David R. Adams
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Improved Identification of Large-effect Rare Genetic Variants using Haplotype Aggregated Allele-specific Expression Data Open
Allele-specific expression (ASE) outlier detection is a powerful tool for identifying genes affected by large effect rare genetic regulatory variants but suffers from data sparsity and noisy signal in low-count genes. Genome phasing can be…
Ampyrone (4-Aminoantipyrine) is a Direct Agonist of Human Tyrosinase and Potential Therapeutic for Oculocutaneous Albinism and Disorders of Hypopigmentation Open
Significant loss of pigmentation can increase visual disability, skin cancer risk, and psychosocial stress. Tyrosinase (TYR) catalyzes the first and rate-limiting step of melanin synthesis. Inhibitors of TYR are well established and are cu…
Comparative Study of Efficient Machine Learning Models for Real-Time Fraud Detection: CatBoost, XGBoost and LightGBM Open
Real-time performance is a key indicator in the design of fraud detection systems. This study focuses on three gradient boosting algorithms (CatBoost, XGBoost and LightGBM) and evaluates their performance in real-time fraud detection scena…
View article: BK channel activity in skin fibroblasts from patients with neurological disorder
BK channel activity in skin fibroblasts from patients with neurological disorder Open
Seventy-five unique variants in the KCNMA1 gene have been identified from individuals with neurological disorders. However, variant pathogenicity and evidence for disease causality are lacking in most cases. In this study, the KCNMA1 varia…
View article: Neurodevelopmental Phenotyping and Genotyping in the Pediatric National Institute of Health Undiagnosed Disease Program
Neurodevelopmental Phenotyping and Genotyping in the Pediatric National Institute of Health Undiagnosed Disease Program Open
The National Institute of Health (NIH) Undiagnosed Diseases Program (UDP) is an NIH project with the goal of providing both a comprehensive diagnosis and a better understanding of the many mechanisms of disease for patients with rare and u…
View article: Targeting non-canonical NF-κB signalling in CYLD cutaneous syndrome by selective inhibition of IκB kinase alpha
Targeting non-canonical NF-κB signalling in CYLD cutaneous syndrome by selective inhibition of IκB kinase alpha Open
CYLD cutaneous syndrome (CCS) skin tumors develop from puberty onwards, can number in the hundreds and progressively grow over time. CCS patients lack medical therapies and require repeated surgery to control tumor burden. CYLD loss of het…
Mitochondrial trifunctional protein deficiency caused by a deep intronic deletion leading to aberrant splicing Open
Trifunctional protein deficiency (TFP) is a disorder of fatty acid beta‐oxidation associated with metabolic, cardiac, and liver dysfunction in severe forms. We present two siblings diagnosed by newborn screening and confirmed by biochemica…
View article: Telehealth Is Effective in the Evaluation of Individuals With Undiagnosed Rare Disorders: An Undiagnosed Diseases Network Study
Telehealth Is Effective in the Evaluation of Individuals With Undiagnosed Rare Disorders: An Undiagnosed Diseases Network Study Open
Patients with undiagnosed and/or rare disorders frequently manifest dysmorphic and neurological features. There is a lack of information on the effectiveness of telehealth in the evaluation of these disorders. We thus compared an unassiste…
View article: Addressing diagnostic gaps and priorities of the global rare diseases community: Recommendations from the IRDiRC diagnostics scientific committee
Addressing diagnostic gaps and priorities of the global rare diseases community: Recommendations from the IRDiRC diagnostics scientific committee Open
The International Rare Diseases Research Consortium (IRDiRC) Diagnostic Scientific Committee (DSC) is charged with discussion and contribution to progress on diagnostic aspects of the IRDiRC core mission. Specifically, IRDiRC goals include…
View article: Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans
Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans Open
Nucleic acid–sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or autoinflammatory disease or virus-associated immunopathology. Here, we …
View article: <i>De novo</i> variants in the non-coding spliceosomal snRNA gene <i>RNU4-2</i> are a frequent cause of syndromic neurodevelopmental disorders
<i>De novo</i> variants in the non-coding spliceosomal snRNA gene <i>RNU4-2</i> are a frequent cause of syndromic neurodevelopmental disorders Open
Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . Increasingly, large genome-sequenced cohorts are improving our ability to disco…
View article: Loss of the endoplasmic reticulum protein Tmem208 affects cell polarity, development, and viability
Loss of the endoplasmic reticulum protein Tmem208 affects cell polarity, development, and viability Open
Nascent proteins destined for the cell membrane and the secretory pathway are targeted to the endoplasmic reticulum (ER) either posttranslationally or cotranslationally. The signal-independent pathway, containing the protein TMEM208, is on…
View article: Cellular Modeling of CLN6 with IPSC-derived Neurons and Glia
Cellular Modeling of CLN6 with IPSC-derived Neurons and Glia Open
Neuronal ceroid lipofuscinosis (NCL), type 6 (CLN6) is a neurodegenerative disorder associated with progressive neurodegeneration leading to dementia, seizures, and retinopathy. CLN6 encodes a resident-ER protein involved in trafficking ly…
View article: Unveiling the crucial neuronal role of the proteasomal ATPase subunit gene <i>PSMC5</i> in neurodevelopmental proteasomopathies
Unveiling the crucial neuronal role of the proteasomal ATPase subunit gene <i>PSMC5</i> in neurodevelopmental proteasomopathies Open
Neurodevelopmental proteasomopathies represent a distinctive category of neurodevelopmental disorders (NDD) characterized by genetic variations within the 26S proteasome, a protein complex governing eukaryotic cellular protein homeostasis.…
View article: GM1 Gangliosidosis Type II: Results of a 10-Year Prospective Study
GM1 Gangliosidosis Type II: Results of a 10-Year Prospective Study Open
Purpose GM1 gangliosidosis (GM1) is an ultra-rare lysosomal storage disease caused by pathogenic variants in galactosidase beta 1 ( GLB1 ; NM_000404), primarily characterized by neurodegeneration, often in children. There are no approved t…
View article: Dual diagnosis of UQCRFS1-related mitochondrial complex III deficiency and recessive GJA8-related cataracts
Dual diagnosis of UQCRFS1-related mitochondrial complex III deficiency and recessive GJA8-related cataracts Open
Biallelic pathogenic variants in UQCRFS1 underlie a rare form of isolated mitochondrial complex III deficiency associated with lactic acidosis and a distinctive scalp alopecia previously described in two unrelated probands. Here, we descri…
P280: Expansion of TAOK1 related developmental delay phenotype Open
Haploinsufficiency of TAOK1 has been associated with developmental delay, intellectual disabilities, behavioral and physical abnormalities. TAOK1 encodes a Thousand and One (TAO) kinase that activates p38 MAP kinase. TAO kinases mediate ac…
View article: P848: Novel structural variant in PDGFB-associated with ectopic intracerebral calcifications
P848: Novel structural variant in PDGFB-associated with ectopic intracerebral calcifications Open
The NIH Undiagnosed Diseases Program (UDP) enrolls participants with diseases that remain undiagnosed despite extensive standard of care clinical evaluation. Frequently, patients present with negative clinical exome, genome sequencing or g…
View article: Biallelic <i>PI4KA</i> mutations Disrupt B Cell Mitochondrial Metabolism and Cause Hypogammaglobulinemia
Biallelic <i>PI4KA</i> mutations Disrupt B Cell Mitochondrial Metabolism and Cause Hypogammaglobulinemia Open
Introduction Biallelic mutations in the PI4KA gene cause PI4KA-related disorder, a novel condition with neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus), gastrointestinal (GI; inflam…
Risks and benefits of anesthesia for combined pediatric procedures in the NIH undiagnosed diseases program Open
The benefits of anesthesia involving multiple diagnostic procedures in a well-coordinated, multidisciplinary, research setting, such as in the pediatric UDP, outweigh the risks.
View article: Macrocephaly and developmental delay caused by missense variants in RAB5C
Macrocephaly and developmental delay caused by missense variants in RAB5C Open
Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 i…
View article: Genomic Diagnoses for Ectopic Intracerebral Calcifications
Genomic Diagnoses for Ectopic Intracerebral Calcifications Open
These findings support the use of genomic testing for symptomatic patients with EICs.