Publications
68 results found
Shashi V, McConkie-Rosell A, Rosell B, et al., 2014, The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders., Genet Med, Vol: 16, Pages: 176-182
PURPOSE: The purpose of this study was to assess the diagnostic yield of the traditional, comprehensive clinical evaluation and targeted genetic testing, within a general genetics clinic. These data are critically needed to develop clinically and economically grounded diagnostic algorithms that consider presenting phenotype, traditional genetics testing, and the emerging role of next-generation sequencing (whole-exome/genome sequencing). METHODS: We retrospectively analyzed a cohort of 500 unselected consecutive patients who received traditional genetic diagnostic evaluations at a tertiary medical center. We calculated the diagnosis rate, number of visits to diagnosis, genetic tests, and the cost of testing. RESULTS: Thirty-nine patients were determined to not have a genetic disorder; 212 of the remaining 461 (46%) received a genetic diagnosis, and 72% of these were diagnosed on the first visit. The cost per subsequent successful genetic diagnosis was estimated at $25,000. CONCLUSION: Almost half of the patients were diagnosed using the traditional approach, most at the initial visit. For those remaining undiagnosed, next-generation sequencing may be clinically and economically beneficial. Estimating a 50% success rate for next-generation sequencing in undiagnosed genetic disorders, its application after the first clinical visit could result in a higher rate of genetic diagnosis at a considerable cost savings per successful diagnosis.
Smith PJ, Need AC, Cirulli ET, et al., 2013, A comparison of the Cambridge Automated Neuropsychological Test Battery (CANTAB) with "traditional" neuropsychological testing instruments, JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY, Vol: 35, Pages: 319-328, ISSN: 1380-3395
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- Citations: 91
Zhu M, Need AC, Han Y, et al., 2012, Using ERDS to Infer Copy-Number Variants in High-Coverage Genomes, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 91, Pages: 408-421, ISSN: 0002-9297
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- Citations: 98
Need AC, McEvoy JP, Gennarelli M, et al., 2012, Exome Sequencing Followed by Large-Scale Genotyping Suggests a Limited Role for Moderately Rare Risk Factors of Strong Effect in Schizophrenia, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 91, Pages: 303-312, ISSN: 0002-9297
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- Citations: 63
Heinzen EL, Depondt C, Cavalleri GL, et al., 2012, Exome Sequencing Followed by Large-Scale Genotyping Fails to Identify Single Rare Variants of Large Effect in Idiopathic Generalized Epilepsy, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 91, Pages: 293-302, ISSN: 0002-9297
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- Citations: 78
Need AC, Shashi V, Hitomi Y, et al., 2012, Clinical application of exome sequencing in undiagnosed genetic conditions, Journal of Medical Genetics, Vol: 49, Pages: 353-361, ISSN: 1468-6244
BACKGROUND: There is considerable interest in the use of next-generation sequencing to help diagnose unidentified genetic conditions, but it is difficult to predict the success rate in a clinical setting that includes patients with a broad range of phenotypic presentations. METHODS: The authors present a pilot programme of whole-exome sequencing on 12 patients with unexplained and apparent genetic conditions, along with their unaffected parents. Unlike many previous studies, the authors did not seek patients with similar phenotypes, but rather enrolled any undiagnosed proband with an apparent genetic condition when predetermined criteria were met. RESULTS: This undertaking resulted in a likely genetic diagnosis in 6 of the 12 probands, including the identification of apparently causal mutations in four genes known to cause Mendelian disease (TCF4, EFTUD2, SCN2A and SMAD4) and one gene related to known Mendelian disease genes (NGLY1). Of particular interest is that at the time of this study, EFTUD2 was not yet known as a Mendelian disease gene but was nominated as a likely cause based on the observation of de novo mutations in two unrelated probands. In a seventh case with multiple disparate clinical features, the authors were able to identify homozygous mutations in EFEMP1 as a likely cause for macular degeneration (though likely not for other features). CONCLUSIONS: This study provides evidence that next-generation sequencing can have high success rates in a clinical setting, but also highlights key challenges. It further suggests that the presentation of known Mendelian conditions may be considerably broader than currently recognised.
Pelak K, Need AC, Fellay J, et al., 2011, Copy Number Variation of KIR Genes Influences HIV-1 Control, PLOS BIOLOGY, Vol: 9, ISSN: 1544-9173
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- Citations: 120
Dennis NA, Cabeza R, Need AC, et al., 2011, Brain-Derived Neurotrophic Factor Val66Met Polymorphism and Hippocampal Activation During Episodic Encoding and Retrieval Tasks, HIPPOCAMPUS, Vol: 21, Pages: 980-989, ISSN: 1050-9631
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- Citations: 36
Ge D, Ruzzo EK, Shianna KV, et al., 2011, SVA: software for annotating and visualizing sequenced human genomes, Bioinformatics, Vol: 27, Pages: 1998-2000, ISSN: 1367-4803
SUMMARY: Here we present Sequence Variant Analyzer (SVA), a software tool that assigns a predicted biological function to variants identified in next-generation sequencing studies and provides a browser to visualize the variants in their genomic contexts. SVA also provides for flexible interaction with software implementing variant association tests allowing users to consider both the bioinformatic annotation of identified variants and the strength of their associations with studied traits. We illustrate the annotation features of SVA using two simple examples of sequenced genomes that harbor Mendelian mutations. AVAILABILITY AND IMPLEMENTATION: Freely available on the web at http://www.svaproject.org.
Need AC, Goldstein DB, 2010, Whole genome association studies in complex diseases: Where do we stand?, Dialogues in Clinical Neuroscience, Vol: 12, Pages: 34-43, ISSN: 1294-8322
Hundreds of genome-wide association studies have been performed in recent years in order to try to identify common variants that associate with complex disease. These have met with varying success. Some of the strongest effects of common variants have been found in late-onset diseases and in drug response. The major histo-compatibility complex has also shown very strong association with a variety of disorders. Although there have been some notable success stories in neuropsychiatric genetics, on the whole, common variation has explained little of the high heritability of these traits. In contrast, early studies of rare copy number variants have led rapidly to a number of genes and loci that strongly associate with neuropsychiatric disorders. It is likely that the use of whole-genome sequencing to extend the study of rare variation in neuropsychiatry will greatly advance our understanding of neuropsychiatric genetics. © 2010, LLS SAS. All rights reserved.
Pelak K, Shianna KV, Ge D, et al., 2010, The Characterization of Twenty Sequenced Human Genomes, PLOS Genetics, Vol: 6, ISSN: 1553-7390
We present the analysis of twenty human genomes to evaluate the prospects for identifying rare functional variants that contribute to a phenotype of interest. We sequenced at high coverage ten "case" genomes from individuals with severe hemophilia A and ten "control" genomes. We summarize the number of genetic variants emerging from a study of this magnitude, and provide a proof of concept for the identification of rare and highly-penetrant functional variants by confirming that the cause of hemophilia A is easily recognizable in this data set. We also show that the number of novel single nucleotide variants (SNVs) discovered per genome seems to stabilize at about 144,000 new variants per genome, after the first 15 individuals have been sequenced. Finally, we find that, on average, each genome carries 165 homozygous protein-truncating or stop loss variants in genes representing a diverse set of pathways.
Cirulli ET, Kasperaviit D, Attix DK, et al., 2010, Erratum: Common genetic variation and performance on standardized cognitive tests (European Journal of Human Genetics (2010) 18 (820) DOI: 10.1038/ejhg.2010.2), European Journal of Human Genetics, Vol: 18, ISSN: 1018-4813
Cirulli ET, Kasperaviciute D, Attix DK, et al., 2010, Common genetic variation and performance on standardized cognitive tests, EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 18, Pages: 815-819, ISSN: 1018-4813
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- Citations: 76
Dennis NA, Browndyke JN, Stokes J, et al., 2010, Temporal lobe functional activity and connectivity in young adult <i>APOE</i> ε4 carriers, ALZHEIMERS & DEMENTIA, Vol: 6, Pages: 303-311, ISSN: 1552-5260
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- Citations: 152
Heinzen EL, Radtke RA, Urban TJ, et al., 2010, Rare Deletions at 16p13.11 Predispose to a Diverse Spectrum of Sporadic Epilepsy Syndromes, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 86, Pages: 707-718, ISSN: 0002-9297
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- Citations: 201
Need AC, Goldstein DB, 2010, Whole genome association studies in complex diseases: where do we stand?, Dialogues in Clinical Neuroscience, Vol: 12, Pages: 37-46, ISSN: 1958-5969
Hundreds of genome-wide association studies have been performed in recent years in order to try to identify common variants that associate with complex disease. These have met with varying success. Some of the strongest effects of common variants have been found in late-onset diseases and in drug response. The major histocompatibility complex has also shown very strong association with a variety of disorders. Although there have been some notable success stories in neuropsychiatric genetics, on the whole, common variation has explained little of the high heritability of these traits. In contrast, early studies of rare copy number variants have led rapidly to a number of genes and loci that strongly associate with neuropsychiatric disorders. It is likely that the use of whole-genome sequencing to extend the study of rare variation in neuropsychiatry will greatly advance our understanding of neuropsychiatric genetics.
Dennis NA, Need AC, LaBar KS, et al., 2010, <i>COMT</i> Val<SUP>108/158</SUP> Met Genotype Affects Neural but not Cognitive Processing in Healthy Individuals, CEREBRAL CORTEX, Vol: 20, Pages: 672-683, ISSN: 1047-3211
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- Citations: 47
Heinzen EL, Need AC, Hayden KM, et al., 2010, Genome-Wide Scan of Copy Number Variation in Late-Onset Alzheimer's Disease, JOURNAL OF ALZHEIMERS DISEASE, Vol: 19, Pages: 69-77, ISSN: 1387-2877
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- Citations: 99
Need AC, Attix DK, McEvoy JM, et al., 2009, A genome-wide study of common SNPs and CNVs in cognitive performance in the CANTAB, HUMAN MOLECULAR GENETICS, Vol: 18, Pages: 4650-4661, ISSN: 0964-6906
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- Citations: 107
Need AC, Goldstein DB, 2009, Next generation disparities in human genomics: concerns and remedies, TRENDS IN GENETICS, Vol: 25, Pages: 489-494, ISSN: 0168-9525
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- Citations: 249
Stefansson H, Ophoff RA, Steinberg S, et al., 2009, Common variants conferring risk of schizophrenia, NATURE, Vol: 460, Pages: 744-U99, ISSN: 0028-0836
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- Citations: 1262
Need AC, Keefe RSE, Ge D, et al., 2009, Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis, EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 17, Pages: 946-957, ISSN: 1018-4813
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- Citations: 83
Pillai SG, Ge D, Zhu G, et al., 2009, A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci, PLOS Genetics, Vol: 5, ISSN: 1553-7390
There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of alpha(1)-antitrypsin, which is present in 1-2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the alpha-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48 x 10(-10), (rs8034191) and 5.74 x 10(-10) (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in thi
Need AC, Ge D, Weale ME, et al., 2009, A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia, PLOS GENETICS, Vol: 5, ISSN: 1553-7404
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- Citations: 345
Need AC, Kasperaviciute D, Cirulli ET, et al., 2009, A genome-wide genetic signature of Jewish ancestry perfectly separates individuals with and without full Jewish ancestry in a large random sample of European Americans, GENOME BIOLOGY, Vol: 10, ISSN: 1474-760X
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- Citations: 46
Stefansson H, Rujescu D, Cichon S, et al., 2008, Large recurrent microdeletions associated with schizophrenia, NATURE, Vol: 455, Pages: 232-U61, ISSN: 0028-0836
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- Citations: 1335
Need AC, Attix DK, McEvoy JM, et al., 2008, Failure to replicate effect of Kibra on human memory in two large cohorts of European origin, AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, Vol: 147B, Pages: 667-668, ISSN: 1552-4841
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- Citations: 58
Price AL, Weale ME, Patterson N, et al., 2008, Long-range LD can confound genome scans in admixed populations, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 83, Pages: 132-135, ISSN: 0002-9297
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- Citations: 240
Ge D, Zhang K, Need AC, et al., 2008, WGAViewer: Software for genomic annotation of whole genome association studies, GENOME RESEARCH, Vol: 18, Pages: 640-643, ISSN: 1088-9051
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- Citations: 137
Eickholt BJ, Ahmed AI, Davies M, et al., 2007, Control of Axonal Growth and Regeneration of Sensory Neurons by the p110δ PI 3-Kinase, PLOS One, Vol: 2, ISSN: 1932-6203
The expression and function of the 8 distinct catalytic isoforms of PI 3-kinase (PI3K) in the nervous system are unknown. Whereas most PI3Ks have a broad tissue distribution, the tyrosine kinase-linked p110δ isoform has previously been shown to be enriched in leukocytes. Here we report that p110δ is also highly expressed in the nervous system. Inactivation of p110δ in mice did not affect gross neuronal development but led to an increased vulnerability of dorsal root ganglia neurons to exhibit growth cone collapse and decreases in axonal extension. Loss of p110δ activity also dampened axonal regeneration following peripheral nerve injury in adult mice and impaired functional recovery of locomotion. p110δ inactivation resulted in reduced neuronal signaling through the Akt protein kinase, and increased activity of the small GTPase RhoA. Pharmacological inhibition of ROCK, a downstream effector of RhoA, restored axonal extension defects in neurons with inactive p110δ, suggesting a key role of RhoA in p110δ signaling in neurons. Our data identify p110δ as an important signaling component for efficient axonal elongation in the developing and regenerating nervous system.
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