least one CA. We evaluate the definition of MCA using pheWAS analyses to compare ‘minor’ vs ‘major’ CA. RESULTS/ANTICIPATED RESULTS: The new CA phecode nomenclature includes 5.8 times more codes for CAs compared with the previous version (365 vs 56), improving granularity. 85 (19.7%) CA-associated genetic disease billing codes were identified through literature review. PheWAS analyses revealed an additional 16 (3.7%) genetic disease billing codes with one or more significant (p< 2.75 x10-5) association with CA-related phecodes. Identifying CA-associated genetic disease billing codes allows researchers to differentiate between idiopathic CAs and those that have a known genetic cause. PheWAS analyses of individuals with previously considered “minor” CAs showed many associated severe health problems, revealing that the differentiation between “minor” vs “major” CAs when identifying individuals with MCA in the EHR is arbitrary. DISCUSSION/SIGNIFICANCE: Our CA identification method is scalable for the growing number of EHR-linked biobanks. Differentiating between idiopathic CAs from those with known causes will increase power in studies discovering additional genetic drivers of CAs. Our novel method allows for expansion and acceleration of CA epidemiological research in EHR-linked biobank data.
Background
Prader–Willi syndrome (PWS) is a complex neuroendocrine disorder affecting approximately 1/15,000–1/30,000 people. Unmet medical needs of individuals with PWS make it a rare disease that ...models the importance of multidisciplinary approaches to care with collaboration between academic centers, medical homes, industry, and parent organizations. Multidisciplinary clinics support comprehensive, patient‐centered care for individuals with complex genetic disorders and their families. Value comes from improved communication and focuses on quality family‐centered care.
Methods
Interviews with medical professionals, scientists, managed care experts, parents, and individuals with PWS were conducted from July 1 to December 1, 2016. Review of the literature was used to provide support.
Results
Data are presented based on consensus from these interviews by specialty focusing on unique aspects of care, research, and management. We have also defined the Center of Excellence beyond the multidisciplinary clinic.
Conclusion
Establishment of clinics motivates collaboration to provide evidence‐based new standards of care, increases the knowledge base including through randomized controlled trials, and offers an additional resource for the community. They have a role in global telemedicine, including to rural areas with few resources, and create opportunities for clinical work to inform basic and translational research. As a care team, we are currently charged with understanding the molecular basis of PWS beyond the known genetic cause; developing appropriate clinical outcome measures and biomarkers; bringing new therapies to change the natural history of disease; improving daily patient struggles, access to care, and caregiver burden; and decreasing healthcare load. Based on experience to date with a PWS multidisciplinary clinic, we propose a design for this approach and emphasize the development of “Centers of Excellence.” We highlight the dearth of evidence for management approaches creating huge gaps in care practices as a means to illustrate the importance of the collaborative environment and translational approaches.
Unmet medical needs of individuals with Prader–Willi syndrome make it a rare disease that models the importance of multidisciplinary approaches to care with collaboration between academic centers, medical homes, industry, and parent organizations. Establishment of centers motivates collaboration of experts to provide evidence‐based new standards of care, increases the knowledge base regarding success of treatments through randomized controlled trials, and offers an additional resource for patient and family concerns.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Early infantile epileptic encephalopathy-44 (EIEE44, MIM: 617132) is a previously described condition resulting from biallelic variants in
, a gene involved in a ubiquitin-like post-translational ...modification system called UFMylation. Here we report five children from four families with biallelic pathogenic variants in
All five children presented with global developmental delay, epilepsy, axial hypotonia, appendicular hypertonia, and a movement disorder, including dystonia in four. Affected individuals in all four families have compound heterozygous pathogenic variants in
All have the recurrent mild c.1111G > A (p.Ala371Thr) variant in
with a second
variant. One patient has the previously described c.562C > T (p. Arg188*) variant, two other unrelated patients have a novel missense variant, c.907T > C (p.Cys303Arg), and the two siblings have a novel missense variant, c.761T > C (p.Leu254Pro). Functional analyses demonstrate that both the p.Cys303Arg variant and the p.Leu254Pro variants result in a significant decrease in protein function. We also review the phenotypes and genotypes of all 15 previously reported families with biallelic
variants, of which two families have presented with distinct phenotypes, and we describe evidence for some limited genotype-phenotype correlation. The overlap of motor and developmental phenotypes noted in our cohort and literature review adds to the increasing understanding of genetic syndromes with movement disorders-epilepsy.
Background
Resources within the Undiagnosed Diseases Network (UDN), such as genome sequencing (GS) and model organisms aid in diagnosis and identification of new disease genes, but are currently ...difficult to access by clinical providers. While these resources do contribute to diagnoses in many cases, they are not always necessary to reach diagnostic resolution. The UDN experience has been that participants can also receive diagnoses through the thoughtful and customized application of approaches and resources that are readily available in clinical settings.
Methods
The UDN Genetic Counseling and Testing Working Group collected case vignettes that illustrated how clinically available methods resulted in diagnoses. The case vignettes were classified into three themes; phenotypic considerations, selection of genetic testing, and evaluating exome/GS variants and data.
Results
We present 12 participants that illustrate how clinical practices such as phenotype‐driven genomic investigations, consideration of variable expressivity, selecting the relevant tissue of interest for testing, utilizing updated testing platforms, and recognition of alternate transcript nomenclature resulted in diagnoses.
Conclusion
These examples demonstrate that when a diagnosis is elusive, an iterative patient‐specific approach utilizing assessment options available to clinical providers may solve a portion of cases. However, this does require increased provider time commitment, a particular challenge in the current practice of genomics.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
While exome sequencing (ES) is commonly the final diagnostic step in clinical genetics, it may miss diagnoses. To clarify the limitations of ES, we investigated the diagnostic yield of genetic tests ...beyond ES in our Undiagnosed Diseases Network (UDN) participants. We reviewed the yield of additional genetic testing including genome sequencing (GS), copy number variant (CNV), noncoding variant (NCV), repeat expansion (RE), or methylation testing in UDN cases with nondiagnostic ES results. Overall, 36/54 (67%) of total diagnoses were based on clinical findings and coding variants found by ES and 3/54 (6%) were based on clinical findings only. The remaining 15/54 (28%) required testing beyond ES. Of these, 7/15 (47%) had NCV, 6/15 (40%) CNV, and 2/15 (13%) had a RE or a DNA methylation disorder. Thus 18/54 (33%) of diagnoses were not solved exclusively by ES. Several methods were needed to detect and/or confirm the functional effects of the variants missed by ES, and in some cases by GS. These results indicate that tests to detect elusive variants should be considered after nondiagnostic preliminary steps. Further studies are needed to determine the cost‐effectiveness of tests beyond ES that provide diagnoses and insights to possible treatment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The knowledge used to classify genetic variants is continually evolving, and the classification can change on the basis of newly available data. Although up-to-date variant classification is ...essential for clinical management, reproductive planning, and identifying at-risk family members, there is no consistent practice across laboratories or clinicians on how or under what circumstances to perform variant reinterpretation.
We conducted exploratory focus groups (N = 142) and surveys (N = 1753) with stakeholders involved in the process of variant reinterpretation (laboratory directors, clinical geneticists, genetic counselors, nongenetic providers, and patients/parents) to assess opinions on key issues, including initiation of reinterpretation, variants to report, termination of the responsibility to reinterpret, and concerns about consent, cost, and liability.
Stakeholders widely agreed that there should be no fixed termination point to the responsibility to reinterpret a previously reported genetic variant. There were significant concerns about liability and lack of agreement about many logistical aspects of variant reinterpretation.
Our findings suggest a need to (1) develop consensus and (2) create transparency and awareness about the roles and responsibilities of parties involved in variant reinterpretation. These data provide a foundation for developing guidelines on variant reinterpretation that can aid in the development of a low-cost, scalable, and accessible approach.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Motivation
Phecodes are widely used and easily adapted phenotypes based on International Classification of Diseases codes. The current version of phecodes (v1.2) was designed primarily to ...study common/complex diseases diagnosed in adults; however, there are numerous limitations in the codes and their structure.
Results
Here, we present phecodeX, an expanded version of phecodes with a revised structure and 1,761 new codes. PhecodeX adds granularity to phenotypes in key disease domains that are under-represented in the current phecode structure—including infectious disease, pregnancy, congenital anomalies, and neonatology—and is a more robust representation of the medical phenome for global use in discovery research.
Availability and implementation
phecodeX is available at https://github.com/PheWAS/phecodeX.
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