Chromosomal Aberrations Associated with Clonal Evolution and Leukemic Transformation in Fanconi Anemia: Clinical and Biological Implications

Fanconi anaemia (FA) is an inherited disease with congenital and developmental abnormalities, bone marrow failure, and extreme risk of leukemic transformation. Bone marrow surveillance is an important part of the clinical management of FA and often reveals cytogenetic aberrations. Here, we review bone marrow findings in FA and discuss the clinical and biological implications of chromosomal aberrations associated with leukemic transformation

Two siblings with immunodeficiency, facial abnormalities and chromosomal instability without mutation in DNMT3B gene but liability towards malignancy; a new chromatin disorder delineation?

<p>Abstract</p> <p>Background</p> <p>ICF syndrome (standing for Immunodeficiency, Centromere instability and Facial anomalies syndrome) is a very rare autosomal recessive immune disorder caused by mutations of the gene de novo DNA-methyltransferase 3B (DNMT3B). However, in the literature similar clinical cases without such mutations are reported, as well.</p> <p>Results</p> <p>We report on a family in which the unrelated spouses had two female siblings sharing similar phenotypic features resembling ICF-syndrome, i.e. congenital abnormalities, immunodeficiency, developmental delay and high level of chromosomal instability, including high frequency of centromeric/pericentromeric rearrangements and breaks, chromosomal fragments despiralization or pulverization. However, mutations in DNMT3B could not be detected.</p> <p>Conclusion</p> <p>The discovery of a new so-called 'chromatin disorder' is suggested. Clinical, molecular genetic and cytogenetic characteristics are reported and compared to other 'chromatin disorders'.</p

Deregulation of the telomerase reverse transcriptase (TERT) gene by chromosomal translocations in B-cell malignancies

Sequence variants at the TERT-CLPTM1L locus in chromosome 5p have been recently associated with disposition for various cancers. Here we show that this locus including the gene encoding the telomerase reverse-transcriptase TERT at 5p13.33 is rarely but recurrently targeted by somatic chromosomal translocations to IGH and non-IG loci in B-cell neoplasms, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma and splenic marginal zone lymphoma. In addition, cases with genomic amplification of TERT locus were identified. Tumors bearing chromosomal aberrations involving TERT showed higher TERT transcriptional expression and increased telomerase activity. These data suggest that deregulation of TERT gene by chromosomal abnormalities leading to increased telomerase activity might contribute to B-cell lymphomagenesis

Successful bone marrow transplantation in a patient with DNA ligase IV deficiency and bone marrow failure

BACKGROUND: DNA Ligase IV deficiency syndrome is a rare autosomal recessive disorder caused by hypomorphic mutations in the DNA ligase IV gene (LIG4). The clinical phenotype shows overlap with a number of other rare syndromes, including Seckel syndrome, Nijmegen breakage syndrome, and Fanconi anemia. Thus the clinical diagnosis is often delayed and established by exclusion. METHODS: We describe a patient with pre- and postnatal growth retardation and dysmorphic facial features in whom the diagnoses of Seckel-, Dubowitz-, and Nijmegen breakage syndrome were variably considered. Cellular radiosensitivity in the absence of clinical manifestations of Ataxia telangiectasia lead to the diagnosis of DNA ligase IV (LIG4) deficiency syndrome, confirmed by compound heterozygous mutations in the LIG4 gene. At age 11, after a six year history of progressive bone marrow failure and increasing transfusion dependency the patient was treated with matched sibling donor hematopoetic stem cell transplantation (HSCT) using a fludarabine-based conditioning regimen without irradiation. RESULTS: The post-transplantation course was uneventful with rapid engraftment leading to complete and stable chimerism. Now at age 16, the patient has gained weight and is in good clinical condition. CONCLUSION: HSCT using mild conditioning without irradiation qualifies as treatment of choice in LIG4-deficient patients who have a matched sibling donor

Molecular cytogenetic characterization of constitutive and somatic chromosomal imbalances

HabilitationsschriftAuf der Basis vergleichender genomischer Hybridisierungen (CGH) und unter Anwendung validierender molekularzytogenetischer, molekulargenetischer und immunologischer Methoden konnten im Rahmen dieser Arbeit verschiedenste de novo entstandene kongenitale intra- und interchromosomale Imbalancen nachgewiesen und eingehend auch in Bezug auf ihre Entstehungsmechanismen charakterisiert werden. Die Analysen verschiedener sporadischer Tumorentitäten führten zum Nachweis spezifischer chromosomaler Imbalancen, die eine Klassifikation der einzelnen Tumoren bezüglich des differentialdiagnostischen Wertes, der prognostischen Relevanz und dem Metastaserisiko ermöglichten. Zudem konnten anhand der Charakterisierung verschiedener Tumorzelllinienmodelle erstmalig chromosomale Imbalancen ermittelt werden, die vermutlich Gene beinhalten, die für die Entwicklung von Resistenzen ursächlich sein können. Anhand der Fanconi Anämie Studien konnten erstmals unter Verwendung molekularzytogenetischer Methoden erfolgreich bisher unbekannte, spezifische chromosomale Imbalancen in präkanzerösen hämatopoetischen FA- Zellen nachgewiesen werden. Nach Ermittlung der prognostischen Bedeutung, konnte eine erfolgreiche Übertragung der Ergebnisse zytogenetischer Grundlagenforschung in die klinische Anwendung erfolgen. Heute werden FA- Patienten mit Imbalancen des Chromosoms 3q, aufgrund ihres extrem erhöhten Leukämierisikos, umgehend knochenmarktransplantiert. Unabdingbar in diesem Zusammenhang ist der frühzeitige Nachweis erster klonaler Veränderungen, der nun mittels Interphase-FISH auch an Zellen des peripheren Blutes möglich ist.On the basis of comparative genomic hybridization (CGH) and other validating molecular cytogenetic, molecular genetic and immunological methods, different intra- and interchromosomal de novo imbalances were detected and characterized in this work in detail with respect to their formation. The analyses of different tumour entities allowed the detection of specific chromosomal imbalances, which permit a classification of single tumours in respect to the prognostic relevance and the risk of metastasis development. Based on the characterization of different tumour cell line models, chromosomal imbalances including genes which are possibly responsible for the establishment of resistance mechanisms could be described. In FA studies, using molecular cytogenetic methods, the detection and characterization of specific, formerly unknown chromosomal imbalances in precancerous hematopoietic FA-cells could be performed. After determination of the prognostic value, the translation of our results in the clinical care programme was successful. Today, FA-patients with imbalances in chromosome 3q are transplanted immediately because of their extremely high risk for leukaemia. Indispensible in this context is the early detection of upcoming clonal imbalances, which has been established routinely by using interphase-FISH on mononuclear cells of the peripheral blood

Konzepte zur Mitteilung genetischer Zusatzbefunde in der medizinischen Diagnostik und Forschung

Die Hochdurchsatzsequenzierung gesamter Genome ist technisch bereits auf einem hohen Stand und wird als kostengünstigere Alternative zu anderen gezielten analytischen Verfahren in der klinischen Diagnostik genetischer Erkrankungen diskutiert. Andererseits besteht bei Genom- oder Exomsequenzierungen eine hohe Wahrscheinlichkeit, nicht mit dem primären Untersuchungsziel im Zusammenhang stehende Zusatzbefunde zu detektieren. Der vorliegende Beitrag versucht, einen Überblick über den aktuellen wissenschaftlichen und technischen Stand der Genom- und Exomsequenzierung sowie über die nationalen und internationalen Empfehlungen zum Umgang mit genetischen Zusatzbefunden, die vor allem im forschungsbezogenen und weniger im klinischen Kontext bereits zur Verfügung stehen, zu geben.High-throughput sequencing of whole genomes is technically already at a high level and is being discussed as a cost-effective alternative to other targeted, analytical procedures for clinical diagnosis of heritable disorders. On the other hand, with whole genome and whole exome sequencing, there is a high likelihood of uncovering secondary findings not associated with the primary aim of the investigation. This article tries to outline the current scientific and technical status of whole genome and whole exome sequencing and of the national and international recommendations concerning the handling of secondary genetic findings which are already available, above all in the research-related context and less so in the clinical context

Humangenetische Beratung in Deutschland: Entwicklung der Inanspruchnahme

Background!#!With the Act on Genetic Testing (GenDG), the German legislator has issued far-reaching regulations for human genetic services, including genetic counseling. This paper presents data on the use of human genetic counseling in the years before and after the entry into force of GenDG in order to provide an informed assessment of the possible effects of the law.!##!Materials and methods!#!Over a period of 13 years (2005 to 2017), the human genetic counseling services provided within the framework of the statutory health insurance and billable by EBM via the Kassenärztliche associations were recorded via a database query at the Central Institute of the National Association of Statutory Health Insurance Physicians (ZI-KBV) and via individual Kassenärztliche Vereinigungen Deutschlands. For the discussion of the observable development of using genetic counseling and possible future development, additional data on the referral behavior, the waiting times, processing time, and reasons for consultations were extracted from the GenBIn database.!##!Results and discussion!#!Demand for genetic counseling has steadily increased at an average rate of approximately 6% per year since 2009. This increase started well before the enactment of the GenDG and may be attributed to a multiplicity of factors. Change in demand for genetic counseling is characterized by increasing self-referrals and by increasing referrals by specialists other than obstetricians/gynecologists. Waiting times between 2011 and 2016/2017 have increased. While demand has been growing, the number of key service providers, the contracted medical specialists in human genetics, has remained almost constant. It is foreseeable that capacity limits will be reached if both trends continue