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1.
Genet Med ; 22(2): 336-344, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31534211

RESUMEN

PURPOSE: The ability of a single technology, next-generation sequencing, to provide both sequence and copy number variant (CNV) results has driven the merger of clinical cytogenetics and molecular genetics. Consequently, the distinction between the definition of a sequence variant and a CNV is blurry. As the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards and guidelines for interpretation of sequence variants address CNV classification only sparingly, this study focused on adapting ACMG/AMP criteria for single-gene CNV interpretation. METHODS: CNV-specific modifications of the 2015 ACMG/AMP criteria were developed and their utility was independently tested by three diagnostic laboratories. Each laboratory team interpreted the same 12 single-gene CNVs using three systems: (1) without ACMG/AMP guidance, (2) with ACMG/AMP criteria, and (3) with new modifications. A replication study of 12 different CNVs validated the modified criteria. RESULTS: The adapted criteria system presented here showed improved concordance and usability for single-gene CNVs compared with using the ACMG/AMP interpretation guidelines focused on sequence variants. CONCLUSION: These single-gene CNV criteria modifications could be used as a supplement to the ACMG/AMP guidelines for sequence variants, allowing for a streamlined workflow and a step toward a uniform classification system for both sequence and copy number alterations.


Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Secuenciación de Nucleótidos de Alto Rendimiento/normas , Análisis de Secuencia de ADN/clasificación , Biología Computacional/métodos , Dosificación de Gen/genética , Pruebas Genéticas/métodos , Variación Genética/genética , Genoma Humano/genética , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Laboratorios , Mutación/genética , Análisis de Secuencia de ADN/métodos
3.
Genet Med ; 19(8): 845-850, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28726804

RESUMEN

Disclaimer: ACMG Clinical Laboratory Practice Resources are developed primarily as an educational tool for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these practice resources is voluntary and does not necessarily assure a successful medical outcome. This Clinical Laboratory Practice Resource should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with this Clinical Laboratory Practice Resource. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Noninvasive prenatal screening (NIPS) using cell-free DNA has been rapidly adopted into prenatal care. Since NIPS is a screening test, diagnostic testing is recommended to confirm all cases of screen-positive NIPS results. For cytogenetics laboratories performing confirmatory testing on prenatal diagnostic samples, a standardized testing algorithm is needed to ensure that the appropriate testing takes place. This algorithm includes diagnostic testing by either chorionic villi sampling or amniocentesis samples and encompasses chromosome analysis, fluorescence in situ hybridization, and chromosomal microarray.


Asunto(s)
Análisis Citogenético , Diagnóstico Prenatal , Algoritmos , Femenino , Asesoramiento Genético , Pruebas Genéticas , Humanos , Recién Nacido , Valor Predictivo de las Pruebas , Embarazo
4.
Am J Obstet Gynecol ; 213(2): 214.e1-5, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25843063

RESUMEN

OBJECTIVE: We sought to determine the positive predictive value (PPV) of noninvasive prenatal screening (NIPS) for various aneuploidies based on cases referred for follow-up cytogenetic testing. Secondarily, we wanted to determine the false-negative (FN) rate for those cases with a negative NIPS result. STUDY DESIGN: We compared the cytogenetic findings (primarily from chromosome analysis) from 216 cases referred to our laboratories with either a positive or negative NIPS result, and classified NIPS results as true positive, false positive, true negative, or FN. Diagnostic cytogenetic testing was performed on the following tissue types: amniotic fluid (n = 137), chorionic villi (n = 69), neonatal blood (n = 6), and products of conception (n = 4). RESULTS: The PPV for NIPS were as follows: 93% for trisomy (T)21 (n = 99; 95% confidence interval [CI], 86-97.1%), 58% for T18 (n = 24; 95% CI, 36.6-77.9%), 45% for T13 (n = 11; 95% CI, 16.7-76.6%), 23% for monosomy X (n = 26; 95% CI, 9-43.6%), and 67% for XXY (n = 6; 95% CI, 22.3-95.7%). Of the 26 cases referred for follow-up cytogenetics after a negative NIPS result, 1 (4%) was FN (T13). Two cases of triploidy, a very serious condition but one not claimed to be detectable by the test providers, were among those classified as true negatives. CONCLUSION: T21, which has the highest prevalence of all aneuploidies, demonstrated a high true-positive rate, resulting in a high PPV. However, the other aneuploidies, with their lower prevalence, displayed relatively high false-positive rates and, therefore, lower PPV. Patients and physicians must fully understand the limitations of this screening test and the need in many cases to follow up with appropriate diagnostic testing to obtain an accurate diagnosis.


Asunto(s)
Aberraciones Cromosómicas , Trastornos de los Cromosomas/diagnóstico , ADN/sangre , Adulto , Amniocentesis , Aneuploidia , Muestra de la Vellosidad Coriónica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 18/genética , Estudios de Cohortes , Análisis Citogenético , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Reacciones Falso Negativas , Femenino , Humanos , Síndrome de Klinefelter/diagnóstico , Síndrome de Klinefelter/genética , Valor Predictivo de las Pruebas , Embarazo , Diagnóstico Prenatal , Estudios Retrospectivos , Trisomía/diagnóstico , Trisomía/genética , Síndrome de la Trisomía 13 , Síndrome de la Trisomía 18 , Síndrome de Turner/diagnóstico , Síndrome de Turner/genética
5.
Int J Cancer ; 127(5): 1011-20, 2010 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-20017137

RESUMEN

Hepatocellular carcinoma (HCC) is a common cancer, and hepatitis B virus (HBV) is a major etiological agent. Convincing epidemiological and experimental evidence also links HCC to aflatoxin, a naturally occurring mycotoxin that produces a signature p53-249(ser) mutation. Recently, we have reported that tumor-derived HBx variants encoded by HBV exhibited attenuated transactivation and proapoptotic functions but retained their ability to block p53-mediated apoptosis. These results indicate that mutations in HBx may contribute to the development of HCC. In this study, we determined whether tumor-derived HBx mutants along, or in cooperation with p53-249(ser), could alter cell proliferation and chromosome stability of normal human hepatocytes. To test this hypothesis, we established a telomerase immortalized normal human hepatocycte line HHT4 that exhibited a near diploid karyotype and expressed many hepatocyte-specific genes. We found that overexpression one of the tumor-derived HBx mutants, CT, significantly increased colony forming efficiency (CFE) while its corresponding wild-type allele CNT significantly decreased CFE in HHT4 cells. p53-249(ser) rescued CNT-mediated inhibition of colony formation. Although HHT4 cells lacked an anchorage independent growth capability as they did not form any colonies in soft agar, the CT-expressing HHT4 cells could form colonies, which could be significantly enhanced by p53-249(ser). Induction of aneuploidy could be observed in HHT4 cells expressing CT, but additionally recurring chromosome abnormalities could only be detected in cells coexpressing CT and p53-249(ser). Our results are consistent with the hypothesis that certain mutations in HBx and p53 at codon 249 may cooperate in contributing to liver carcinogenesis.


Asunto(s)
Aneuploidia , Hepatocitos/metabolismo , Mutación/genética , Telomerasa/metabolismo , Transactivadores/genética , Proteína p53 Supresora de Tumor/genética , Apoptosis , Biomarcadores/metabolismo , Western Blotting , Adhesión Celular , Proliferación Celular , Transformación Celular Neoplásica , Células Cultivadas , Bandeo Cromosómico , Ensayo de Unidades Formadoras de Colonias , Perfilación de la Expresión Génica , Virus de la Hepatitis B , Hepatocitos/citología , Humanos , Hibridación Fluorescente in Situ , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Cariotipificación Espectral , Transactivadores/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Reguladoras y Accesorias Virales
6.
Am J Med Genet C Semin Med Genet ; 154C(1): 146-8, 2010 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-20104610

RESUMEN

Holoprosencephaly (HPE) is the most common malformation of the human forebrain. When a clinician identifies a patient with HPE, a routine chromosome analysis is often the first genetic test sent for laboratory analysis in order to assess for a structural or numerical chromosome anomaly. An abnormality of chromosome number is overall the most frequently identified etiology in a patient with HPE. These abnormalities include trisomy 13, trisomy 18, and triploidy, though several others have been reported. Such chromosome number abnormalities are almost universally fatal early in gestation or in infancy. Clinical features of specific chromosome number abnormalities may be recognized by phenotypic manifestations in addition to the HPE.


Asunto(s)
Aberraciones Cromosómicas , Holoprosencefalia/genética , Poliploidía , Cromosomas Humanos Par 13 , Femenino , Asesoramiento Genético/métodos , Holoprosencefalia/diagnóstico , Humanos , Recién Nacido , Mutación/fisiología , Embarazo , Diagnóstico Prenatal
8.
Genet Med ; 10(6): 457-60, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18496227

RESUMEN

In 1996, a practice guideline on genetic counseling for advanced paternal age was published. The current document updates the state of knowledge of advanced paternal age effects on single gene mutations, chromosome anomalies, and complex traits.


Asunto(s)
Asesoramiento Genético/métodos , Asesoramiento Genético/normas , Edad Paterna , Adulto , Anciano , Aberraciones Cromosómicas , Predisposición Genética a la Enfermedad , Servicios Genéticos/normas , Pruebas Genéticas/normas , Guías como Asunto , Humanos , Masculino , Persona de Mediana Edad , Mutación , Riesgo
9.
BMC Med Genet ; 7: 2, 2006 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-16412230

RESUMEN

BACKGROUND: Unbalanced chromosomal translocations may present with a variety of clinical and laboratory findings and provide insight into the functions of genes on the involved chromosomal segments. CASE PRESENTATION: A 9 year-old boy presented to our clinic with Factor VII deficiency, microcephaly, a seizure disorder, multiple midline abnormalities (agenesis of the corpus callosum, imperforate anus, bilateral optic nerve hypoplasia), developmental delay, hypopigmented macules, short 5th fingers, and sleep apnea due to enlarged tonsils. Cytogenetic and fluorescence in situ hybridization analyses revealed an unbalanced translocation involving the segment distal to 16p13 replacing the segment distal to 13q33 [46, XY, der(13)t(13;16)(q33;p13.3)]. Specific BAC-probes were used to confirm the extent of the 13q deletion. CONCLUSION: This unique unbalanced chromosomal translocation may provide insights into genes important in midline development and underscores the previously-reported phenotype of Factor VII deficiency in 13q deletions.


Asunto(s)
Anomalías Múltiples/genética , Cromosomas Humanos Par 13 , Cromosomas Humanos Par 16 , Discapacidades del Desarrollo/genética , Deficiencia del Factor VII/genética , Translocación Genética , Anomalías Múltiples/diagnóstico , Niño , Discapacidades del Desarrollo/diagnóstico , Deficiencia del Factor VII/diagnóstico , Humanos , Cariotipificación , Masculino , Monosomía , Trisomía
11.
J Am Acad Child Adolesc Psychiatry ; 41(7): 806-10, 2002 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-12108805

RESUMEN

OBJECTIVE: To systematically assess the prevalence of fragile X syndrome, velocardiofacial syndrome, and other cytogenetic abnormalities in a group of children with attention-defict/hyperactivity disorder (ADHD). METHOD: Blood samples were obtained from 100 children (64 boys) with combined type ADHD and normal intelligence and analyzed for the presence of fragile X mutation expansions, the 22q11.2 microdeletion associated with velocardiofacial syndrome, and cytogenetic abnormalities that would be detected with high resolution chromosomal banding. RESULTS: One girl with ADHD had a sex chromosome aneuploidy (47,XXX). One boy had a premutation-sized allele for fragile X; no subjects showed the full mutation. Testing for 22q11.2 microdeletion was negative for all subjects with ADHD screened. None of these differences exceeded those expected by chance. CONCLUSIONS: In the absence of clinical signs or positive family history, these relatively expensive laboratory assessments are not clinically indicated for children with ADHD and normal intelligence, and are not recommended as a component of other genetic investigations of this disorder.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/genética , Citogenética/métodos , Síndrome del Cromosoma X Frágil/genética , Anomalías Múltiples , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Niño , Cromosomas Humanos Par 22/genética , Cara/anomalías , Femenino , Síndrome del Cromosoma X Frágil/epidemiología , Cardiopatías Congénitas/epidemiología , Humanos , Masculino , Paladar Blando/anomalías , Síndrome
12.
Cancer Genet Cytogenet ; 190(2): 125-30, 2009 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-19380032

RESUMEN

We describe the cases of two unrelated patients who exhibited multiple chromosomal abnormalities in donor cells after allogeneic peripheral blood stem cell transplantation (PBSCT). The patients were diagnosed with chronic myeloid leukemia and chronic lymphocytic leukemia, respectively, and both underwent nonmyeloablative conditioning with cyclophosphamide and fludarabine followed by PBSCT from their HLA-matched opposite-sex siblings. Post-transplant bone marrow cytogenetics showed full engraftment, and the early post-transplant studies demonstrated only normal donor metaphases. Subsequent studies of both patients, however, revealed a population of metaphase cells with abnormal, but apparently balanced, donor karyotypes. Chromosome studies performed on peripheral blood cells collected from both donors after transplantation were normal. Both patients remained in clinical remission during follow-up of approximately 8 years in one case, and 6 years in the other case, despite the persistence of the abnormal clones. Chromosomal abnormalities in residual recipient cells after bone marrow or PBSCT are not unusual. In contrast, only rare reports of chromosome abnormalities in donor cells exist, all of which have been associated with post-bone marrow transplant myelodysplastic syndrome or acute leukemias. The present cases demonstrate the rare phenomenon of persistent clonal nonpathogenic chromosome aberrations in cells of donor origin.


Asunto(s)
Aberraciones Cromosómicas , Trasplante de Células Madre Hematopoyéticas , Anciano , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/inmunología , Masculino , Persona de Mediana Edad
13.
Breast Cancer Res Treat ; 104(1): 13-9, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17004106

RESUMEN

BACKGROUND: The tissue of origin of the cell line MDA-MB-435 has been a matter of debate since analysis of DNA microarray data led Ross et al. (2000, Nat Genet 24(3):227-235) to suggest they might be of melanocyte origin due to their similarity to melanoma cell lines. We have previously shown that MDA-MB-435 cells maintained in multiple laboratories are of common origin to those used by Ross et al. and concluded that MDA-MB-435 cells are not a representative model for breast cancer. We could not determine, however, whether the melanoma-like properties of the MDA-MB-435 cell line are the result of misclassification or due to transdifferention to a melanoma-like phenotype. METHODS: We used karyotype, comparative genomic hybridization (CGH), and microsatalite polymorphism analyses, combined with bioinformatics analysis of gene expression and single nucleotide polymorphism (SNP) data, to test the hypothesis that the MDA-MB-435 cell line is derived from the melanoma cell line M14. RESULTS: We show that the MDA-MB-435 and M14 cell lines are essentially identical with respect to cytogenetic characteristics as well as gene expression patterns and that the minor differences found can be explained by phenotypic and genotypic clonal drift. CONCLUSIONS: All currently available stocks of MDA-MB-435 cells are derived from the M14 melanoma cell line and can no longer be considered a model of breast cancer. These cells are still a valuable system for the study of cancer metastasis and the extensive literature using these cells since 1982 represent a valuable new resource for the melanoma research community.


Asunto(s)
Neoplasias de la Mama/patología , Melanoma/patología , Proteínas de Neoplasias/genética , Neoplasias Cutáneas/patología , Línea Celular Tumoral , Dermatoglifia del ADN , ADN de Neoplasias/análisis , Femenino , Expresión Génica , Humanos , Polimorfismo de Nucleótido Simple
15.
Am J Med Genet A ; 124A(2): 118-28, 2004 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-14699608

RESUMEN

A subtle balanced translocation involving the terminal regions of 1q and 3p was identified in a large family by high-resolution karyotype analysis and confirmed by fluorescence in situ hybridization (FISH) analysis. In this family, segregation of a balanced t(1:3)(q42.3;p25) chromosome translocation led to two types of viable unbalanced complements. The proband inherited the derivative chromosome 3, resulting in partial trisomy of 1q and partial monosomy of 3p. A paternal uncle and cousin had the reciprocal rearrangement with a derivative of chromosome 1, resulting in partial monosomy for 1q and partial trisomy for 3p. While profound mental and physical retardation and congenital heart defects were characteristics for both rearrangements, facial dysmorphism was quite distinct for each imbalance. Individuals who had the derivative chromosome 3 had a long face, wide eyebrows, small palpebral fissures, hypertelorism, prominent glabella, a large tip of the nose, long philtrum with thin upper lip, and low set-ears. In contrast, family members with the derivative of chromosome 1 had a tall forehead with bifrontal narrowing, full and large cheeks, and large simple ears. Since the translocated segments are small and approximately equal in size in this family, it is not surprising that viability was seen in individuals with both types of adjacent-1 segregation. In this kindred, the ratio of normal to abnormal individuals born to balanced carriers is believed to be about 1:1.5. This suggests that the recurrence risk for carriers is 50%.


Asunto(s)
Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 3/genética , Translocación Genética , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Adulto , Bandeo Cromosómico , Segregación Cromosómica , Cara/anomalías , Salud de la Familia , Resultado Fatal , Femenino , Trastornos del Crecimiento/patología , Cardiopatías Congénitas/patología , Humanos , Hipertelorismo/patología , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Discapacidad Intelectual/patología , Cariotipificación , Masculino , Nariz/anomalías , Linaje
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