Arthur L Beaudet

Baylor College of Medicine, Houston, Texas, United States

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Publications (440)3547.92 Total impact

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    ABSTRACT: Background: Large-scale cohort-based whole exome sequencing of individuals with neurodevelopmental disorders (NDDs) has identified numerous novel candidate disease genes; however, detailed phenotypic information is often lacking in such studies. De novo mutations in pogo transposable element with zinc finger domain (POGZ) have been identified in six independent and diverse cohorts of individuals with NDDs ranging from autism spectrum disorder to developmental delay. Methods: Whole exome sequencing was performed on five unrelated individuals. Sanger sequencing was used to validate variants and segregate mutations with the phenotype in available family members. Results: We identified heterozygous truncating mutations in POGZ in five unrelated individuals, which were confirmed to be de novo or not present in available parental samples. Careful review of the phenotypes revealed shared features that included developmental delay, intellectual disability, hypotonia, behavioral abnormalities, and similar facial characteristics. Variable features included short stature, microcephaly, strabismus and hearing loss. Conclusions: While POGZ has been associated with neurodevelopmental disorders in large cohort studies, our data suggest that loss of function variants in POGZ lead to an identifiable syndrome of NDD with specific phenotypic traits. This study exemplifies the era of human reverse clinical genomics ushered in by large disease-directed cohort studies; first defining a new syndrome molecularly and, only subsequently, phenotypically.
    Full-text · Article · Dec 2016 · Genome Medicine
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    ABSTRACT: Purpose: Whole-exome sequencing (WES) is increasingly used as a diagnostic tool in medicine, but prior reports focus on predominantly pediatric cohorts with neurologic or developmental disorders. We describe the diagnostic yield and characteristics of WES in adults. Methods: We performed a retrospective analysis of consecutive WES reports for adults from a diagnostic laboratory. Phenotype composition was determined using Human Phenotype Ontology terms. Results: Molecular diagnoses were reported for 17.5% (85/486) of adults, which is lower than that for a primarily pediatric population (25.2%; P = 0.0003); the diagnostic rate was higher (23.9%) for those 18-30 years of age compared to patients older than 30 years (10.4%; P = 0.0001). Dual Mendelian diagnoses contributed to 7% of diagnoses, revealing blended phenotypes. Diagnoses were more frequent among individuals with abnormalities of the nervous system, skeletal system, head/neck, and growth. Diagnostic rate was independent of family history information, and de novo mutations contributed to 61.4% of autosomal dominant diagnoses. Conclusion: Early WES experience in adults demonstrates molecular diagnoses in a substantial proportion of patients, informing clinical management, recurrence risk, and recommendations for relatives. A positive family history was not predictive, consistent with molecular diagnoses often revealed by de novo events, informing the Mendelian basis of genetic disease in adults.Genet Med advance online publication 03 December 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.142.
    No preview · Article · Dec 2015 · Genetics in medicine: official journal of the American College of Medical Genetics
  • Arthur L Beaudet · Linyan Meng
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    ABSTRACT: The concept of orphan drugs for treatment of orphan genetic diseases is perceived enthusiastically at present, and this is leading to research investment on the part of governments, disease-specific foundations, and industry. This review attempts to survey the potential to use traditional pharmaceuticals as opposed to biopharmaceuticals to treat single gene disorders. The available strategies include the use of antisense oligonucleotides to alter splicing or knock-down expression of a transcript, siRNAs to knock-down gene expression, and drugs for nonsense mutation read-through. There is an approved drug for biallelic knock-down of the APOB gene as treatment for familial hypercholesterolemia. Both ASOs and siRNAs are being explored to knock-down the TTR gene to prevent the related form of amyloidosis. The use of ASOs to alter gene-splicing to treat spinal muscular atrophy is in phase 3 clinical trials. Work is progressing on the use of ASOs to activate the normally silent paternal copy of the imprinted UBE3A gene in neurons as a treatment for Angelman syndrome. A gene activation or gene-specific ramp-up strategy would be generally helpful if such could be developed. There is exciting theoretical potential for converting biopharmaceutical strategies such gene correction and CRISPR-cas9 editing to a synthetic pharmaceutical approach.
    No preview · Article · Dec 2015 · Human Molecular Genetics
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    Mohammad Haeri · Violet Gelowani · Arthur L. Beaudet
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    ABSTRACT: Pathological copy number variants (CNVs) and point mutations are major genetic causes of hundreds of disorders. Comparative genomic hybridization (CGH) also known as chromosomal microarray analysis (CMA) is the best available tool to detect copy number variations in chromosomal make up. We have optimized several different protocols and introduce a high throughput approach to perform a cost-effective, fast, high-throughput and high-quality CMA. We managed to reach to high quality arrays with 17±0.04 (Mean±SD, n=90) Derivative Log Ratio (DLR) spread, a measure of array quality (< 0.20 considered as Excellent) for our arrays. High-throughput and high quality arrays are gaining more attention and the current manuscript is a step forward to this increasing demand.
    Preview · Article · Dec 2015 · MethodsX
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    ABSTRACT: Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5′ end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1st coding exon), c.16A>T (p.Lys6∗) and c.35-38delTCAA (p.Ile12Lysfs∗4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5′ end of the geminin protein. All three GMNN mutations identified alter sites 5′ to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.
    No preview · Article · Dec 2015 · The American Journal of Human Genetics
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    Arthur L Beaudet

    Preview · Article · Sep 2015 · Science
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    ABSTRACT: Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).
    Full-text · Article · Sep 2015 · Neuron

  • No preview · Article · Sep 2015 · Ultrasound in Obstetrics and Gynecology
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    Arthur L Beaudet
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    ABSTRACT: Editorial summary Expanded genetic carrier testing is changing clinical practice. Current experience highlights the need for rigorous curation of tens of thousands of variants as to their pathogenicity and phenotypic effects. There is an urgent need for strategies to present a range of options to families to enable them to make informed decisions. The potential exists to avoid the great majority of serious inherited, but not de novo, single-gene disabilities.
    Preview · Article · Jul 2015 · Genome Medicine
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    ABSTRACT: Disorders of carnitine biosynthesis have recently been associated with neurodevelopmental syndromes such as autism spectrum disorder (ASD). A 4-year-old male with autism and two episodes of neurodevelopmental regression was identified to have a mutation in the TMLHE gene, which encodes the first enzyme in the carnitine biosynthesis pathway, and concurrent carnitine deficiency. Following carnitine supplementation, the patient's regression ended, and the boy started gaining developmental milestones. This case report suggests that deficits in carnitine biosynthesis may be responsible for some cases of regression in individuals with ASD, and that testing for the respective biochemical pathway should be considered. Furthermore, this case suggests that carnitine supplementation may be useful in treating (and potentially preventing) regressive episodes in patients with carnitine deficiency. Further work to better define the role of disorders of carnitine biosynthesis in autism spectrum disorder is warranted. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · May 2015 · American Journal of Medical Genetics Part A
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    ABSTRACT: Global metabolic profiling currently achievable by untargeted mass spectrometry-based metabolomic platforms has great potential to advance our understanding of human disease states, including potential utility in the detection of novel and known inborn errors of metabolism (IEMs). There are few studies of the technical reproducibility, data analysis methods, and overall diagnostic capabilities when this technology is applied to clinical specimens for the diagnosis of IEMs. We explored the clinical utility of a metabolomic workflow capable of routinely generating semi-quantitative z-score values for ~900 unique compounds, including ~500 named human analytes, in a single analysis of human plasma. We tested the technical reproducibility of this platform and applied it to the retrospective diagnosis of 190 individual plasma samples, 120 of which were collected from patients with a confirmed IEM. Our results demonstrate high intra-assay precision and linear detection for the majority compounds tested. Individual metabolomic profiles provided excellent sensitivity and specificity for the detection of a wide range of metabolic disorders and identified novel biomarkers for some diseases. With this platform, it is possible to use one test to screen for dozens of IEMs that might otherwise require ordering multiple unique biochemical tests. However, this test may yield false negative results for certain disorders that would be detected by a more well-established quantitative test and in its current state should be considered a supplementary test. Our findings describe a novel approach to metabolomic analysis of clinical specimens and demonstrate the clinical utility of this technology for prospective screening of IEMs. Electronic supplementary material The online version of this article (doi:10.1007/s10545-015-9843-7) contains supplementary material, which is available to authorized users.
    Full-text · Article · Apr 2015 · Journal of Inherited Metabolic Disease
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    ABSTRACT: Angelman syndrome is a single-gene disorder characterized by intellectual disability, developmental delay, behavioural uniqueness, speech impairment, seizures and ataxia. It is caused by maternal deficiency of the imprinted gene UBE3A, encoding an E3 ubiquitin ligase. All patients carry at least one copy of paternal UBE3A, which is intact but silenced by a nuclear-localized long non-coding RNA, UBE3A antisense transcript (UBE3A-ATS). Murine Ube3a-ATS reduction by either transcription termination or topoisomerase I inhibition has been shown to increase paternal Ube3a expression. Despite a clear understanding of the disease-causing event in Angelman syndrome and the potential to harness the intact paternal allele to correct the disease, no gene-specific treatment exists for patients. Here we developed a potential therapeutic intervention for Angelman syndrome by reducing Ube3a-ATS with antisense oligonucleotides (ASOs). ASO treatment achieved specific reduction of Ube3a-ATS and sustained unsilencing of paternal Ube3a in neurons in vitro and in vivo. Partial restoration of UBE3A protein in an Angelman syndrome mouse model ameliorated some cognitive deficits associated with the disease. Although additional studies of phenotypic correction are needed, we have developed a sequence-specific and clinically feasible method to activate expression of the paternal Ube3a allele.
    Preview · Article · Dec 2014 · Nature
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    ABSTRACT: Importance Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders.Objective To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome.Design, Setting, and Patients Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient’s physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay.Main Outcomes and Measures Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings.Results A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95% CI, 23.5%-31.2%) for the neurological group, 282/1147 (24.6%; 95% CI, 22.1%-27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95% CI, 26.1%-47.5%) for the specific neurological group, and 49/244 (20.1%; 95% CI, 15.6%-25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics.Conclusions and Relevance Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.
    No preview · Article · Oct 2014 · JAMA The Journal of the American Medical Association
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    ABSTRACT: 5q31.3 microdeletion syndrome is characterized by neonatal hypotonia, encephalopathy with or without epilepsy, and severe developmental delay, and the minimal critical deletion interval harbors three genes. We describe 11 individuals with clinical features of 5q31.3 microdeletion syndrome and de novo mutations in PURA, encoding transcriptional activator protein Pur-α, within the critical region. These data implicate causative PURA mutations responsible for the severe neurological phenotypes observed in this syndrome.
    Full-text · Article · Oct 2014 · The American Journal of Human Genetics
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    ABSTRACT: Background Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of sub-phenotyping of a well-characterized ASD sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. Methods Genome-wide genotypic data of 2576 families from the Simons Simplex Collection (SSC) were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. Results Association analyses revealed no genome-wide significant association signal. Sub-phenotyping did not increase power substantially. Moreover, allele scores built from the most associated SNPs, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. Conclusions In genome-wide association analysis of the SSC sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of sub-phenotypes is not a productive path forward for discovering genetic risk variants in ASD.
    No preview · Article · Sep 2014 · Biological Psychiatry
  • Arthur L Beaudet
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    ABSTRACT: A new study compares the copy number variants (CNVs) in 29,085 children with developmental delay to those in 19,584 healthy controls, providing a valuable compilation of such data. The phenotypic variability and wide range of penetrance for these variants present societal challenges regarding how these findings might be incorporated into newborn screening, early intervention and, perhaps, carrier testing and prenatal diagnosis.
    No preview · Article · Sep 2014 · Nature Genetics
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    ABSTRACT: The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status. Autism Res 2014, ●: ●●–●●. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.
    No preview · Article · Jun 2014 · Autism Research
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    ABSTRACT: Clinical whole-exome sequencing (WES) for identification of mutations leading to Mendelian disease has been offered to the medical community since 2011. Clinically undiagnosed neurological disorders are the most frequent basis for test referral, and currently, approximately 25% of such cases are diagnosed at the molecular level. To date, there are approximately 4,000 "known" disease-associated loci, and many are associated with striking dysmorphic features, making genotype-phenotype correlations relatively straightforward. A significant fraction of cases, however, lack characteristic dysmorphism or clinical pathognomonic traits and are dependent upon molecular tests for definitive diagnoses. Further, many molecular diagnoses are guided by recent gene-disease association discoveries. Hence, there is a critical interplay between clinical testing and research leading to gene-disease association discovery. Here, we describe four probands, all of whom presented with hypotonia, intellectual disability, global developmental delay, and mildly dysmorphic facial features. Three of the four also had sleep apnea. Each was a simplex case without a remarkable family history. Using WES, we identified AHDC1 de novo truncating mutations that most likely cause this genetic syndrome.
    Full-text · Article · May 2014 · The American Journal of Human Genetics
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    ABSTRACT: Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare disorder of enteric smooth muscle function affecting the intestine and bladder. Patients with this severe phenotype are dependent on total parenteral nutrition and urinary catheterization. The cause of this syndrome has remained a mystery since Berdon's initial description in 1976. No genes have been clearly linked to MMIHS. We used whole-exome sequencing for gene discovery followed by targeted Sanger sequencing in a cohort of patients with MMIHS and intestinal pseudo-obstruction. We identified heterozygous ACTG2 missense variants in 15 unrelated subjects, ten being apparent de novo mutations. Ten unique variants were detected, of which six affected CpG dinucleotides and resulted in missense mutations at arginine residues, perhaps related to biased usage of CpG containing codons within actin genes. We also found some of the same heterozygous mutations that we observed as apparent de novo mutations in MMIHS segregating in families with intestinal pseudo-obstruction, suggesting that ACTG2 is responsible for a spectrum of smooth muscle disease. ACTG2 encodes γ2 enteric actin and is the first gene to be clearly associated with MMIHS, suggesting an important role for contractile proteins in enteric smooth muscle disease.
    Full-text · Article · Mar 2014 · PLoS Genetics
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    ABSTRACT: Author Summary Angelman syndrome (AS) is a devastating neurodevelopmental disorder diagnosed in young children, currently with no effective treatments. It is characterized by absence of speech, ataxia, intellectual disability, epilepsy, and a characteristic behavior of frequent laughter and smiling. The disease is caused by loss of the maternal allele of UBE3A, which is preferentially silenced on the paternal chromosome and expressed on the maternal chromosome in neurons due to genomic imprinting. It has been long proposed that by activating the originally silenced paternal allele of UBE3A, the disease may be cured. Here in our research, we demonstrated the feasibility of activating paternal Ube3a in mice by terminating the transcription of its antisense RNA Ube3a-ATS genetically. In the AS mouse model who additionally receives the terminated Ube3a-ATS allele from the paternal side, we observed restoration of Ube3a expression, amelioration of behavioral defects and reversal of the impaired long-term potentiation. We further studied the imprinting mechanisms of Ube3a and proposed a novel transcriptional collision model. These results provide solid in vivo evidence for a key regulatory role of Ube3a-ATS in the disease and open up an exciting possibility of a gene-specific treatment for Angelman syndrome.
    Preview · Article · Dec 2013 · PLoS Genetics

Publication Stats

28k Citations
3,547.92 Total Impact Points

Institutions

  • 1975-2016
    • Baylor College of Medicine
      • • Department of Molecular & Human Genetics
      • • Department of Pediatrics
      • • Department of Medicine
      Houston, Texas, United States
  • 2008
    • Government of Manitoba, Canada
      Winnipeg, Manitoba, Canada
  • 2007
    • University of Toronto
      Toronto, Ontario, Canada
  • 2006
    • University of Florida
      Gainesville, Florida, United States
  • 2002
    • Migal - Galilee Technology Center
      Mas-ha, Northern District, Israel
  • 1986-1995
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1991
    • SickKids
      Toronto, Ontario, Canada
  • 1980-1991
    • Baylor University
      Waco, Texas, United States