Jeanne M. Meck

Statement on guidance for genetic counseling in advanced paternal age

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.

Assessing copy number from exome sequencing and exome array CGH based on CNV spectrum in a large clinical cohort.

Purpose:Detection of copy-number variation (CNV) is important for investigating many genetic disorders. Testing a large clinical cohort by array comparative genomic hybridization provides a deep perspective on the spectrum of pathogenic CNV. In this context, we describe a bioinformatics approach to extract CNV information from whole-exome sequencing and demonstrate its utility in clinical testing.Methods:Exon-focused arrays and whole-genome chromosomal microarray analysis were used to test 14,228 and 14,000 individuals, respectively. Based on these results, we developed an algorithm to detect deletions/duplications in whole-exome sequencing data and a novel whole-exome array.Results:In the exon array cohort, we observed a positive detection rate of 2.4% (25 duplications, 318 deletions), of which 39% involved one or two exons. Chromosomal microarray analysis identified 3,345 CNVs affecting single genes (18%). We demonstrate that our whole-exome sequencing algorithm resolves CNVs of three or more exons.Conclusion:These results demonstrate the clinical utility of single-exon resolution in CNV assays. Our whole-exome sequencing algorithm approaches this resolution but is complemented by a whole-exome array to unambiguously identify intragenic CNVs and single-exon changes. These data illustrate the next advancements in CNV analysis through whole-exome sequencing and whole-exome array.Genet Med 17 8, 623–629.

Histiocytic sarcoma transdifferentiated from follicular lymphoma presenting as a cutaneous tumor

Histiocytic sarcoma represents a rare and poorly understood tumor of histiocytic/dendritic cell lineage that can rarely present in the skin. Previously reported cases of histiocytic sarcoma after follicular lymphoma suggested that follicular lymphoma can transdifferentiate into histiocytic sarcoma. We describe another case involving a 40‐year old male who developed histiocytic sarcoma in his right thigh 4 years after the diagnosis of grade 1 follicular lymphoma in the left neck. The two neoplasms were morphologically and immunophenotypically different but had identical immunoglobulin heavy chain gene and bcl‐2 gene rearrangements, as demonstrated by polymerase chain gene reaction analysis, and the presence of t(14;18)(q32;q21) translocation was confirmed via fluorescence in situ hybridization (FISH) analysis. Because of spindle cell morphology and focal S‐100 positivity, malignant peripheral nerve sheath tumor and melanoma diagnoses were made initially and extensive workup was required to discover the correct diagnosis. Lineage transdifferentiation can occur in mature lymphoid neoplasms and awareness of this phenomenon and appropriate workup is crucial for correct diagnosis, as different treatment protocols and prognosis may vary.

A systematic analysis of small supernumerary marker chromosomes using array CGH exposes unexpected complexity

Purpose:A small supernumerary marker chromosome is often seen in patients with developmental disorders. Prior to array-based comparative genomic hybridization markers were rarely genotyped end to end. In this study, a valid genotype-to-phenotype correlation was possible because the supernumerary marker chromosomes were fully characterized by array-based comparative genomic hybridization in a genome-wide analysis.Methods:Ten consecutive de novo small supernumerary marker chromosome cases were systematically genotyped using G-banding, C-banding, AgNOR staining, whole-genome array-based comparative genomic hybridization, and fluorescence in situ hybridization.Results:Among 10 small supernumerary marker chromosome cases studied, 4 (40%) were not identified by array-based comparative genomic hybridization because of low-level mosaicism or because they lacked euchromatin. One case (10%) was a simple pericentromeric marker extending from 5p13.3 to 5q11.2. Five (50%) markers showed unexpected complexity. Two cases had markers that were derivative acrocentric (AgNOR+) chromosomes with the euchromatin from chromosomes 18p or 19p. Each of the other three cases with complex markers had unusual characteristics including a marker from noncontiguous segments of chromosome 19q, a highly complex rearrangement involving a chromosome 20 homolog as well as the small supernumerary marker chromosome, and a mosaic duplication of a proximal 8p marker.Conclusion:Small supernumerary marker chromosomes are frequently complex on the basis of our small sample. Whole-genome array-based comparative genomic hybridization characterization of the small supernumerary marker chromosome provided informed genetic counseling.Genet Med 2013:15(1):3–13

Detection of Mosaicism in amniotic fluid cultures: A CYT02000 collaborative study

Purpose: To evaluate the assumptions on which the American College of Medical Genetics (ACMG) Standards and Guidelines for detecting mosaicism in amniotic fluid cultures are based.Methods: Data from 653 cases of amniotic fluid mosaicism were collected from 26 laboratories. A chi-square goodness-of-fit test was used to compare the observed number of mosaic cases with the expected number based on binomial distribution theory.Results: Comparison of observed data from the in situ colony cases with the expected distribution of cases detected based on the binomial distribution did not reveal a significant difference (P = 0.525).Conclusions: The empirical data fit the binomial distribution. Therefore, binomial theory can be used as an initial discussion point for determining whether ACMG Standards and Guidelines are adequate for detecting mosaicism.

Long-term persistence of nonpathogenic clonal chromosome abnormalities in donor hematopoietic cells after allogeneic stem cell transplantation.

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.

Molecular cytogenetic characterization of two small supernumerary marker chromosomes derived from chromosome 19

Molecular Cytogenetic Characterization of Two Small Supernumerary Marker Chromosomes Derived from Chromosome 19 Thomas R. Dennis,* Gina N. Raptoulis, Heather J. Stalker, Debra Boles, Jeanne M. Meck, Donna M. Krasnewich, Raphael Schiffmann, and Roberto T. Zori Shodair Children’s Hospital, Department of Genetics, Helena, Montana College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, Florida Department of Pediatrics, Division of Genetics, University of Florida, Gainesville, Florida Carilion Labs, Cytogenetics Laboratory, Charlotte, North Carolina Quest Diagnostics/Nichols Institute, Cytogenetics Laboratory, Chantilly, VA Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

Cytogenetic analysis using telemedicine consultation: An improved means of providing expert cross‐coverage

Purpose: We used telemedicine in providing cross-coverage for a clinical cytogenetics laboratory. A genetic teleconsultation system was used to provide expert cross-coverage for a laboratory in a neighboring metropolitan region for a 6 month period while the usual provider of these services was on military reserve duty.Methods: The teleconsultation system was a commercially available Perceptive Scientific Instruments (PSI) workstation. Five hundred thirty-nine cytogenetic cases were performed during the study period in the home laboratory in Baltimore, Maryland.Results: Karyotypes and supporting metaphase spreads were transmitted by modem to the covering director, whereas work sheets and reports were faxed. Physical transfer of data was not necessary, and turn-around-time was not increased.Conclusion: This ability to employ a remote part time director has significant benefits for the laboratory with an absentee director for short or even extended periods of time. We conclude that the use of telemedicine in clinical cytogenetics proved to be an efficient and a cost effective means of providing expert genetics services to a region during a time of cross-coverage need.

Diagnostic cytogenetic testing following positive noninvasive prenatal screening results: a clinical laboratory practice resource of the American College of Medical Genetics and Genomics (ACMG)

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.

Deletion 6p as the sole chromosome abnormality in a patient with therapy-related myelodysplastic syndrome: case report and review of the literature

Rearrangement or deletion of 6p in hematologic malignancies is an unusual finding [1,2]. The majority of cases appear to be associated with therapy-related myelodysplastic syndrome (t-MDS) and therapy-related acute myeloid leukemia (t-AML), where deletion 6p is present in the context of a complex karyotype that frequently includes 5/del(5q) or 7/del(7q) [2]. To our knowledge, deletion 6 p has not previously been reported as a sole abnormality in t-MDS or t-AML. We present the case of a 62-year-old woman with refractory anemia with excess blasts type 2 (RAEB2). The patient has a history of stage I breast carcinoma diagnosed in 2002. At that time, she underwent