A5058064935- Genomics and Rare Diseases
- Parathyroid Disorders and Treatments
- Genomic variations and chromosomal abnormalities
- Genetic Syndromes and Imprinting
- Fibroblast Growth Factor Research
- Genetics and Neurodevelopmental Disorders
- RNA modifications and cancer
- Acute Lymphoblastic Leukemia research
- Cancer Genomics and Diagnostics
- Medical Imaging and Pathology Studies
- Connective tissue disorders research
- Bone health and treatments
- RNA regulation and disease
- Magnesium in Health and Disease
- Genetic factors in colorectal cancer
- BRCA gene mutations in cancer
- Neurogenetic and Muscular Disorders Research
- Ubiquitin and proteasome pathways
- Metabolism and Genetic Disorders
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Mitochondrial Function and Pathology
- Neonatal Respiratory Health Research
- Congenital heart defects research
- Immunodeficiency and Autoimmune Disorders
Children's Mercy Hospital
2016-2025
University of Missouri–Kansas City
2016-2025
Mercy Research
2022-2025
Mercy Hospital
2017-2024
Mercy Hospital
2022-2024
Musgrove Park Hospital
2023
Gloucestershire Hospitals NHS Foundation Trust
2023
Cheltenham General Hospital
2022
University of Nottingham
2021
Pacific Biosciences (United States)
2021
Monogenic diseases are frequent causes of neonatal morbidity and mortality, disease presentations often undifferentiated at birth. More than 3500 monogenic have been characterized, but clinical testing is available for only some them many feature genetic heterogeneity. Hence, an immense unmet need exists improved molecular diagnosis in infants. Because progression extremely rapid, albeit heterogeneous, newborns, diagnoses must occur quickly to be relevant decision-making. We describe 50-hour...
Neurodevelopmental disorders (NDDs) affect more than 3% of children and are attributable to single-gene mutations at 1000 loci. Traditional methods yield molecular diagnoses in less one-half with NDD. Whole-genome sequencing (WGS) whole-exome (WES) can enable diagnosis NDD, but their clinical cost-effectiveness unknown. One hundred families 119 affected by NDD received diagnostic WGS and/or WES parent-child trios, wherein the approach was guided acuity illness. Forty-five percent diagnoses....
Autosomal dominant hypophosphatemic rickets (ADHR) is unique among the disorders involving Fibroblast growth factor 23 (FGF23) because individuals with R176Q/W and R179Q/W mutations in FGF23 176 RXXR 179 /S 180 proteolytic cleavage motif can cycle from unaffected status to delayed onset of disease. This may occur physiological states associated iron deficiency, including puberty pregnancy. To test role development ADHR phenotype, WT R176Q-Fgf23 knock-in mice were placed on control or...
While the cost of whole genome sequencing (WGS) is approaching realm routine medical tests, it remains too tardy to help guide management many acute conditions. Rapid WGS imperative in light growing evidence its utility care, such as diagnosis genetic diseases very ill infants, and genotype-guided choice chemotherapy at cancer relapse. In situations, delayed, empiric, or phenotype-based clinical decisions may meet with substantial morbidity mortality. We previously described a rapid method,...
Genetic disorders are a leading cause of morbidity and mortality in infants neonatal pediatric intensive care units (NICU/PICU). While genomic sequencing is useful for genetic disease diagnosis, results usually reported too late to guide inpatient management. We performed an investigator-initiated, partially blinded, pragmatic, randomized, controlled trial test the hypothesis that rapid whole-genome (rWGS) increased proportion NICU/PICU receiving diagnosis within 28 days. The participants...
Spinal muscular atrophy, a leading cause of early infant death, is caused by bi-allelic mutations SMN1. Sequence analysis SMN1 challenging due to high sequence similarity with its paralog SMN2. Both genes have variable copy numbers across populations. Furthermore, without pedigree information, it currently not possible identify silent carriers (2+0) two copies on one chromosome and zero the other. We developed Paraphase, an informatics method that identifies full-length SMN2 haplotypes,...
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 virus-associated immunopathology. Here, we report a systematic scanning-alanine mutagenesis screen of all cytosolic luminal residues the TLR chaperone protein UNC93B1, which identified both negative positive regulatory regions affecting TLR3, TLR7, TLR9 responses. We subsequently two families harboring...
Personalized antisense oligonucleotides (ASOs) have achieved positive results in the treatment of rare genetic disease1. As clinical sequencing technologies continue to advance, ability identify patients with disease harbouring pathogenic variants amenable this therapeutic strategy will probably improve. Here we describe a scalable platform for generating patient-derived cellular models and demonstrate that these personalized can be used preclinical evaluation patient-specific ASOs. We...
Fibroblast growth factor-23 (FGF23), a hormone central to phosphate and vitamin D metabolism, reduces renal absorption of by downregulating the sodium-phosphate cotransporter Npt2a. However, mechanisms FGF23 action in kidney are unclear, as Npt2a localizes proximal tubule (PT) coreceptor alpha-Klotho (KL) distal convoluted (DCT). Immunofluorescent analyses following injection mice showed robust staining for phospho-ERK1/2, marker bioactivity, only within DCT subset KL-positive cells. This...
The FGF23 coreceptor αKlotho (αKL) is expressed as a membrane-bound protein (mKL) that forms heteromeric complexes with FGF receptors (FGFRs) to initiate intracellular signaling. It also circulates an endoproteolytic cleavage product of mKL (cKL). Previously, patient increased plasma cKL the result translocation [t(9;13)] in αKLOTHO (KL) gene presented rickets and complex endocrine profile, including paradoxically elevated FGF23, despite hypophosphatemia. goal this study was test whether...
Alström Syndrome (ALMS), a recessive, monogenic ciliopathy caused by mutations in ALMS1, is typically characterized multisystem involvement including early cone-rod retinal dystrophy and blindness, hearing loss, childhood obesity, type 2 diabetes mellitus, cardiomyopathy, fibrosis, multiple organ failure. The precise function of ALMS1 remains elusive, but roles endosomal ciliary transport cell cycle regulation have been shown. aim our study was to further define the spectrum patients with...
ABSTRACT Fibroblast growth factor 23 (FGF23) gain of function mutations can lead to autosomal dominant hypophosphatemic rickets (ADHR) disease onset at birth, or delayed following puberty pregnancy. We previously demonstrated that the combination iron deficiency and a knock-in R176Q FGF23 mutation in mature mice induced expression hypophosphatemia paralleled late-onset ADHR phenotype. Because anemia pregnancy premature infants is common, goal this study was test whether alters phosphate...
An important component of precision medicine-the use whole-genome sequencing (WGS) to guide lifelong healthcare-is electronic decision support inform drug choice and dosing. To achieve this, automated identification genetic variation in genes involved absorption, distribution, metabolism, excretion response (ADMER) is required. CYP2D6 a major enzyme for bioactivation elimination. activity predominantly governed by variation; however, it technically arduous haplotype. Not only the nucleotide...
PurposeThis study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program.MethodsExtensive of 960 families with suspected genetic disorders included short-read exome sequencing genome (srGS); PacBio HiFi long-read (HiFi-GS); variant calling single nucleotide variants (SNV), structural (SV), repeat variants; machine-learning prioritization. Structured phenotypes, prioritized variants, pedigrees were...
Abstract Rare DNA alterations that cause heritable diseases are only partially resolvable by clinical next-generation sequencing due to the difficulty of detecting structural variation (SV) in all genomic contexts. Long-read, high fidelity genome (HiFi-GS) detects SVs with increased sensitivity and enables assembling personal graph genomes. We leverage standard reference genomes, public assemblies ( n = 94) a large collection HiFi-GS data from rare disease program (Genomic Answers for Kids,...
Previous studies have suggested a regulatory relationship between serum phosphorus, vitamin D, and fibroblast growth factor 23 (FGF23), hormone that promotes renal excretion of phosphate. Despite these associations, the identity primary regulator FGF23 is unresolved. Jansen's metaphyseal chondrodysplasia rare autosomal dominant disorder associated with short-limbed dwarfism other characteristic skeletal abnormalities. This condition caused by mutations in PTH/PTHrP receptor result...
The epileptic encephalopathies are a group of highly heterogeneous genetic disorders. majority disease-causing mutations alter genes encoding voltage-gated ion channels, neurotransmitter receptors, or synaptic proteins. We have identified novel de novo pathogenic K+ channel variant in an idiopathic encephalopathy family. Here, we report the effects this mutation on function and heterologous expression cell lines. present case infantile young girl, trio-exome sequencing to determine etiology...