Publications by authors named "Joie Davis"

Gonadal and gonosomal mosaicism describe phenomena in which a seemingly healthy individual carries a genetic variant in a subset of their gonadal tissue or gonadal and somatic tissue(s), respectively, with risk of transmitting the variant to their offspring. In families with one or more affected offspring, occurrence of the same apparently variants can be an indicator of mosaicism in either parent. Panel-based deep sequencing has the capacity to detect low-level mosaic variants with coverage exceeding the typical limit of detection provided by current, readily available sequencing techniques.

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Familial platelet disorder with associated myeloid malignancies (FPDMM) is caused by germline RUNX1 mutations and characterized by thrombocytopenia and increased risk of hematologic malignancies. We recently launched a longitudinal natural history study for patients with FPDMM. Among 27 families with research genomic data by the end of 2021, 26 different germline RUNX1 variants were detected.

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Article Synopsis
  • Deleterious RUNX1 variants cause familial platelet disorder with myeloid malignancy (FPDMM), leading to symptoms like low platelet counts, dysfunctional platelets, and increased risk of blood cancers.
  • A study enrolled 214 participants from 2019 to 2021, revealing that many patients experienced thrombocytopenia and other blood abnormalities; some also had blood malignancies like leukemia.
  • Findings emphasize the need for a multidisciplinary approach to detect and manage these inherited disorders, aiming to improve understanding of FPDMM and guide future treatments.
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Mutations in the transcription factor GATA2 can cause MonoMAC syndrome, a GATA2 deficiency disease characterized by several findings, including disseminated nontuberculous mycobacterial infections, severe deficiencies of monocytes, natural killer cells, and B lymphocytes, and myelodysplastic syndrome. GATA2 mutations are found in ∼90% of patients with a GATA2 deficiency phenotype and are largely missense mutations in the conserved second zinc-finger domain. Mutations in an intron 5 regulatory enhancer element are also well described in GATA2 deficiency.

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Article Synopsis
  • Germline mutations cause familial platelet disorder with associated myeloid malignancies (FPDMM), leading to low platelet counts and a significant risk (35-45%) of blood cancers throughout life.
  • In a study of 29 families, researchers identified 28 different germline variants, including various mutations that impact patient health, with a notable presence of somatic mutations linked to blood cancers in 44.4% of non-malignant patients.
  • Monitoring the changes in these mutations over time is crucial for improving clinical management of patients and understanding the progression to myeloid malignancies.
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  • Disseminated coccidioidomycosis (DCM) is a serious illness caused by Coccidioides fungi, primarily affecting individuals in the southwestern U.S. and Mexico, with only 30% of infected individuals showing symptoms and less than 1% developing DCM.
  • Through whole-exome sequencing of 67 DCM patients, researchers identified genetic mutations, including haploinsufficient STAT3 and defects in β-glucan sensing and response, in a significant number of cases, influencing disease dissemination.
  • A validation study with an additional 111 patients confirmed specific variants in genes like CLEC7A and PLCG2 that linked to weakened immune responses, indicating that impaired recognition of the fungi and lowered cytok
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Article Synopsis
  • This study focused on a holistic genetic evaluation of patients with immune-related issues, recognizing that multiple genetic factors might contribute to their health conditions rather than just a single gene explanation.
  • Researchers analyzed genetic data from 1505 individuals, uncovering 361 molecular diagnoses linked to various immune presentations, with significant updates obtained through reanalysis and new gene discoveries.
  • The findings indicate that the majority of molecular diagnoses could inform treatment options, highlighting the potential for whole exome analysis to enhance our understanding of genetic contributions to health on a large scale.
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Patients with primary immunodeficiencies (PIDs) are potentially cured by allogeneic hematopoietic cell transplantation (HCT). The spectrum of PIDs has expanded greatly beyond those that present in infancy or are diagnosed on newborn screening and require urgent, preemptive HCT. Many PID diagnoses are now made later in life, and the role of HCT is only considered for severe disease manifestations; in these cases, the kinetics and goals of a donor search may be different than for severe combined immunodeficiency.

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The region encompassing the Pacific Northwest (PNW), Vancouver Island, Oregon, and Washington has been the location of an ongoing outbreak since the 1990s, and there is evidence that the outbreak is expanding along the West Coast into California. Here we report a clinical case of a 69-year-old, HIV-negative man from North Carolina who was diagnosed with a fungal brain mass by magnetic resonance imaging (MRI) and pathology. He had traveled to Seattle and Vancouver 3 years earlier and to Costa Rica 4 months prior to presentation.

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Ras-related C3 botulinum toxin substrate 2 (RAC2), through interactions with reduced NAD phosphate oxidase component p67 , activates neutrophil superoxide production, whereas interactions with p21-activated kinase are necessary for fMLF-induced actin remodeling. We identified 3 patients with de novo RAC2[E62K] mutations resulting in severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections. Neutrophils from RAC2[E62K] patients exhibited excessive superoxide production, impaired fMLF-directed chemotaxis, and abnormal macropinocytosis.

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We report a male with longstanding warts who presented with severe West Nile virus encephalitis (WNVE) and recovered after interferon alfa-2b and intravenous immunoglobulin. He was later found to have GATA2 deficiency and underwent successful hematopoietic stem cell transplant.

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Background: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing.

Objectives: We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles.

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Traditionally, the use of genomic information for personalized medical decisions relies on prior discovery and validation of genotype-phenotype associations. This approach constrains care for patients presenting with undescribed problems. The National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) hypothesized that defining disease as maladaptation to an ecological niche allows delineation of a logical framework to diagnose and evaluate such patients.

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Article Synopsis
  • Toll-like receptors (TLRs) are key to how immune cells respond to microbes, and the study explored their signaling pathways in humans and mice using RNA interference.
  • The findings highlighted significant differences in protein requirements for TLR signaling, specifically noting that human macrophages rely more on IRAK1, while mouse macrophages depend on IRAK4 and IRAK2.
  • This research not only sheds light on the roles of different IRAK family members in TLR pathways but also suggests potential connections to autoimmune diseases and future therapeutic strategies targeting TLR responses.
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Purpose: Medical diagnosis and molecular or biochemical confirmation typically rely on the knowledge of the clinician. Although this is very difficult in extremely rare diseases, we hypothesized that the recording of patient phenotypes in Human Phenotype Ontology (HPO) terms and computationally ranking putative disease-associated sequence variants improves diagnosis, particularly for patients with atypical clinical profiles.

Methods: Using simulated exomes and the National Institutes of Health Undiagnosed Diseases Program (UDP) patient cohort and associated exome sequence, we tested our hypothesis using Exomiser.

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Purpose: Autosomal Dominant Hyper IgE Recurrent Infection Syndrome (AD-HIES) is caused by mutations in STAT3 and characterized by eczema, recurrent bacterial infections, and skeletal and connective tissue abnormalities. To further understand the minimal trauma fractures of AD-HIES, we examined bone mineral density (BMD) and laboratory markers of bone turnover.

Methods: Patients with AD-HIES enrolled in a prospective natural history study were examined with dual x-ray absorptiometry (DEXA) scans and laboratory studies of bone metabolism.

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Autoimmune lymphoproliferative syndrome (ALPS) presents in childhood with nonmalignant lymphadenopathy and splenomegaly associated with a characteristic expansion of mature CD4 and CD8 negative or double negative T-cell receptor αβ(+) T lymphocytes. Patients often present with chronic multilineage cytopenias due to autoimmune peripheral destruction and/or splenic sequestration of blood cells and have an increased risk of B-cell lymphoma. Deleterious heterozygous mutations in the FAS gene are the most common cause of this condition, which is termed ALPS-FAS.

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Background: Autosomal dominant hyper-IgE syndrome (AD-HIES) is caused by mutations in signal transducer and activator of transcription 3 (STAT3). We describe 2 subjects in whom somatic mosaicism was associated with intermediate phenotypes.

Objective: Somatic mosaics might shed light on the pathogenesis of dominant STAT3 mutations and the mechanisms behind the immunologic and nonimmunologic features of the disease.

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Purpose: Autosomal dominant hyper-IgE syndrome (AD-HIES) due to heterozygous STAT3 mutation is a primary immunodeficiency characterized by eczema, elevated serum IgE, recurrent infections, and connective tissue and skeletal findings. Healing of pneumonias is often abnormal with formation of pneumatoceles and bronchiectasis. We aimed to explore whether healing after lung surgery is also aberrant.

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Deleterious mutations in genes involved in the Fas apoptosis pathway lead to Autoimmune Lymphoproliferative Syndrome (ALPS). Demonstration of an apoptosis defect is critical for the diagnosis and study of ALPS. The traditional in vitro apoptosis assay, however, requires a week of experimental procedures.

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