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1.  DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies 
European Journal of Human Genetics  2015;23(11):1473-1481.
Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from −2 SD to −5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broad-based gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype–phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.
PMCID: PMC4613469  PMID: 25944381
2.  The next generation of cancer management 
Cancer Biology & Medicine  2016;13(1):1-2.
PMCID: PMC4850118  PMID: 27144057
Next-generation sequencing; tumor sequencing; targeted sequencing; incidental findings; variants of uncertain significance
3.  Instability of a dinucleotide repeat in the 3′-untranslated region (UTR) of the microsomal prostaglandin E synthase-1 (mPGES-1) gene in microsatellite instability-high (MSI-H) colorectal carcinoma 
Molecular oncology  2015;9(7):1252-1258.
DNA mismatch-repair gene mutations, with consequent loss of functional protein expression, result in microsatellite instability (MSI). Microsatellite sequences are found in coding regions and in regulatory regions of genes (i.e., 5′-UTRs and 3′-UTRs). In addition to being a surrogate marker of defective mismatch repair, deletion or insertion microsatellite sequences can dysregulate gene expression in MSI-H (microsatellite instability-high) tumors. The microsomal prostaglandin E synthase-1 (mPGES-1) gene product, mPGES-1, participates in prostaglandin E2 (PGE2) production. Moreover, mPGES-1 is often overexpressed in human colorectal tumors, and is thought to contribute to progression of these tumors. Here we identified a dinucleotide repeat, (GT)24, in the mPGES-1 gene 3′ untranslated region (3′-UTR), and analyzed its mutation frequencies in MSI-H and microsatellite stable (MSS) tumors. The (GT)24 repeat exhibited instability in all MSI-H tumors examined (14), but not in any of the MSS tumors (13). In most cases, (GT)24 repeat instability resulted in insertion of additional GT units. We also determined mPGES-1 mRNA levels in MSI-H and MSS colorectal cancer cell lines. Three of four previously designated “MSI-H” cell lines showed higher mPGES-1 mRNA levels compared to MSS cell lines; correlations between elevated mPGES-1 mRNA levels and microsatellite (GT)24 repeat characteristics are present for all six cell lines. Our results demonstrate that mPGES-1 is a target gene of defective mismatch repair in human colorectal cancer, with functional consequence.
PMCID: PMC4523444  PMID: 25817443
mPGES-1; dinucleotide repeat; microsatellite instability; colorectal cancer
4.  The M694V Mutation in Armenian-Americans: A Ten-Year Retrospective Study of MEFV Mutation Testing for Familial Mediterranean Fever at UCLA 
Clinical genetics  2012;84(1):55-59.
Familial Mediterranean Fever (FMF), inherited in an autosomal recessive manner, is a systemic auto-inflammatory disorder characterized by recurrent attacks of fever with peritonitis, pleuritis, synovitis and erysipeloid rash. The marenostrin-encoding fever gene (MEFV), located on chromosome 16p13.3, is the only gene in which mutations are currently known to cause FMF. To correlate specific genotypes with adverse phenotypes of affected populations residing in the Western United States, a retrospective case series review was conducted of all MEFV gene mutation testing completed at UCLA Clinical Molecular Diagnostic Laboratory between February 2002 and February 2012, followed by clinical chart review of all subjects who either have a single or double mutation. All 12 common mutations in the MEFV gene were analyzed and the M694V variant was found to be associated with an adverse FMF clinical outcome in the Armenian-American population, manifested by earlier onset of disease, increased severity of disease, and renal amyloidosis.
PMCID: PMC3570680  PMID: 23038988
5.  Current Landscape and New Paradigms of Proficiency Testing and External Quality Assessment for Molecular Genetics 
Participation in proficiency testing (PT) or external quality assessment (EQA) programs allows the assessment and comparison of test performance among different clinical laboratories and technologies. In addition to the approximately 2300 tests for individual genetic disorders, recent advances in technology have enabled the development of clinical tests which quickly and economically analyze the entire human genome. New PT/EQA approaches are needed to ensure the continued quality of these complex tests.
To review the availability and scope of PT/EQA for molecular genetic testing for inherited conditions in Europe, Australasia and the United States; to evaluate the successes and demonstrated value of available PT/EQA programs; and to examine the challenges to the provision of comprehensive PT/EQA posed by new laboratory practices and methodologies.
Data Sources
The available literature on this topic was reviewed and supplemented with personal experiences of several PT/EQA providers.
PT/EQA schemes are available for common genetic disorders tested in many clinical laboratories, but are not available for most genetic tests offered by only one or a few laboratories. Provision of broad, method-based PT schemes, such as DNA sequencing, would allow assessment of a large number of tests for which formal PT is not currently available. Participation in PT/EQA improves the quality of testing by identifying inaccuracies that laboratories can trace to errors in the testing process. Areas of research and development to ensure that PT/EQA programs can meet the needs of new and evolving genetic tests and technologies are identified and discussed.
PMCID: PMC4684176  PMID: 23808472
6.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology 
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.
PMCID: PMC4544753  PMID: 25741868
clinical genetic testing; ACMG laboratory guideline; sequence variation; variant terminology; interpretation; reporting
7.  Exome Sequencing in the Clinical Diagnosis of Sporadic or Familial Cerebellar Ataxia 
JAMA neurology  2014;71(10):1237-1246.
Cerebellar ataxias are a diverse collection of neurologic disorders with causes ranging from common acquired etiologies to rare genetic conditions. Numerous genetic disorders have been associated with chronic progressive ataxia and this consequently presents a diagnostic challenge for the clinician regarding how to approach and prioritize genetic testing in patients with such clinically heterogeneous phenotypes. Additionally, while the value of genetic testing in early-onset and/or familial cases seems clear, many patients with ataxia present sporadically with adult onset of symptoms and the contribution of genetic variation to the phenotype of these patients has not yet been established.
To investigate the contribution of genetic disease in a population of patients with predominantly adult- and sporadic-onset cerebellar ataxia.
We examined a consecutive series of 76 patients presenting to a tertiary referral center for evaluation of chronic progressive cerebellar ataxia.
Next-generation exome sequencing coupled with comprehensive bioinformatic analysis, phenotypic analysis, and clinical correlation.
We identified clinically relevant genetic information in more than 60% of patients studied (n = 46), including diagnostic pathogenic gene variants in 21% (n = 16), a notable yield given the diverse genetics and clinical heterogeneity of the cerebellar ataxias.
This study demonstrated that clinical exome sequencing in patients with adult-onset and sporadic presentations of ataxia is a high-yield test, providing a definitive diagnosis in more than one-fifth of patients and suggesting a potential diagnosis in more than one-third to guide additional phenotyping and diagnostic evaluation. Therefore, clinical exome sequencing is an appropriate consideration in the routine genetic evaluation of all patients presenting with chronic progressive cerebellar ataxia.
PMCID: PMC4324730  PMID: 25133958
8.  Assessing the necessity of confirmatory testing for exome sequencing results in a clinical molecular diagnostic laboratory 
Sanger sequencing is currently considered the gold standard methodology for clinical molecular diagnostic testing. However, next generation sequencing (NGS) has already emerged as a much more efficient means to identify genetic variants within gene panels, the exome, or the genome. We sought to assess the accuracy of NGS variant identification in our clinical genomics laboratory with the goal of establishing a quality score threshold for confirmatory Sanger-based testing.
Confirmation data for reported results from 144 sequential clinical exome sequencing cases (94 unique variants) and an additional set of 16 variants from comparable research samples were analyzed.
103 of 110 total SNVs analyzed had a quality score ≥Q500, 103 (100%) of which were confirmed by Sanger sequencing. Of the remaining 7 variants with quality scores
For single nucleotide variants, we predict we will be able to reduce our Sanger confirmation workload going forward by 70–80%. This serves as a proof of principle that as long as sufficient validation and quality control measures are implemented, the volume of Sanger confirmation can be reduced, alleviating a significant amount of the labor and cost burden on clinical laboratories wishing to utilize NGS technology. However, Sanger confirmation of low quality single nucleotide variants and all indels (insertions or deletions less than 10 bp) remains necessary at this time in our laboratory.
PMCID: PMC4079763  PMID: 24406459
JAMA  2014;312(18):1880-1887.
Clinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders.
To report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types.
Design, Setting, and Participants
Clinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available.
Main outcomes and Measures
Clinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES.
Of the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value = .002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants.
Conclusions and Relevance
In this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted.
PMCID: PMC4278636  PMID: 25326637
The urea cycle exists for the removal of excess nitrogen from the body. Six separate enzymes comprise the urea cycle, and a deficiency in any one of them causes a urea cycle disorder (UCD) in humans. Arginase is the only urea cycle enzyme with an alternate isoform, though no known human disorder currently exists due to a deficiency in the second isoform. While all of the UCDs usually present with hyperammonemia in the first few days to months of life, most disorders are distinguished by a characteristic profile of plasma amino acid alterations that can be utilized for diagnosis. While enzyme assay is possible, an analysis of the underlying mutation is preferable for an accurate diagnosis. Mouse models for each of the urea cycle disorders exist (with the exception of NAGS deficiency), and for almost all of them, their clinical and biochemical phenotypes rather closely resemble the phenotypes seen in human patients. Consequently, all of the current mouse models are highly useful for future research into novel pharmacological and dietary treatments and gene therapy protocols for the management of urea cycle disorders.
PMCID: PMC2692509  PMID: 17933574
urea; hyperammonemia; knockout; N-acetylglutamate synthase; carbamyl phosphate synthetase I; ornithine transcarbamylase; argininosuccinate synthetase; argininosuccinate lyase; arginase
Molecular genetics and metabolism  2013;110(3):222-230.
Human arginase deficiency is characterized by hyperargininemia and infrequent episodes of hyperammonemia, which lead to neurological impairment with spasticity, loss of ambulation, seizures, and severe mental and growth retardation; uncommonly, patients suffer early death from this disorder. In a murine targeted knockout model, onset of the phenotypic abnormality is heralded by weight loss at around day 15, and death occurs typically by postnatal day 17 with hyperargininemia and markedly elevated ammonia. This discrepancy between the more attenuated juvenile-onset human disease and the lethal neonatal murine model has remained suboptimal for studying and developing therapy for the more common presentation of argianse deficiency. These investigations aimed to address this issue by creating an adult conditional knockout mouse to determine whether later onset of arginase deficiency also resulted in lethality. Animal survival and ammonia levels, body weight, circulating amino acids, and tissue arginase levels were examined as outcome parameters after widespread Cre-recombinase activation in a conditional knockout model of arginase 1 deficiency. One hundred percent of adult female and 70 percent of adult male mice died an average of 21.0 and 21.6 days, respectively, after the initiation of tamoxifen administration. Animals demonstrated elevated circulating ammonia and arginine at the onset of phenotypic abnormalities. In addition, brain and liver amino acids demonstrated abnormalities. These studies demonstrate that (a) the absence of arginase in adult animals results in a disease profile (leading to death) similar to that of the targeted knockout and (b) the phenotypic abnormalities seen in the juvenile-onset model are not exclusive to the age of the animal but instead to the biochemistry of the disorder. This adult model will be useful for developing gene- and cell-based therapies for this disorder that will not limited by by the small animal size of neonatal therapy and for developing a better understanding of the characteristics of hyperargininemia.
PMCID: PMC3800271  PMID: 23920045
Arginase deficiency; Hyperargininemia; Conditional knockout; Animal model
BMC Medical Genetics  2014;15:49.
Wiedemann-Steiner Syndrome (WSS) is characterized by short stature, a variety of dysmorphic facial and skeletal features, characteristic hypertrichosis cubiti (excessive hair on the elbows), mild-to-moderate developmental delay and intellectual disability. [MIM#: 605130]. Here we report two unrelated children for whom clinical exome sequencing of parent-proband trios was performed at UCLA, resulting in a molecular diagnosis of WSS and atypical clinical presentation.
Case presentation
For patient 1, clinical features at 9 years of age included developmental delay, craniofacial abnormalities, and multiple minor anomalies. Patient 2 presented at 1 year of age with developmental delay, microphthalmia, partial 3–4 left hand syndactyly, and craniofacial abnormalities. A de novo missense c.4342T>C variant and a de novo splice site c.4086+G>A variant were identified in the KMT2A gene in patients 1 and 2, respectively.
Based on the clinical and molecular findings, both patients appear to have novel presentations of WSS. As the hallmark hypertrichosis cubiti was not initially appreciated in either case, this syndrome was not suspected during the clinical evaluation. This report expands the phenotypic spectrum of the clinical phenotypes and KMT2A variants associated with WSS.
PMCID: PMC4072606  PMID: 24886118
Wiedemann-Steiner syndrome; Clinical exome sequencing; KMT2A; Intellectual disability; Developmental delay
Rapid progress in genomics and nanotechnology continue to advance our approach to patient care, from diagnosis and prognosis, to targeting and personalization of therapeutics. However, the clinical application of molecular diagnostics in ophthalmology has been limited even though there have been demonstrations of disease risk and pharmacogenetic associations. There is a high clinical need for therapeutic personalization and dosage optimization in ophthalmology and may be the focus of individualized medicine in this specialty. In several retinal conditions, such as age-related macular degeneration, diabetic macular edema, retinal vein occlusion and pre-threshold retinopathy of prematurity, anti-vascular endothelial growth factor therapeutics have resulted in enhanced outcomes. In glaucoma, recent advances in cytoskeletal agents and prostaglandin molecules that affect outflow and remodel the trabecular meshwork have demonstrated improved intraocular pressure control. Application of recent developments in nanoemulsion and polymeric micelle for targeted delivery and drug release are models of dosage optimization, increasing efficacy and improving outcomes in these major eye diseases.
PMCID: PMC3947950  PMID: 24624293
personalized medicine; pharmacogenetics; clinical utility; ophthalmology; VEGF; age-related macular degeneration; glaucoma; retinopathy; drug delivery; nanotechnology
14.  Pathology 
Western Journal of Medicine  1986;145(3):375-376.
PMCID: PMC1306938  PMID: 18750076
Gene therapy  2013;20(8):785-796.
Complete arginase I deficiency is the least severe urea cycle disorder, characterized by hyperargininemia and infrequent episodes of hyperammonemia. Patients suffer from neurological impairment with cortical and pyramidal tract deterioration, spasticity, loss of ambulation, and seizures, and is associated with intellectual disability. In mice, onset is heralded by weight loss beginning around day 15; gait instability follows progressing to inability to stand and development of tail tremor with seizure-like activity and death. Here we report that hyperargininemic mice treated neonatally with an adeno-associated virus expressing arginase and followed long-term lack any presentation consistent with brain dysfunction. Behavioral and histopathological evaluation demonstrated that treated mice are indistinguishable from littermates and that putative compounds associated with neurotoxicity are diminished. In addition, treatment results in near complete resolution of metabolic abnormalities early in life; however there is the development of some derangement later with decline in transgene expression. Ammonium challenging revealed that treated mice are affected by exogenous loading much greater than littermates. These results demonstrate that AAV-based therapy for hyperargininemia is effective and prevents development of neurological abnormalities and cognitive dysfunction in a mouse model of hyperargininemia; however nitrogen challenging reveals that these mice remain impaired in the handling of waste nitrogen.
PMCID: PMC3679314  PMID: 23388701
Hyperargininemia; AAV; Gene Therapy; Brain
In clinical exome and genome sequencing, there is potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing, which emphasized the importance of disclosing the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exome and Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing. This Working Group conducted a year-long consensus process, including review by outside experts, and produced recommendations that have been approved by the ACMG Board. Specific and detailed recommendations, and the background and rationale for these recommendations, are described herein. We recommend that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the ‘normal’ of tumor-normal subtractive analyses in all subjects, irrespective of age, but excluding fetal samples. We recognize that there are insufficient data on clinical utility to fully support these recommendations and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected.
PMCID: PMC3727274  PMID: 23788249
secondary findings; incidental findings; genome; genomic medicine; personalized medicine; whole-exome; whole-genome; sequencing
To explore specific conditions and types of genetic variants that specialists in genetics recommend should be returned as incidental findings in clinical sequencing.
Sixteen specialists in clinical genetics and/or molecular medicine selected variants in 99 common conditions to return to the ordering physician if discovered incidentally through whole genome sequencing. For most conditions, the specialists independently considered 3 molecular scenarios for both adults and minor children: a known pathogenic mutation, a truncating variant presumed pathogenic (where other truncating variants were known to be pathogenic), or a missense variant predicted in silico to be pathogenic.
On average, for adults and children respectively, each specialist selected 83.5 and 79.0 conditions or genes out of 99 in the known pathogenic mutation categories, 57.0 and 53.5 out of 72 in the truncating variant categories, and 33.4 and 29.7 out of 72 in the missense variant categories. Concordance in favor of disclosure within the adult/known pathogenic mutation category was 100% for 21 conditions or genes and 80% or higher for 64 conditions or genes.
Specialists were highly concordant for the return of findings in 64 conditions or genes if discovered incidentally during whole exome or whole genome sequencing.
PMCID: PMC3763716  PMID: 22422049
whole genome sequencing; incidental findings
In the field of oncology, clinical molecular diagnostics and biomarker discoveries are constantly advancing as the intricate molecular mechanisms that transform a normal cell into an aberrant state in concert with the dysregulation of alternative complementary pathways are increasingly understood. Progress in biomarker technology, coupled with the companion clinical diagnostic laboratory tests, continue to advance this field, where individualized and customized treatment appropriate for each individual patient define the standard of care. Here, we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing: BRAF V600E for vemurafenib in melanoma; EML4–ALK for crizotinib and EGFR for erlotinib and gefitinib in non-small-cell lung cancer; KRAS against the use of cetuximab and panitumumab in colorectal cancer; ERBB2 (HER2/neu) for trastuzumab in breast cancer; BCR–ABL for tyrosine kinase inhibitors in chronic myeloid leukemia; and PML/RARα for all-trans-retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia.
PMCID: PMC3495985  PMID: 22845480
biomarker; cancer; clinical laboratory; clinical utility; molecular diagnostics; oncology; personalized medicine; pharmacogenetic; predictive medicine; testing
Rapid progress in genomics and nanotechnology continue to advance our approach to patient care, from diagnosis and prognosis, to targeting and personalization of therapeutics. However, the clinical application of molecular diagnostics in ophthalmology has been limited even though there have been demonstrations of disease risk and pharmacogenetic associations. There is a high clinical need for therapeutic personalization and dosage optimization in ophthalmology and may be the focus of individualized medicine in this specialty. In several retinal conditions, such as age-related macular degeneration, diabetic macular edema, retinal vein occlusion and pre-threshold retinopathy of prematurity, anti-vascular endothelial growth factor therapeutics have resulted in enhanced outcomes. In glaucoma, recent advances in cytoskeletal agents and prostaglandin molecules that affect outflow and remodel the trabecular meshwork have demonstrated improved intraocular pressure control. Application of recent developments in nanoemulsion and polymeric micelle for targeted delivery and drug release are models of dosage optimization, increasing efficacy and improving outcomes in these major eye diseases.
PMCID: PMC3947950  PMID: 24624293
personalized medicine; pharmacogenetics; clinical utility; ophthalmology; VEGF; age-related macular degeneration; glaucoma; retinopathy; drug delivery; nanotechnology
Pharmacogenomics  2012;13(4):465-475.
In the past decade, significant strides have been made in the area of cardiovascular pharmacogenomic research, with the discovery of associations between certain genotypes and drug-response phenotypes. While the motivations for personalized and predictive medicine are promising for patient care and support a model of health system efficiency, the implementation of pharmacogenomics for cardiovascular therapeutics on a population scale faces substantial challenges. The greatest obstacle to clinical implementation of cardiovascular pharmacogenetics may be the lack of both reproducibility and agreement about the validity and utility of the findings. In this review, we present the scientific evidence in the literature for diagnostic variants for the US FDA-labeled cardiovascular therapies, namely CYP2C19 and clopidogrel, CYP2C9/VKORC1 and warfarin, and CYP2D6/ADRB1 and β-blockers. We also discuss the effect of HMGCR/LDLR in decreasing the effectiveness of low-density lipoprotein cholesterol with statin therapy, the SLCO1B1 genotype and simvastatin myotoxicity, and ADRB1/ADD1 for antihypertensive response.
PMCID: PMC3306231  PMID: 22380001
biomarker; cardiovascular; clinical utility; clopidogrel; drug label; genetics; personalized medicine; pharmacogenetics; predictive medicine; warfarin
Rare Diseases  2013;1:e23579.
In this article we discuss the steps taken by the United States (US) and the European Union (EU) to meet the health care needs of children with rare diseases and suggest possible directions for future endeavors for further improvement. We reviewed 23 reports and nine legislative documents related to pediatric rare diseases and public policy. We assessed the outcome measures of access and satisfaction with medical services by utilizing the surveys done by the European Organization for Rare Diseases -Eurordis (n = 5,963). Comparable surveys were not available in the US. Our analyses of the existing policies and surveys indicate multiple differences between the US and EU. While the US policies seem to be aimed at disease diagnosis and neonatal screening, EU legislators appear to be focusing on access to existing specialized care. However, both systems have struggled with effectively promoting new treatments. Also, while Eurordis surveys have evaluated areas such as the access to medical services, access to social services and satisfaction with the services received in Europe, there are no comparable surveys in the United States. We conclude that better tools are needed to measure the quality of care, needs-assessment and outcome of pediatric rare diseases in both the EU and US. We suggest a better assessment of areas such as access to primary and specialty care, legal advocacy, comfort-care, end-of-life care, social and financial services, psychological support and quality outcome-measures.
PMCID: PMC3932940  PMID: 25002987
pediatric rare diseases; orphan diseases; public policy; special-needs children
PMCID: PMC3130532  PMID: 21707452
privacy; patient privacy; data; data management; sequencing; next-generation sequencing; massively parallel next-generation sequencing; full gene sequencing; microarray; oligonucleotide microarray; consent; patient consent; genetics; genetics research; genetic testing; ethics; discrimination; whole-genome; genomics; human genetics; medical genetics; personalized; diagnostic; molecular pathology; diagnostic molecular pathology; bioinformatics; genes; complex
This article examines the relationship between cultural affiliation and deaf adults’ motivations for genetic testing for deafness in the first prospective, longitudinal study to examine the impact of genetic counseling and genetic testing on deaf adults and the deaf community. Participants (n = 256), classified as affiliating with hearing, Deaf, or both communities, rated interest in testing for 21 reasons covering 5 life domains. Findings suggest strong interest in testing to learn why they are deaf, but little interest in using it for decisions about a partner or having children. Culturally mediated variation was also demonstrated. Deaf and both communities groups viewed testing as useful for more life domains than the hearing community group. Deaf and both communities had similar motivations related to further exploration, understanding, or strengthening of deafness. Motivations related to “hearing” were also relevant for both communities. We conclude that cultural affiliation is an important factor for constructing motivations for genetic testing.
PMCID: PMC2902357  PMID: 20488870

Results 1-25 (31)