A L Beaudet

Baylor College of Medicine, Houston, Texas, United States

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Publications (415)3378.86 Total impact

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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.
    Autism Research 06/2014; · 3.99 Impact Factor
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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.
    The American Journal of Human Genetics 05/2014; 94(5):784-9. · 11.20 Impact Factor
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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.
    PLoS Genetics 03/2014; 10(3):e1004258. · 8.52 Impact Factor
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    ABSTRACT: Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by maternal deficiency of the imprinted gene UBE3A. Individuals with AS suffer from intellectual disability, speech impairment, and motor dysfunction. Currently there is no cure for the disease. Here, we evaluated the phenotypic effect of activating the silenced paternal allele of Ube3a by depleting its antisense RNA Ube3a-ATS in mice. Premature termination of Ube3a-ATS by poly(A) cassette insertion activates expression of Ube3a from the paternal chromosome, and ameliorates many disease-related symptoms in the AS mouse model, including motor coordination defects, cognitive deficit, and impaired long-term potentiation. Studies on the imprinting mechanism of Ube3a revealed a pattern of biallelic transcription initiation with suppressed elongation of paternal Ube3a, implicating transcriptional collision between sense and antisense polymerases. These studies demonstrate the feasibility and utility of unsilencing the paternal copy of Ube3a via targeting Ube3a-ATS as a treatment for Angelman syndrome.
    PLoS Genetics 12/2013; 9(12):e1004039. · 8.52 Impact Factor
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    ABSTRACT: Background Whole-exome sequencing is a diagnostic approach for the identification of molecular defects in patients with suspected genetic disorders. Methods We developed technical, bioinformatic, interpretive, and validation pipelines for whole-exome sequencing in a certified clinical laboratory to identify sequence variants underlying disease phenotypes in patients. Results We present data on the first 250 probands for whom referring physicians ordered whole-exome sequencing. Patients presented with a range of phenotypes suggesting potential genetic causes. Approximately 80% were children with neurologic phenotypes. Insurance coverage was similar to that for established genetic tests. We identified 86 mutated alleles that were highly likely to be causative in 62 of the 250 patients, achieving a 25% molecular diagnostic rate (95% confidence interval, 20 to 31). Among the 62 patients, 33 had autosomal dominant disease, 16 had autosomal recessive disease, and 9 had X-linked disease. A total of 4 probands received two nonoverlapping molecular diagnoses, which potentially challenged the clinical diagnosis that had been made on the basis of history and physical examination. A total of 83% of the autosomal dominant mutant alleles and 40% of the X-linked mutant alleles occurred de novo. Recurrent clinical phenotypes occurred in patients with mutations that were highly likely to be causative in the same genes and in different genes responsible for genetically heterogeneous disorders. Conclusions Whole-exome sequencing identified the underlying genetic defect in 25% of consecutive patients referred for evaluation of a possible genetic condition. (Funded by the National Human Genome Research Institute.).
    New England Journal of Medicine 10/2013; · 51.66 Impact Factor
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    ABSTRACT: Prader-Willi syndrome (PWS) is caused by the absence of paternally expressed, maternally silenced genes at 15q11-q13. We report four individuals with truncating mutations on the paternal allele of MAGEL2, a gene within the PWS domain. The first subject was ascertained by whole-genome sequencing analysis for PWS features. Three additional subjects were identified by reviewing the results of exome sequencing of 1,248 cases in a clinical laboratory. All four subjects had autism spectrum disorder (ASD), intellectual disability and a varying degree of clinical and behavioral features of PWS. These findings suggest that MAGEL2 is a new gene causing complex ASD and that MAGEL2 loss of function can contribute to several aspects of the PWS phenotype.
    Nature Genetics 09/2013; · 35.21 Impact Factor
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    ABSTRACT: Curation and interpretation of copy number variants identified by genome-wide testing is challenged by the large number of events harbored in each personal genome. Conventional determination of phenotypic relevance relies on patterns of higher frequency in affected individuals versus controls; however, an increasing amount of ascertained variation is rare or private to clans. Consequently, frequency data have less utility to resolve pathogenic from benign. One solution is disease-specific algorithms that leverage gene knowledge together with variant frequency to aid prioritization. We used large-scale resources including Gene Ontology, protein-protein interactions and other annotation systems together with a broad set of 83 genes with known associations to epilepsy to construct a pathogenicity score for the phenotype. We evaluated the score for all annotated human genes and applied Bayesian methods to combine the derived pathogenicity score with frequency information from our diagnostic laboratory. Analysis determined Bayes factors and posterior distributions for each gene. We applied our method to subjects with abnormal chromosomal microarray results and confirmed epilepsy diagnoses gathered by electronic medical record review. Genes deleted in our subjects with epilepsy had significantly higher pathogenicity scores and Bayes factors compared to subjects referred for non-neurologic indications. We also applied our scores to identify a recently validated epilepsy gene in a complex genomic region and to reveal candidate genes for epilepsy. We propose a potential use in clinical decision support for our results in the context of genome-wide screening. Our approach demonstrates the utility of integrative data in medical genomics.
    PLoS Genetics 09/2013; 9(9):e1003797. · 8.52 Impact Factor
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    ABSTRACT: Helper-dependent adenoviral vectors (HDAd) have been shown to mediate considerably longer duration of transgene expression compared to first generation adenoviral vectors. We have previously shown that transgene expression from HDAd transduced hepatocytes can persist at high levels for up to 2.6 years in nonhuman primates following a single vector administration. Because duration of transgene expression and long-term toxicity are critical for risk:benefit assessment, we have continued to monitor these animals. We report here that transgene expression has persisted for the entire observation period of up to 7 years for all animals without long-term adverse effect. However, in all cases, transgene expression level slowly declined over time to less than 10% of peak values by the end of the observation period but remained 2.3 to 111-fold above baseline values. These results will provide important information for a more informed risk:benefit assessment prior to clinical application of HDAd.
    Human gene therapy 07/2013; · 4.20 Impact Factor
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    ABSTRACT: White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ∼70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.
    The American Journal of Human Genetics 06/2013; · 11.20 Impact Factor
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    ABSTRACT: In clinical diagnostics, both array comparative genomic hybridization (array CGH) and single nucleotide polymorphism (SNP) genotyping have proven to be powerful genomic technologies utilized for the evaluation of developmental delay, multiple congenital anomalies, and neuropsychiatric disorders. Differences in the ability to resolve genomic changes between these arrays may constitute an implementation challenge for clinicians: which platform (SNP vs array CGH) might best detect the underlying genetic cause for the disease in the patient? While only SNP arrays enable the detection of copy number neutral regions of absence of heterozygosity (AOH), they have limited ability to detect single-exon copy number variants (CNVs) due to the distribution of SNPs across the genome. To provide comprehensive clinical testing for both CNVs and copy-neutral AOH, we enhanced our custom-designed high-resolution oligonucleotide array that has exon-targeted coverage of 1860 genes with 60 000 SNP probes, referred to as Chromosomal Microarray Analysis - Comprehensive (CMA-COMP). Of the 3240 cases evaluated by this array, clinically significant CNVs were detected in 445 cases including 21 cases with exonic events. In addition, 162 cases (5.0%) showed at least one AOH region >10 Mb. We demonstrate that even though this array has a lower density of SNP probes than other commercially available SNP arrays, it reliably detected AOH events >10 Mb as well as exonic CNVs beyond the detection limitations of SNP genotyping. Thus, combining SNP probes and exon-targeted array CGH into one platform provides clinically useful genetic screening in an efficient manner.European Journal of Human Genetics advance online publication, 22 May 2013; doi:10.1038/ejhg.2013.77.
    European journal of human genetics: EJHG 05/2013; · 3.56 Impact Factor
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    ABSTRACT: Over 1,200 recessive disease genes have been described in humans. The prevalence, allelic architecture, and per-genome load of pathogenic alleles in these genes remain to be fully elucidated, as does the contribution of DNA copy-number variants (CNVs) to carrier status and recessive disease. We mined CNV data from 21,470 individuals obtained by array comparative genomic hybridization in a clinical diagnostic setting to identify deletions encompassing or disrupting recessive disease genes. We identified 3,212 heterozygous potential carrier deletions affecting 419 unique recessive disease genes. Deletion frequency of these genes ranged from one occurrence to 1.5%. When compared with recessive disease genes never deleted in our cohort, the 419 recessive disease genes affected by at least one carrier deletion were longer and were located farther from known dominant disease genes, suggesting that the formation and/or prevalence of carrier CNVs may be affected by both local and adjacent genomic features and by selection. Some subjects had multiple carrier CNVs (307 subjects) and/or carrier deletions encompassing more than one recessive disease gene (206 deletions). Heterozygous deletions spanning multiple recessive disease genes may confer carrier status for multiple single-gene disorders, for complex syndromes resulting from the combination of two or more recessive conditions, or may potentially cause clinical phenotypes due to a multiply heterozygous state. In addition to carrier mutations, we identified homozygous and hemizygous deletions potentially causative for recessive disease. We provide further evidence that CNVs contribute to the allelic architecture of both carrier and recessive disease-causing mutations. Thus, a complete recessive carrier screening method or diagnostic test should detect CNV alleles.
    Genome Research 05/2013; · 14.40 Impact Factor
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    ABSTRACT: We delineated and analyzed directly oriented paralogous low-copy repeats (DP-LCRs) in the most recent version of the human haploid reference genome. The computationally defined DP-LCRs were cross-referenced with our Chromosomal Microarray Analysis (CMA) database of 25,144 patients subjected to genome-wide assays. This computationally guided approach to the empirically-derived large dataset allowed us to investigate genomic rearrangement relative frequencies and identify new loci for recurrent nonallelic homologous recombination (NAHR)-mediated copy-number variants (CNVs). The most commonly observed recurrent CNVs were NPHP1 duplications (233), CHRNA7 duplications (175), and 22q11.21 deletions (DiGeorge/Velocardiofacial syndrome, 166). In the ~ 25% of CMA cases for which parental studies were available, we identified 190 de novo recurrent CNVs. In this group, the most frequently observed events were deletions of 22q11.21 (48), 16p11.2 (autism, 34), and 7q11.23 (Williams-Beuren syndrome, 11). Several features of DP-LCRs, including length, distance between NAHR substrate elements, DNA sequence identity (fraction matching), GC content, and concentration of the homologous recombination (HR) hot spot motif 5'-CCNCCNTNNCCNC-3' correlate with the frequencies of the recurrent CNVs events. Four novel adjacent DP-LCR-flanked and NAHR-prone regions, involving 2q12.2q13 were elucidated in association with novel genomic disorders. Our study quantitates genome architectural features responsible for NAHR mediated genomic instability and further elucidates the role of NAHR in human disease.
    Genome Research 05/2013; · 14.40 Impact Factor
  • Ray-Chang Wu, Ming Jiang, Arthur L Beaudet, Mei-Yi Wu
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    ABSTRACT: ARID4A and ARID4B are homologous members of the ARID (AT-rich interaction domain) gene family. ARID4A and ARID4B physically interact with each other. ARID4A is a retinoblastoma (RB)-binding protein. Biological function of these interactions is still unknown. Here, we report that mice with complete deficiency of Arid4a, combined with haploinsufficiency of Arid4b (Arid4a(-/-)Arid4b(+/-)), showed progressive loss of male fertility, accompanied by hypogonadism and seminal vesicle agenesis/hypodysplasia. Arid4a and Arid4b are expressed mainly in Sertoli cells of testes, which implies that their roles in Sertoli cell function are to support spermatogenesis and create the impermeable blood-testis barrier. In fact, evaluation of germ cell development in the Arid4a(-/-)Arid4b(+/-) mice showed spermatogenic arrest at the stages of meiotic spermatocytes and postmeiotic haploid spermatids. Analysis of the integrity of the blood-testis barrier showed increased permeability of seminiferous tubules in the Arid4a(-/-)Arid4b(+/-) testes. Interestingly, phenotypic Sertoli cell dysfunction in the Arid4a(-/-)Arid4b(+/-) mice, including spermatogenic failures and the impaired blood-testis barrier, recapitulated the defects found in the Sertoli cell-specific androgen receptor (AR) knockout mice and the Sertoli cell-specific RB knockout mice. Investigation of the molecular mechanism identified several AR- and RB-responsive genes as downstream targets of ARID4A and ARID4B. Our results thus indicate that ARID4A and ARID4B function as transcriptional coactivators for AR and RB and play an integral part in the AR and RB regulatory pathways involved in the regulation of Sertoli cell function and male fertility.
    Proceedings of the National Academy of Sciences 03/2013; · 9.81 Impact Factor
  • Arthur L Beaudet
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    ABSTRACT: Chromosomal microarray analysis (CMA) has emerged as a powerful new tool to identify genomic abnormalities associated with a wide range of developmental disabilities including congenital malformations, cognitive impairment, and behavioral abnormalities. CMA includes array comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) arrays, both of which are useful for detection of genomic copy number variants (CNV) such as microdeletions and microduplications. The frequency of disease-causing CNVs is highest (20%-25%) in children with moderate to severe intellectual disability accompanied by malformations or dysmorphic features. Disease-causing CNVs are found in 5%-10% of cases of autism, being more frequent in severe phenotypes. CMA has replaced Giemsa-banded karyotype as the first-tier test for genetic evaluation of children with developmental and behavioral disabilities.
    Child Development 01/2013; · 4.92 Impact Factor
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    ABSTRACT: Purpose:Chromosomal microarray analysis enables the detection of microdeletions/duplications and has become the standard in clinical diagnostic testing for individuals with congenital anomalies and developmental disabilities. In the era of genomic arrays, the value of traditional chromosome analysis needs to be reassessed.Methods:We studied 3,710 unrelated patients by chromosomal microarray analysis and chromosome analysis simultaneously and compared the results.Results:We found that chromosomal microarray analysis detected the chromosomal imbalances that were identified by chromosome analysis with the exception of six cases (0.16%) that had mosaic abnormalities. Of note, one case showed mosaicism for two abnormal cell lines, resulting in a balanced net effect and a normal chromosomal microarray analysis. Further structural abnormalities such as unbalanced translocations, rings, and complex rearrangements were subsequently clarified by chromosome analysis in 18% of the cases with abnormal chromosomal microarray analysis results. Apparently balanced rearrangements were detected by chromosome analysis in 30 cases (0.8%).Conclusion:Our data demonstrate that although chromosomal microarray analysis should be the first-tier test for clinical diagnosis of chromosome abnormalities, chromosome analysis remains valuable in the detection of mosaicism and delineation of chromosomal structural rearrangements.Genet Med advance online publication 13 December 2012Genetics in Medicine (2012); doi:10.1038/gim.2012.152.
    Genetics in medicine: official journal of the American College of Medical Genetics 12/2012; · 3.92 Impact Factor
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    ABSTRACT: Background Chromosomal microarray analysis has emerged as a primary diagnostic tool for the evaluation of developmental delay and structural malformations in children. We aimed to evaluate the accuracy, efficacy, and incremental yield of chromosomal microarray analysis as compared with karyotyping for routine prenatal diagnosis. Methods Samples from women undergoing prenatal diagnosis at 29 centers were sent to a central karyotyping laboratory. Each sample was split in two; standard karyotyping was performed on one portion and the other was sent to one of four laboratories for chromosomal microarray. Results We enrolled a total of 4406 women. Indications for prenatal diagnosis were advanced maternal age (46.6%), abnormal result on Down's syndrome screening (18.8%), structural anomalies on ultrasonography (25.2%), and other indications (9.4%). In 4340 (98.8%) of the fetal samples, microarray analysis was successful; 87.9% of samples could be used without tissue culture. Microarray analysis of the 4282 nonmosaic samples identified all the aneuploidies and unbalanced rearrangements identified on karyotyping but did not identify balanced translocations and fetal triploidy. In samples with a normal karyotype, microarray analysis revealed clinically relevant deletions or duplications in 6.0% with a structural anomaly and in 1.7% of those whose indications were advanced maternal age or positive screening results. Conclusions In the context of prenatal diagnostic testing, chromosomal microarray analysis identified additional, clinically significant cytogenetic information as compared with karyotyping and was equally efficacious in identifying aneuploidies and unbalanced rearrangements but did not identify balanced translocations and triploidies. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT01279733 .).
    New England Journal of Medicine 12/2012; 367(23):2175-2184. · 51.66 Impact Factor
  • Arthur L Beaudet
    Science 10/2012; 338(6105):342-3. · 31.20 Impact Factor
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    ABSTRACT: Disturbances in the form of microduplications and microdeletions have been found throughout the genome and have been associated with autism, intellectual disability, and recognizable malformation syndromes. In our study of 187 probands with autism, we have identified a duplication in Xq25 including full gene duplication of OCRL and six flanking genes. Activity of the enzyme gene product in fibroblasts was elevated to over twice the level in control fibroblasts. The boy had no somatic or neurological findings reminiscent of Lowe syndrome. © 2012 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2012; 158A(10):2602-5. · 2.30 Impact Factor

Publication Stats

20k Citations
3,378.86 Total Impact Points

Institutions

  • 1977–2014
    • Baylor College of Medicine
      • • Department of Molecular & Human Genetics
      • • Department of Pediatrics
      Houston, Texas, United States
  • 2013
    • University of Warsaw
      Warszawa, Masovian Voivodeship, Poland
    • Telethon Institute of Genetics and Medicine
      Napoli, Campania, Italy
  • 2011
    • Rady Children's Hospital
      San Diego, California, United States
  • 1986–2010
    • Howard Hughes Medical Institute
      Maryland, United States
  • 2008
    • Government of Manitoba, Canada
      Winnipeg, Manitoba, Canada
    • Guy's and St Thomas' NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2003–2005
    • University of California, Davis
      • Department of Dermatology
      Davis, CA, United States
  • 2001
    • Southwest Foundation For Biomedical Research
      San Antonio, Texas, United States
  • 1996–1999
    • Harvard University
      • Department of Environmental Health
      Boston, MA, United States
  • 1998
    • University of Chicago
      • Department of Human Genetics
      Chicago, IL, United States
  • 1997
    • National Human Genome Research Institute
      Maryland, United States
  • 1996–1997
    • Indiana University-Purdue University Indianapolis
      • Herman B Wells Center for Pediatric Research
      Indianapolis, IN, United States
  • 1995
    • University of Texas MD Anderson Cancer Center
      • Department of Biochemistry and Molecular Biology
      Houston, TX, United States
  • 1993
    • University of Minnesota Twin Cities
      • Department of Laboratory Medicine and Pathology
      Minneapolis, MN, United States
  • 1991
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem District, Israel
  • 1984
    • Taipei Veterans General Hospital
      T’ai-pei, Taipei, Taiwan
  • 1978
    • Houston Zoo
      Houston, Texas, United States