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Раздел 6. Наследственные заболевания и врожденные пороки развития
INTERPHASE MOLECULAR CYTOGENETIC DETECTION RATES OF CHRONIC LYMPHOCYTIC LEUKEMIA-SPECIFIC ABERRATIONS ARE HIGHER IN CULTIVATED CELLS THAN IN BLOOD OR BONE MARROW SMEARS Alhourani E., Glaser A., Schlie C., Pohle B, Liehr T. Jena University Hospital, Institute of Human Genetics, Jena, Germany
Banding cytogenetics is still the gold standard in many fields of leukemia diagnostics. However, in chronic lymphocytic leukemia (CLL), GTG-banding results are hampered by a low mitotic rate of the corresponding malignant lymphatic cells. Thus, interphase fluorescence in situ hybridization (iFISH) for the detection of specific cytogenetic aberrations is done nowadays as a supplement to or even instead of banding cytogenetics in many diagnostic laboratories. These iFISH studies can be performed on native blood or bone marrow smears or in nuclei after cultivation and stimulation by a suitable mitogen. As there are only few comparative studies with partially conflicting results for the detection rates of aberrations in cultivated and native cells, this question was studied in 38 CLL cases with known aberrations in 11q22.2, 11q22.3, 12, 13q14.3, 14q32.33, 17p13.1, or 18q21.32. The obtained results implicate that iFISH directly applied on smears is in general less efficient fo r the detection of CLL-specific genetic abnormalities than for cultivated cells. This also shows thatapplied cell culture conditions are well suited for malignant CLL cells. Thus, to detect malignant aberrant cells in CLL, cell cultivation and cytogenetic workup should be performed and the obtained material should be subjected to banding cytogenetics and iFISH.
INSULIN-LIKE GROWTH FACTOR TYPE 1 DEFICIENCY IN A MOROCCAN PATIENT WITH DE NOVO INVERTED DUPLICATION 9p24p12 AND DEVELOPMENTAL DELAY: A CASE REPORT
AmasdlS.1-2, Natiq A.23, Elalaoui S.C.2, Sbiti A.2, Liehr T.4, Sefiani A.1'2
'Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Université Mohammed V Souissi, Rabat, Morocco;
2Département de Génétique Médicale, Institut National d'Hygiène, Rabat, Morocco;
3Faculté des Sciences, Université Mohammed V, Agdal, Rabat, Morocco;
"Institute of Human Genetics, University Hospital Jena, Jena, Germany
9p duplication is a structural chromosome abnormality, described in more than 150 patients to date. In most cases the duplicated segment was derived from a parent being a reciprocal translocation carrier. However, about 15 cases with de novo 9p duplication have been reported previously. Clinically, this condition is characterized by mental retardation, short stature, developmental delay, facial dysmorphism, hand and toe anomalies, heart defects
and/or ocular manifestations. We report here the case of a 2-year-old Moroccan girl with a de novo duplication of 9p24 to p12. Clinical manifestations included failure to thrive, psychomotor delay, microcephaly, dysmorphic features, equinus feet, and umbilical hernia. Further clinical investigations showed an insulin-like growth factor type 1 deficiency. Banding cytogenetics identified a derivative chromosome 9, with an abnormally elongated short arm. Molecular cytogenetics based on multicolor banding probes characterized an inverted duplication 9p24 to p12 involving several genes especially an insulin-like growth factor binding protein named insulin-like growth factor binding protein-like 1, which seemed to be overexpressed, leading to the insulin-like growth factor deficiency in our patient. This study showed that insulin-like growth factor type 1 deficiency can be another feature of 9p duplication, suggesting a likely involvement of insulin-like growth factor binding protein-like 1 overexpression in growth delay. However, further studies of the gene expressions are needed to better understand the phenotype-karyotype correlations.
20p12.3 DELETION IS RARE CAUSE OF SYNDROM-IC CLEFT PALATE: CASE REPORT AND REVIEW OF LITERATURE
Amasdl S.1~2, Natiq A.2~3, Sbiti A.2, Zerkaoui M.1~2, Lyahyai J.1, Amzazi S.3, Liehr T.4, Sefiani A.1,2 •Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Université Mohammed V, Rabat, Morocco;
2Département de Génétique Médicale, Institut National d'Hygiène, Rabat, Morocco;
3Faculté des Sciences, Université Mohammed V, Rabat, Morocco;
"Institut de Génétique Humaine, Hôspital Universitaire de Jena, Jena, Germany
Orofacial cleft (OFC) is one of the most common congenital malformations with a global incidence of approximately 1/700 live births. Clinically, OFCs can be syndromic or non-syndromic. A 5 years old boy admitted for genetic evaluation because of psychomotor delay, failure to thrive, dysmorphic features and cleft palate. Conventional cytogenetic showed a notably short p arm of one chromosome 20. FISH analysis identified the derivative chromosome 20 as a de novo 20p12.3 deletion. We present in this paper a Moroccan patient with syn-dromic cleft palate caused by a de novo 20p12.3 deletion, and we highlight the interest of FISH in the diagnosis confirmation of chromosomal rearrangement. In practice, 20p12.3 deletion should be considered as an etiological diagnosis in the case of syndromic cleft palate.
MOLECULAR CYTOGENETIC STUDIES IDENTIFY NOVEL CHROMOSOMAL ABERRATIONS IN MY-ELOID MALIGNANCES OF FANCONI ANEMIA
Borges M.L.R.12, Soares-Ventura E.M.1, de Araûjo Silva Amaral B.1, Cornélio M. T.M.N.1~2, Araûjo S.M.1, Liehr T.3,
РОССИЙСКИЙ ВЕСТНИК ПЕРИНАТОЛОГИИ И ПЕДИАТРИИ, 4, 2016 ROSSIYSKIY VESTNIK PERINATOLOGY IPEDIATRII, 4, 2016
ИННОВАЦИОННЫЕ ТЕХНОЛОГИИ В ПЕДИАТРИИ И ДЕТСКОЙ ХИРУРГИИ
Silva M.L.M.4, de Jesus Marques-Salles T.1 'Pediatric Oncohematology Center, Hospital Oswaldo Cruz/ Pos Graduation Course of the Faculty of Medical Sciences, University of Pernambuco, Recife/PE, Brazil; 2Biologic Sciences Institute, Pernambuco University, Recife/PE, Brazil;
3Jena University Hospital, Institute of Human Genetics, Jena, Germany;
"Cytogenetic Department, National Center for Bone Marrow Transplant (CEMO-INCA), National Cancer Institute, Rio de Janeiro/RJ, Brazil
Fanconi Anemia (FA) is an inherited disorder with congenital and developmental abnormalities, bone marrow failure and an extreme risk to develop myelodys-plastic syndrome or acute myeloid leukemia. Cytogenetic surveillance of bone marrow is an important part of the clinical management of FA as cytogenetic aberrations can help to estimate the moment of malignant trans-fomation. Here, we characterized bone marrow features and implications of chromosomal aberrations in four cases of FA. The molecular karyotyping revealed different acquired abnormalities in three of the four cases, e.g. a high complex and rare karyotype. A fourth patient was also included as an asymptomatic carrier with duplication of chromosome 1. These features showed that FA provokes serious chromosomes abnormalities which in most cases evolve to hematological malignances with fatal outcome. Due to the appearance of rare and complex chromosomal abnormalities, molecular cytogenetics studies are important to determine the real significance of chromosomal aberrations in malignancies derived from FA.
ALPHA-FETOPROTEIN AND ITS VALUE FOR PREDICTING PREGNANCY OUTCOMES - A RE-EVALUATION
Darouich A.A.1, Liehr T.1, Weise A.1, Schleußner E.2, Kiehntopf M.3, Schreyer I.1'4
'Jena University Hospital, Friedrich Schiller University, Institute of Human Genetics, Jena, Germany; 2Jena University Hospital, Friedrich Schiller University, Placenta-Labor, Department of Obstetrics, Jena, Germany;
3Jena University Hospital, Friedrich Schiller University, Institute of Clinical Chemistry and Laboratory Diagnostics, Jena, Germany; "Jena University Hospital, Zentrum für ambulante Medizin, Jena, Germany
A retrospective study based on 3,119 singleton and 56 twin pregnancies is presented. The standard levels of am-nion fluid derived alpha-fetoprotein level (AF-AFP) between 12th and 36th week of gestation were determined. Additionally, acetylcholinesterase (AChE) test results for 63 cases, ultrasonography results for 32 cases and abnormal karyotypic findings for 100 cases were available for selected cases. According to the present data the AF-AFP test is reliable and provides expected test results
in terms of population studies. However, individual AF-AFP test results can be subject to high individual variations. In this study AF-AFP multiple of medians (MoM) over 1.7 were indicative for neuronal tube defects and/or omphalocele in only 6.3% of the cases, while such AF-AFP values were hints on severe sonographic signs in 62% of the cases. Also, altered AF-AFP concentrations were present in 82% of cytogenetically abnormal cases. Overall, even though predicative value of the AF-AFP-test is matter of discussion it continues to be widely applied in invasive prenatal diagnostics. This study indicates that it only can be applied reliably in combination with other tests like banding cytogenetics, ultrasonography and all embedded in well-established genetic counseling.
MOLECULAR CHARACTERIZATION OF KMT2A FUSION PARTNER GENES IN 13 CASES OF PEDIATRIC LEUKEMIA WITH COMPLEX OR CRYPTIC KARYOTYPES
Garcia D.R.N.12, de Souza M.T.2-3, de Figueiredo A.F.2-3, Othman M.A.K.5, Abdelhay E.3, de Matos R.R.C.23, Meyer C.6, Marschalek R.6, Land M.G.P.14, Liehr T.5, Ribeiro R.C.7, Silva M.L.M.123 1Clinical Medicine Postgraduate Program, College of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;
Cytogenetics Department, Bone Marrow Transplantation Unit, National Cancer Institute, Rio de Janeiro, Brazil; 3Oncology Post Graduation Program, National Cancer Institute, Rio de Janeiro, Brazil; "Martagao Gesteira Institute of Pediatrics and Child Development, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;
'Institute of Human Genetics, Jena University Hospital, Jena, Germany;
6Institute of Pharmaceutical Biology, Diagnostic Center of Acute Leukemia, Goethe-University of Frankfurt, Frankfurt/Main, Germany;
'Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States
In pediatric acute leukemias, reciprocal chromosomal translocations frequently cause gene fusions involving the lysine (K)-specific methyltransferase 2A gene (KMT2A, also known as MLL). Specific KMT2A fusion partners are associated with the disease phenotype (lym-phoblastic vs. myeloid), and the type of KMT2A rearrangement also has prognostic implications. However, the KMT2A partner gene cannot always be identified by banding karyotyping. We sought to identify such partner genes in 13 cases of childhood leukemia with uninformative karyotypes by combining molecular techniques, including multicolor banding FISH, reverse-transcriptase PCR, and long-distance inverse PCR. Of the KMT2A fusion partner genes, MLLT3 was present in five patients, all with acute lymphoblastic leukemia, MLLT1 in two patients, and MLLT10, MLLT4, MLLT11, and AFF1
РОССИЙСКИЙ ВЕСТНИК ПЕРИНАТОЛОГИИ И ПЕДИАТРИИ, 4, 2016 ROSSIYSKIY VESTNIK PERINATOLOGY IPEDIATRII, 4, 2016
