22 results on '"Andrea Zanko"'
Search Results
2. Duplication of C7orf58, WNT16 and FAM3C in an obese female with a t(7;22)(q32.1;q11.2) chromosomal translocation and clinical features resembling Coffin-Siris Syndrome.
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Jun Zhu, Jun Qiu, Gregg Magrane, Malak Abedalthagafi, Andrea Zanko, Mahin Golabi, and Farid F Chehab
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Medicine ,Science - Abstract
We characterized the t(7;22)(q32;q11.2) chromosomal translocation in an obese female with coarse features, short stature, developmental delay and a hypoplastic fifth digit. While these clinical features suggest Coffin-Siris Syndrome (CSS), we excluded a CSS diagnosis by exome sequencing based on the absence of deleterious mutations in six chromatin-remodeling genes recently shown to cause CSS. Thus, molecular characterization of her translocation could delineate genes that underlie other syndromes resembling CSS. Comparative genomic hybridization microarrays revealed on chromosome 7 the duplication of a 434,682 bp region that included the tail end of an uncharacterized gene termed C7orf58 (also called CPED1) and spanned the entire WNT16 and FAM3C genes. Because the translocation breakpoint on chromosome 22 did not disrupt any apparent gene, her disorder was deemed to result from the rearrangement on chromosome 7. Mapping of yeast and bacterial artificial chromosome clones by fluorescent in situ hybridization on chromosome spreads from this patient showed that the duplicated region and all three genes within it were located on both derivative chromosomes 7 and 22. Furthermore, DNA sequencing of exons and splice junctional regions from C7orf58, WNT16 and FAM3C revealed the presence of potential splice site and promoter mutations, thereby augmenting the detrimental effect of the duplicated genes. Hence, dysregulation and/or disruptions of C7orf58, WNT16 and FAM3C underlie the phenotype of this patient, serve as candidate genes for other individuals with similar clinical features and could provide insights into the physiological role of the novel gene C7orf58.
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- 2012
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3. Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas
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Christine Kobelka, Andrzej Poplawski, Alicia Gomes, David K. Crossman, Judith A. Westman, Michael R. Crowley, Jing Xie, Dusica Babovic-Vuksanovic, Stephanie Hurst, Pim Suwannarat, Bruce R. Korf, Molly S. Daniels, Andrea L Blumenthal, Chuanhua Fu, Piotr Madanecki, Ludwine Messiaen, Amanda L. Bergner, Rebecca Nagy, Linlea Armstrong, Katherine A. Rauen, Ying F Liu, Arkadiusz Piotrowski, Andrea Zanko, Jaishri O. Blakeley, Kathy Gardner, John M. Slopis, Howard Feit, and Chung Lee
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Models, Molecular ,Neurofibromatosis 2 ,DNA, Complementary ,Chromosomal Proteins, Non-Histone ,Protein Conformation ,Chromosomes, Human, Pair 22 ,Molecular Sequence Data ,Loss of Heterozygosity ,Biology ,medicine.disease_cause ,Article ,Germline ,Loss of heterozygosity ,Germline mutation ,otorhinolaryngologic diseases ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,SMARCB1 ,Allele ,Schwannomatosis ,Germ-Line Mutation ,Loss function ,Genes, Dominant ,Mutation ,Base Sequence ,SMARCB1 Protein ,Sequence Analysis, DNA ,medicine.disease ,Pedigree ,DNA-Binding Proteins ,Gene Components ,Cancer research ,Neurilemmoma ,Microsatellite Repeats ,Transcription Factors - Abstract
Constitutional SMARCB1 mutations at 22q11.23 have been found in ~50% of familial and
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- 2013
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4. TAA repeat variation in the GRIK2 gene does not influence age at onset in Huntington’s disease
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Tammy Gillis, Tiffany C. Hadzi, Ruth K. Abramson, Andrea Novelletto, Eliana Marisa Ramos, Ira Shoulson, Marcy E. MacDonald, Ronald J. Trent, Ferdinando Squitieri, Madaline B. Harrison, Russell L. Margolis, James F. Gusella, Estrella Gómez-Tortosa, Ji Hyun Lee, Steven M. Hersch, Patrick J. Morrison, Karen Marder, Carmen Ayuso, Shotaro Kishikawa, H. D. Rosas, Oksana Suchowersky, Elizabeth McCusker, Randi Jones, Audrey E. Hendricks, Andrea Zanko, Diane Lucente, Jayalakshmi S. Mysore, G. Bernhard Landwehrmeyer, Christopher A. Ross, Samuel Frank, Cinzia Gellera, Martha Nance, Jong-Min Lee, Marina Frontali, Tetsuo Ashizawa, Marie Saint-Hilaire, Richard H. Myers, Michael R. Hayden, and Jorge Sequeiros
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Adult ,Male ,Adolescent ,Biophysics ,Disease ,Biology ,Biochemistry ,Article ,Young Adult ,Receptors, Kainic Acid ,Genetic ,Trinucleotide Repeats ,Huntington's disease ,Polymorphism (computer science) ,GRIK2 ,Codon, Terminator ,Age of Onset ,Polymorphism, Genetic ,Humans ,Aged ,Child ,Child, Preschool ,Alleles ,Aged, 80 and over ,Middle Aged ,3' Untranslated Regions ,Female ,Huntington Disease ,Receptors ,80 and over ,medicine ,Terminator ,Polymorphism ,Allele ,Young adult ,Codon ,Preschool ,Molecular Biology ,Genetics ,Kainic Acid ,Cell Biology ,medicine.disease ,Settore BIO/18 - Genetica ,biology.protein ,Age of onset ,Trinucleotide repeat expansion - Abstract
Huntington's disease is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat whose length is the major determinant of age at onset but remaining variation appears to be due in part to the effect of genetic modifiers. GRIK2, which encodes GluR6, a mediator of excitatory neurotransmission in the brain, has been suggested in several studies to be a modifier gene based upon a 3′ untranslated region TAA trinucleotide repeat polymorphism. Prior to investing in detailed studies of the functional impact of this polymorphism, we sought to confirm its effect on age at onset in a much larger dataset than in previous investigations. We genotyped the HD CAG repeat and the GRIK2 TAA repeat in DNA samples from 2,911 Huntington's disease subjects with known age at onset, and tested for a potential modifier effect of GRIK2 using a variety of statistical approaches. Unlike previous reports, we detected no evidence of an influence of the GRIK2 TAA repeat polymorphism on age at motor onset. Similarly, the GRIK2 polymorphism did not show significant modifier effect on psychiatric and cognitive age at onset in HD. Comprehensive analytical methods applied to a much larger sample than in previous studies do not support a role for GRIK2 as a genetic modifier of age at onset of clinical symptoms in Huntington's disease.
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- 2012
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5. Population stratification may bias analysis of PGC-1α as a modifier of age at Huntington disease motor onset
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Estrella Gómez-Tortosa, Ferdinando Squitieri, Marie-Helene Saint-Hilaire, Isabel Alonso, Marcy E. MacDonald, James F. Gusella, Samuel Frank, Marina Frontali, H. D. Rosas, Andrea Novelletto, Richard H. Myers, Ji Hyun Lee, Martha Nance, Madaline B. Harrison, Russell L. Margolis, Stefano Di Donato, Jong-Min Lee, Elizabeth McCusker, Karen Marder, Steven M. Hersch, Oksana Suchowersky, Randi Jones, Jeanne C. Latourelle, Diane Lucente, Jayalakshmi S. Mysore, Ronald J. Trent, Eliana Marisa Ramos, Tetsuo Ashizawa, Patrick J. Morrison, Tammy Gillis, Carmen Ayuso, Andrea Zanko, Christopher A. Ross, Michael R. Hayden, Jorge Sequeiros, and Alba Di Pardo
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Adult ,Male ,Population ,Nerve Tissue Proteins ,Biology ,Population stratification ,Polymorphism, Single Nucleotide ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Genotype ,Genetics ,Humans ,Genetics(clinical) ,Allele ,Age of Onset ,education ,Genetics (clinical) ,Heat-Shock Proteins ,030304 developmental biology ,Genetic association ,Original Investigation ,0303 health sciences ,education.field_of_study ,Huntingtin Protein ,Middle Aged ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,Minor allele frequency ,Europe ,Settore BIO/18 - Genetica ,Genetics, Population ,Huntington Disease ,Female ,Age of onset ,Trinucleotide repeat expansion ,Trinucleotide Repeat Expansion ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by motor, cognitive and behavioral disturbances, caused by the expansion of a CAG trinucleotide repeat in the HD gene. The CAG allele size is the major determinant of age at onset (AO) of motor symptoms, although the remaining variance in AO is highly heritable. The rs7665116 SNP in PPARGC1A, encoding the mitochondrial regulator PGC-1α, has been reported to be a significant modifier of AO in three European HD cohorts, perhaps due to affected cases from Italy. We attempted to replicate these findings in a large collection of (1,727) HD patient DNA samples of European origin. In the entire cohort, rs7665116 showed a significant effect in the dominant model (p value = 0.008) and the additive model (p value = 0.009). However, when examined by origin, cases of Southern European origin had an increased rs7665116 minor allele frequency (MAF), consistent with this being an ancestry-tagging SNP. The Southern European cases, despite similar mean CAG allele size, had a significantly older mean AO (p
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- 2012
6. Common SNP-Based Haplotype Analysis of the 4p16.3 Huntington Disease Gene Region
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H. D. Rosas, Marie Saint-Hilaire, Richard H. Myers, Carmen Ayuso, James F. Gusella, Madaline B. Harrison, Stefano Di Donato, Diane Lucente, Samuel Frank, Marina Frontali, Andrea Zanko, Karen Marder, Oksana Suchowersky, Ruth K. Abramson, Ronald J. Trent, Ferdinando Squitieri, Martha Nance, Eliana Marisa Ramos, Estrella Gómez-Tortosa, Jong-Min Lee, Jayalakshmi S. Mysore, Marcy E. MacDonald, Tetsuo Ashizawa, Steven M. Hersch, Andrea Novelletto, Elizabeth McCusker, Christopher A. Ross, Randi Jones, Annamaria Griguoli, Russell L. Margolis, Michael R. Hayden, Jorge Sequeiros, Tammy Gillis, and Patrick J. Morrison
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Population ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,0302 clinical medicine ,Trinucleotide Repeats ,Genetic variation ,Genetics ,Humans ,Genetics(clinical) ,Age of Onset ,Allele ,education ,Alleles ,Genetics (clinical) ,030304 developmental biology ,Genetic association ,0303 health sciences ,education.field_of_study ,Haplotype ,Founder Effect ,Settore BIO/18 - Genetica ,Huntington Disease ,Haplotypes ,Case-Control Studies ,Mutation ,Chromosomes, Human, Pair 4 ,Trinucleotide repeat expansion ,030217 neurology & neurosurgery ,Genome-Wide Association Study ,Founder effect - Abstract
Age at the onset of motor symptoms in Huntington disease (HD) is determined largely by the length of a CAG repeat expansion in HTT but is also influenced by other genetic factors. We tested whether common genetic variation near the mutation site is associated with differences in the distribution of expanded CAG alleles or age at the onset of motor symptoms. To define disease-associated single-nucleotide polymorphisms (SNPs), we compared 4p16.3 SNPs in HD subjects with population controls in a case:control strategy, which revealed that the strongest signals occurred at a great distance from the HD mutation as a result of “synthetic association” with SNP alleles that are of low frequency in population controls. Detailed analysis delineated a prominent ancestral haplotype that accounted for ∼50% of HD chromosomes and extended to at least 938 kb on about half of these. Together, the seven most abundant haplotypes accounted for ∼83% of HD chromosomes. Neither the extended shared haplotype nor the individual local HTT haplotypes were associated with altered CAG-repeat length distribution or residual age at the onset of motor symptoms, arguing against modification of these disease features by common cis-regulatory elements. Similarly, the 11 most frequent control haplotypes showed no trans-modifier effect on age at the onset of motor symptoms. Our results argue against common local regulatory variation as a factor influencing HD pathogenesis, suggesting that genetic modifiers be sought elsewhere in the genome. They also indicate that genome-wide association analysis with a small number of cases can be effective for regional localization of genetic defects, even when a founder effect accounts for only a fraction of the disorder.
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- 2012
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7. Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease
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Colin J. D. Ross, Estrella Gómez-Tortosa, L. A. Cupples, Qiong Yang, Catherine Dodé, Martha Nance, Ronald J. Trent, Ruth K. Abramson, Elizabeth McCusker, Luc Djoussé, D. Mayo, Marina Frontali, Patrick J. Morrison, Jane S. Paulsen, Randi Jones, Russell L. Margolis, Ryan R. Brinkman, Madeline Harrison, J. F. Gusella, Andrea Zanko, Oksana Suchowersky, Adam Rosenblatt, Alexandra Durr, Richard H. Myers, Andrea Novelletto, E. Almqvist, Beth Knowlton, Marcy E. MacDonald, and Michael R. Hayden
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Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Biology ,Heritability ,medicine.disease ,Central nervous system disease ,Degenerative disease ,Endocrinology ,Internal medicine ,Cohort ,medicine ,Allele ,Age of onset ,Trinucleotide repeat expansion ,Genetics (clinical) ,Cohort study - Abstract
Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P = 0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.
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- 2003
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8. In Memoriam: Dr. Charles Epstein (1993–2011)
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Judy Derstine, Andrea Zanko, Beth Crawford, and Vicki Cox
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medicine.medical_specialty ,Family medicine ,Public health ,Genetic counseling ,medicine ,Psychology ,Genetics (clinical) ,Human genetics - Published
- 2011
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9. Case report: concurrent Wilson disease and Huntington disease: lightning can strike twice
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Andrea Zanko and Liane Abrams
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Adult ,Male ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Genetic counseling ,Physical examination ,Disease ,Human genetics ,Huntington Disease ,Hepatolenticular Degeneration ,Medicine ,Medical genetics ,Humans ,Differential diagnosis ,Medical diagnosis ,business ,Psychiatry ,Psychosocial ,Genetics (clinical) - Abstract
Differential diagnosis in clinical genetics often involves an exercise in logical deductive reasoning with a sequential approach in pursuit of an etiology. In the medical genetics field, the differential diagnosis is guided by a combination of pedigree analysis, medical and developmental histories, and physical examination, imaging studies, cytogenetics, molecular genetics/next generation sequencing and a myriad of metabolic and hematologic studies. However, even with all these testing options, there is still value in the art of gestalt – that observation of the whole – when considering a diagnosis. We know that the thunder of hooves is likely to be the horse rather than the zebra. But what if the two are grazing side by side? We present a patient with physical, cognitive and psychiatric symptoms, all of which are evident in both Wilson and Huntington diseases. In addition to the complexities of having co-morbid diagnoses, this case illustrates the psychosocial consequences of having two conditions with discordant natures; one being autosomal recessive and treatable, the other being autosomal dominant and not treatable. Lastly, this case illustrates the importance of timely genetic counseling in the face of a difficult diagnostic picture and complex family dynamics. Case History
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- 2014
10. Psychological impact of news of genetic risk for Huntington disease
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Andrea Zanko, Charles J. Epstein, Frank M. Longo, Edward F. Donnelly, Mardi J. Horowitz, and Nigel P. Field
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medicine.medical_specialty ,Longitudinal study ,medicine.diagnostic_test ,business.industry ,Disease ,medicine.disease ,Numero sign ,Central nervous system disease ,Degenerative disease ,Internal medicine ,Medicine ,Psychological testing ,Risk factor ,business ,Genetics (clinical) ,Genetic testing - Abstract
A one-year longitudinal study was conducted investigating the psychological effects of the news of genetic testing for the Huntington disease (HD) gene. Participants were assessed at baseline (before obtaining news of test results) and at three, six, and 12 months after test results on stress-specific symptom measures. Among carriers of the HD gene, a considerable number (55%) showed evidence of neurological impairment at baseline, indicative of HD. Also noteworthy, these individuals had significantly higher psychological symptom scores at baseline than carriers without neurological impairment or noncarriers. Despite this, these individuals were no more aware of their carrier status at baseline than carriers without HD symptoms or noncarriers. Furthermore, the psychological symptom levels of HD carriers with neurological impairment remained elevated across the follow-up assessments. Results for noncarriers and carriers without HD neurological symptoms were consistent with the findings of previous studies indicating that news of genetic testing for the HD gene had limited detrimental impact. The clinical implications of the results are discussed.
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- 2001
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11. Duplication of C7orf58, WNT16 and FAM3C in an Obese Female with a t(7;22)(q32.1;q11.2) Chromosomal Translocation and Clinical Features Resembling Coffin-Siris Syndrome
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Jun Zhu, Jun Qiu, Mahin Golabi, Farid F. Chehab, Gregg Magrane, Malak Abedalthagafi, and Andrea Zanko
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Genetics ,Multidisciplinary ,Science ,Gene duplication ,medicine ,Correction ,Medicine ,Chromosomal translocation ,Biology ,medicine.disease ,Coffin–Siris syndrome - Published
- 2013
12. Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington's disease motor onset
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Marie Saint-Hilaire, Patrick J. Morrison, Richard H. Myers, James F. Gusella, Diane Lucente, Ronald J. Trent, H. D. Rosas, Andrea Novelletto, Cinzia Gellera, Tammy Gillis, Isabel Alonso, Elizabeth McCusker, Oksana Suchowersky, Jayalakshmi S. Mysore, Marcy E. MacDonald, Michael R. Hayden, Carmen Ayuso, Jeanne C. Latourelle, Estrella Gómez-Tortosa, Tetsuo Ashizawa, Jorge Sequeiros, Steven M. Hersch, Randi Jones, Alba Di Pardo, Russell L. Margolis, Madaline B. Harrison, Stefano Di Donato, Martha Nance, Karen Marder, Andrea Zanko, Christopher A. Ross, Jong-Min Lee, Marina Frontali, Samuel Frank, F Squitieri, Ruth K. Abramson, and Eliana Marisa Ramos
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Genetic modifiers ,Catechol O-Methyltransferase ,Receptors, N-Methyl-D-Aspartate ,Receptors, Dopamine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Huntington's disease ,Dopamine ,mental disorders ,Neural Pathways ,medicine ,Genetics ,Humans ,Genetics(clinical) ,Age of Onset ,Dopamine pathway ,Genetics (clinical) ,Genetic Association Studies ,030304 developmental biology ,0303 health sciences ,Dopamine Plasma Membrane Transport Proteins ,Catechol-O-methyl transferase ,Polymorphism, Genetic ,biology ,Settore BIO/18 ,Receptors, Dopamine D2 ,Dopaminergic ,Receptors, Dopamine D4 ,Glutamate receptors ,medicine.disease ,Variable number tandem repeat ,Huntington Disease ,biology.protein ,GRIN2A ,GRIN2B ,Original Article ,Age of onset ,030217 neurology & neurosurgery ,medicine.drug ,Huntington’s disease - Abstract
Huntington’s disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3′ UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations.
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- 2013
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13. Huntington disease: A case study describing the complexities and nuances of predictive testing of monozygotic twins
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Andrea Zanko and Audrey Heimler
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Adult ,Freedom ,medicine.medical_specialty ,Databases, Factual ,Genetic counseling ,media_common.quotation_subject ,Twins ,Monozygotic twin ,Genetic Counseling ,Disclosure ,medicine ,Humans ,Family ,Confidentiality ,Genetic Testing ,Age of Onset ,Family history ,Predictive testing ,Psychiatry ,Genetics (clinical) ,media_common ,Informed Consent ,Geography ,Communication ,Public health ,United States ,Zygosity ,Huntington Disease ,Personal Autonomy ,Databases, Nucleic Acid ,Psychology ,Stress, Psychological ,Autonomy - Abstract
When a candidate for predictive testing for the Huntington disease gene is a monozygotic twin, confidentiality of the co-twin's diagnosis and autonomy of participation are among the critical genetic counseling issues. Predictive testing can proceed when twins voluntarily and simultaneously request counseling and evaluation in an HD testing program. This case describes a young man referred for predictive testing to an HD testing site on the East Coast of the United States. Family history revealed a twin brother of unknown zygosity who resided on the West Coast of the United States. The genetic counselors on opposite coasts collaborated to provide genetic counseling and evaluation for voluntary, informed predictive testing of the twins, protecting their rights while observing national protocol guidelines.
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- 1995
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14. In memoriam: Dr. Charles Epstein (1933-2011). [corrected]
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Andrea, Zanko, Vicki, Cox, Beth, Crawford, and Charles, Epstein
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Genetic Counseling ,History, 20th Century ,History, 21st Century ,United States - Published
- 2011
15. Interstitial deletions of chromosome 6q: genotype-phenotype correlation utilizing array CGH
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M. Gilats, Ophir D. Klein, F. Conte, Katherine A. Rauen, Mathew W. Moore, Philip D. Cotter, Charles J. Epstein, and Andrea Zanko
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Male ,Adolescent ,Genotype ,Developmental Disabilities ,Aneuploidy ,Biology ,Gene mapping ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Child ,Genetics (clinical) ,Oligonucleotide Array Sequence Analysis ,Breakpoint ,Chromosome ,Karyotype ,medicine.disease ,Phenotype ,Cytogenetic Analysis ,Eye disorder ,Chromosomes, Human, Pair 6 ,Female ,Chromosome Deletion ,Comparative genomic hybridization - Abstract
Interstitial deletions of the long arm of chromosome 6 are relatively rare, with fewer than 100 cases reported. Phenotypic variation is in large part due to differences in size and location of the segmental aneuploidy. We report three new patients with interstitial deletions of chromosome 6q defined at the molecular level by array comparative genomic hybridization (array CGH). In two of three cases, the molecular breakpoints differed from those indicated by conventional karyotyping, demonstrating the enhanced resolution of array CGH. Two patients had minimal deletions of 6 and 8.8 Mb involving 6q16.2-->q21, and the third patient had a deletion of 11.3 Mb spanning 6q15-->q21. All three had developmental delay, craniofacial dysmorphology, and functional eye disorders, suggesting that genes affecting brain and craniofacial development are located in 6q16.2-->q21, the deleted region common to all three patients. Furthermore, gene(s) for discordant phenotypic features, such as central diabetes insipidus, may reside at 6q15, the monosomic region unique to patient 3. All three cases described here showed loss of paternal alleles within the deleted segment, providing further evidence of the predominantly paternal origin for 6q deletions and rearrangements.
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- 2007
16. Genome-wide significance for a modifier of age at neurological onset in Huntington's Disease at 6q23-24: the HD MAPS study
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Carmen Ayuso García, Martha Nance, Andrea Novelletto, Gang Xu, Oksana Suchowersky, Alice Lazzarini, Jang Ho J. Cha, Steven M. Hersch, Russell L. Margolis, Andrea Zanko, Vanessa C. Wheeler, Anthony J. Lechich, P. Michael Conneally, Ruth K. Abramson, Ferdinando Squitieri, Patrick J. Morrison, Ranjana Prakash, Adam Rosenblatt, John B. Penney, Jayalakshmi S. Mysore, Marina Frontali, Jane S. Paulsen, Marie Saint-Hilaire, Ayana Duckett, Luc Djoussé, Richard H. Myers, Alexandra Durr, Simon C. Warby, Tammy Gillis, Michael R. Hayden, James F. Gusella, Chirstopher A. Ross, Elizabeth McCusker, Ronald J. Trent, Susan Perlman, Marcy E. MacDonald, Michael Hakky, Randi Jones, Luigi Frati, Jian-Liang Li, Tetsuo Ashizawa, Madaline B. Harrison, Karen Marder, L. Adrienne Cupples, Mary Lou Klimek, and Estrella Gómez-Tortosa
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molecular cloning ,Genetic Linkage ,correlation analysis ,genotype ,data analysis ,Pedigree chart ,genetic analysis ,variance ,Nervous system--Diseases--Genetic aspects ,quantitative trait locus ,0302 clinical medicine ,Trinucleotide Repeats ,genetic variability ,guanine ,Genetics(clinical) ,sibling ,Age of Onset ,cytosine ,Genetics (clinical) ,Genetics ,0303 health sciences ,pathogenesis ,Brain--Diseases--Age factors ,article ,microsatellite marker ,Huntington's disease ,Middle Aged ,Huntington Disease ,Microsatellite ,Chromosomes, Human, Pair 6 ,DNA modification ,trinucleotide repeat ,Research Article ,onset age ,Adult ,Genetic Markers ,lcsh:Internal medicine ,gene locus ,Adolescent ,lcsh:QH426-470 ,huntingtin ,heredity ,Quantitative Trait Loci ,Age factors in disease ,Locus (genetics) ,Biology ,Quantitative trait locus ,adenine ,DNA ,adolescent ,adult ,age ,aged ,chromosome 18q ,chromosome 6q ,controlled study ,follow up ,gene identification ,gene interaction ,gene replication ,genetic epistasis ,genetic linkage ,human ,human cell ,Huntington chorea ,linkage analysis ,major clinical study ,pedigree analysis ,03 medical and health sciences ,medicine ,Humans ,lcsh:RC31-1245 ,030304 developmental biology ,Aged ,Linkage (software) ,Models, Genetic ,Genome, Human ,FOS: Clinical medicine ,Neurosciences ,medicine.disease ,Settore BIO/18 - Genetica ,lcsh:Genetics ,Epistasis ,Trinucleotide repeat expansion ,030217 neurology & neurosurgery - Abstract
Background Age at onset of Huntington's disease (HD) is correlated with the size of the abnormal CAG repeat expansion in the HD gene; however, several studies have indicated that other genetic factors also contribute to the variability in HD age at onset. To identify modifier genes, we recently reported a whole-genome scan in a sample of 629 affected sibling pairs from 295 pedigrees, in which six genomic regions provided suggestive evidence for quantitative trait loci (QTL), modifying age at onset in HD. Methods In order to test the replication of this finding, eighteen microsatellite markers, three from each of the six genomic regions, were genotyped in 102 newly recruited sibling pairs from 69 pedigrees, and data were analyzed, using a multipoint linkage variance component method, in the follow-up sample and the combined sample of 352 pedigrees with 753 sibling pairs. Results Suggestive evidence for linkage at 6q23-24 in the follow-up sample (LOD = 1.87, p = 0.002) increased to genome-wide significance for linkage in the combined sample (LOD = 4.05, p = 0.00001), while suggestive evidence for linkage was observed at 18q22, in both the follow-up sample (LOD = 0.79, p = 0.03) and the combined sample (LOD = 1.78, p = 0.002). Epistatic analysis indicated that there is no interaction between 6q23-24 and other loci. Conclusion In this replication study, linkage for modifier of age at onset in HD was confirmed at 6q23-24. Evidence for linkage was also found at 18q22. The demonstration of statistically significant linkage to a potential modifier locus opens the path to location cloning of a gene capable of altering HD pathogenesis, which could provide a validated target for therapeutic development in the human patient.
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- 2006
17. Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16
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Marina Frontali, Jane S. Paulsen, Elizabeth McCusker, Qiong Yang, Ruth K. Abramson, Russel L. Margolis, Alexandra Durr, Randi Jones, Estrella Gómez-Tortosa, L. Adrienne Cupples, Andrea Zanko, Richard H. Myers, Martha Nance, Madaline B. Harrison, Oksana Suchowersky, Christopher A. Ross, Adam Rosenblatt, Ronald J. Trent, Luc Djoussé, Andrea Novelletto, James F. Gusella, Michael R. Hayden, Jayalakshmi S. Mysore, Ryan R. Brinkman, David Mayo Cabrero, E. Almqvist, Beth Knowlton, Marcy E. MacDonald, Catherine Dodé, and Patrick J. Morrison
- Subjects
Adult ,Adolescent ,Genotype ,Genetic Linkage ,Biology ,Article ,Cellular and Molecular Neuroscience ,Trinucleotide Repeats ,Genetic linkage ,Genetics ,Coding region ,Humans ,Allele ,Age of Onset ,Child ,Gene ,Genetics (clinical) ,Aged ,Aged, 80 and over ,Homeodomain Proteins ,MSX1 Transcription Factor ,Chromosome ,Middle Aged ,Huntington disease - Modifier - Onset age - Genetics - Trinucleotide repeat - HD gene ,Settore BIO/18 - Genetica ,Huntington Disease ,Age of onset ,Chromosomes, Human, Pair 4 ,Trinucleotide repeat expansion ,Transcription Factors - Abstract
Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. A recent genome scan for genetic modifiers of age at onset of motor symptoms (AO) in HD suggests that one modifier may reside in the region close to the HD gene itself. We used data from 535 HD participants of the New England Huntington cohort and the HD MAPS cohort to assess whether AO was influenced by any of the three markers in the 4p16 region: MSX1 (Drosophila homeo box homologue 1, formerly known as homeo box 7, HOX7), Delta2642 (within the HD coding sequence), and BJ56 ( D4S127). Suggestive evidence for an association was seen between MSX1 alleles and AO, after adjustment for normal CAG repeat, expanded repeat, and their product term (model P value 0.079). Of the variance of AO that was not accounted for by HD and normal CAG repeats, 0.8% could be attributed to the MSX1 genotype. Individuals with MSX1 genotype 3/3 tended to have younger AO. No association was found between Delta2642 (P=0.44) and BJ56 (P=0.73) and AO. This study supports previous studies suggesting that there may be a significant genetic modifier for AO in HD in the 4p16 region. Furthermore, the modifier may be present on both HD and normal chromosomes bearing the 3 allele of the MSX1 marker.
- Published
- 2004
18. A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study
- Author
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L. Adrienne Cupples, Marie Saint-Hilaire, Richard H. Myers, Estrella Gómez-Tortosa, Larry D. Atwood, Andrea Novelletto, Steven M. Hersch, Marina Frontali, Suzanne Tariot, Catherine Dodé, Jane S. Paulsen, E. Almqvist, Luc Djoussé, Ronald J. Trent, Vanessa C. Wheeler, Beth Knowlton, Marcy E. MacDonald, Martha Nance, Alexandra Durr, Ryan R. Brinkman, James F. Gusella, Jayalakshmi S. Mysore, Walter J. Koroshetz, Oksana Suchowersky, Andrea Zanko, Patrick J. Morrison, Ruth K. Abramson, Ana L. Russ, Madeline Harrison, Christopher A. Ross, Michael R. Hayden, Jang Ho J. Cha, David Mayo Cabrero, Michael F. Gusella, Adam Rosenblatt, Elizabeth McCusker, Randi Jones, Russell L. Margolis, and Jian-Liang Li
- Subjects
Genetics ,Genome ,Genome Scan ,Chromosome Mapping ,Locus (genetics) ,Pedigree chart ,Biology ,medicine.disease ,Identity by descent ,Degenerative disease ,Huntington Disease ,Trinucleotide Repeats ,Report ,medicine ,Coding region ,Humans ,Genetics(clinical) ,Age of onset ,Age of Onset ,Gene ,Genetics (clinical) - Abstract
Huntington disease (HD) is caused by the expansion of a CAG repeat within the coding region of a novel gene on 4p16.3. Although the variation in age at onset is partly explained by the size of the expanded repeat, the unexplained variation in age at onset is strongly heritable (h2=0.56), which suggests that other genes modify the age at onset of HD. To identify these modifier loci, we performed a 10-cM density genomewide scan in 629 affected sibling pairs (295 pedigrees and 695 individuals), using ages at onset adjusted for the expanded and normal CAG repeat sizes. Because all those studied were HD affected, estimates of allele sharing identical by descent at and around the HD locus were adjusted by a positionally weighted method to correct for the increased allele sharing at 4p. Suggestive evidence for linkage was found at 4p16 (LOD=1.93), 6p21–23 (LOD=2.29), and 6q24–26 (LOD=2.28), which may be useful for investigation of genes that modify age at onset of HD.
- Published
- 2003
19. Coping with grim news from genetic tests
- Author
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Mardi J. Horowitz, Eva Sundin, Roger Lauer, and Andrea Zanko
- Subjects
Typology ,Coping (psychology) ,medicine.medical_specialty ,Genetic counseling ,media_common.quotation_subject ,Disease ,Anxiety ,Developmental psychology ,Cytogenetics ,Denial ,Arts and Humanities (miscellaneous) ,Neoplasms ,Adaptation, Psychological ,medicine ,Humans ,Psychiatry ,Applied Psychology ,Genetic testing ,media_common ,medicine.diagnostic_test ,Psychotherapy ,Psychiatry and Mental health ,Huntington Disease ,Feeling ,medicine.symptom ,Psychology - Abstract
Clinicians need to recognize and respond to stress response syndromes that may occur after patients have received genetic testing for inherited susceptibility to serious diseases. For patients whose test results convey high risk, increased attention to prevention, surveillance, and early medical treatment may be possible, but the grim news may also lead to a formation of symptoms ranging from extreme denial to unwelcomed intrusive ideas and feelings. Genetic counseling alone may be insufficient for some people, and evaluation and psychotherapy for stress response syndromes may be indicated for them.
- Published
- 2001
20. Testing for HD in twins
- Author
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Andrea Zanko, Elsa Reich, and Audrey Heimler
- Subjects
Freedom ,medicine.medical_specialty ,business.industry ,Public health ,Genetic counseling ,Coercion ,Twins ,Genetic Counseling ,Truth Disclosure ,Human genetics ,Pedigree ,Huntington Disease ,Privacy ,Family medicine ,Personal Autonomy ,Medicine ,Humans ,Family ,Genetic Testing ,business ,Genetic Privacy ,Genetics (clinical) ,Confidentiality - Published
- 1996
21. Erratum to: In Memoriam: Dr. Charles Epstein (1933–2011)
- Author
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Beth Crawford, Andrea Zanko, Judy Derstine, and Vicki Cox
- Subjects
medicine.medical_specialty ,Genetic counseling ,Public health ,Family medicine ,medicine ,Psychology ,Genetics (clinical) ,Human genetics - Published
- 2011
- Full Text
- View/download PDF
22. Early Warning
- Author
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Charles J. Epstein and Andrea Zanko
- Subjects
General Medicine ,General Biochemistry, Genetics and Molecular Biology - Published
- 1999
- Full Text
- View/download PDF
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