Dikow N.,University of Heidelberg |
Maas B.,University of Heidelberg |
Gaspar H.,Institute of Human Genetics |
Kreiss-Nachtsheim M.,University of Bonn |
And 10 more authors.
American Journal of Medical Genetics, Part A | Year: 2013
Loss-of-function mutations of NSD1 and 5q35 microdeletions encompassing NSD1 are a major cause of Sotos syndrome (Sos), which is characterized by overgrowth, macrocephaly, characteristic facies, and variable intellectual disability (ID). Microduplications of 5q35.2-q35.3 including NSD1 have been reported in only five patients so far and described clinically as a reversed Sos resulting from a hypothetical gene dosage effect of NSD1. Here, we report on nine patients from five families with interstitial duplication 5q35 including NSD1 detected by molecular karyotyping. The clinical features of all 14 individuals are reviewed. Patients with microduplications including NSD1 appear to have a consistent phenotype consisting of short stature, microcephaly, learning disability or mild to moderate ID, and distinctive facial features comprising periorbital fullness, short palpebral fissures, a long nose with broad or long nasal tip, a smooth philtrum and a thin upper lip vermilion. Behavioral problems, ocular and minor hand anomalies may be associated. Based on our findings, we discuss the possible etiology and conclude that it is possible, but so far unproven, that a gene dosage effect of NSD1 may be the major cause. © 2013 Wiley Periodicals, Inc.
Morak M.,Ludwig Maximilians University of Munich |
Heidenreich B.,Ludwig Maximilians University of Munich |
Keller G.,TU Munich |
Hampel H.,Ohio State University |
And 3 more authors.
European Journal of Human Genetics | Year: 2014
The hallmarks of Lynch syndrome (LS) include a positive family history of colorectal cancer (CRC), germline mutations in the DNA mismatch repair (MMR) genes, tumours with high microsatellite instability (MSI-H) and loss of MMR protein expression. However, in ∼10-15% of clinically suspected LS cases, MMR mutation analyses cannot explain MSI-H and abnormal immunohistochemistry (IHC) results. The highly variable phenotype of MUTYH-associated polyposis (MAP) can overlap with the LS phenotype, but is inherited recessively. We analysed the MUTYH gene in 85 'unresolved' patients with tumours showing IHC MMR-deficiency without detectable germline mutation. Biallelic p.(Tyr179Cys) MUTYH germline mutations were found in one patient (frequency 1.18%) with CRC, urothelial carcinoma and a sebaceous gland carcinoma. LS was suspected due to a positive family history of CRC and because of MSI-H and MSH2-MSH6 deficiency on IHC in the sebaceous gland carcinoma. Sequencing of this tumour revealed two somatic MSH2 mutations, thus explaining MSI-H and IHC results, and mimicking LS-like histopathology. This is the first report of two somatic MSH2 mutations leading to an MSI-H tumour lacking MSH2-MSH6 protein expression in a patient with MAP. In addition to typical transversion mutations in KRAS and APC, MAP can also induce tumourigenesis via the MSI-pathway. © 2014 Macmillan Publishers Limited All rights reserved.
Neuhann T.M.,MGZ Medizinisch Genetisches Zentrum |
Stegerer A.,MGZ Medizinisch Genetisches Zentrum |
Riess A.,Applied Genomics |
Blair E.,University of Oxford |
And 5 more authors.
American Journal of Medical Genetics, Part A | Year: 2015
ADAMTSL4 mutations seem to be the most common cause of isolated ectoplia lentis (EL) and thus are important concerning the differential diagnosis of connective tissue syndromes with EL as main feature. In this study, we describe an additional cohort of patients with apparently isolated EL. All underwent a detailed clinical exam with cardiac evaluation combined with ADAMTSL4 mutation analysis. Mutations were identified in 12/15 patients with EL. Besides the European founder mutation p. (Gln256Profs*38) we identified five further mutations not yet described in the literature: p. (Leu249Tyrfs*21), p. (Ala388Glyfs*8), p. (Arg746His), p. (Gly592Ser), and p. (Arg865His). Clinical evaluation showed common additional ocular features such as high myopia, but no major systemic findings. In particular: no dilatation of the aortic root was reported on. This report increases the total number of patients with ADAMTSL4 mutations reported on today and reviews in detail the clinical findings in all patients reported on to date demonstrate, that these patients have a mainly ocular phenotype. There are no consistent systemic findings. The differentiation between syndromic and isolated EL is crucial for the further surveillance, treatment, and counseling of these patients, especially in young children. © 2015 Wiley Periodicals, Inc.
Wurfel W.,KCM Kinderwunsch Centrum Munich |
Suttner R.,KCM Kinderwunsch Centrum Munich |
Shakeshaft D.,KCM Kinderwunsch Centrum Munich |
Mayer V.,MGZ Medizinisch Genetisches Zentrum |
And 7 more authors.
Geburtshilfe und Frauenheilkunde | Year: 2013
Objective: To demonstrate that a PGD program can be successfully established after the 2011 verdict of the German Bundestag concerning PGD. Material and Method: Eight years previously, the couple had had a daughter who suffered from clinically manifest hemophilia A due to an unbalanced X-inactivation, as well as microdeletion syndrome resulting in severe physical and mental disability. The couple wished to have a second child but refused the idea of a "trialo" pregnancy. Given the indications for both, it was necessary to carry out polar body diagnosis (PBD) to rule out hemophilia A and, during the same cycle, a subsequent PGD on the blastocysts to rule out genetic aberrations. The PBD and PGD (trophectoderm biopsy, TEB) were performed after high-dosage ovarian stimulation and ICSI fertilization of the oocytes. A blastocyst was successfully transferred on day 6. Results: The patient conceived immediately. The pregnancy developed normally and the patient gave birth to a girl in the 40th week of pregnancy. Post-natal examinations showed that the baby is free from hemophilia A and is developing normally both physically and mentally. Conclusion: Establishment of a PGD program is now possible after legalization of PGD in Germany. It is possible to apply two investigative techniques in a single treatment cycle if multifactorial diagnosis is required. © Georg Thieme Verlag KG Stuttgart. New York.
Czeschik J.C.,University of Duisburg - Essen |
Bauer P.,University Hospital of Tuebingen |
Buiting K.,University of Duisburg - Essen |
Dufke C.,University Hospital of Tuebingen |
And 11 more authors.
Orphanet Journal of Rare Diseases | Year: 2013
X-linked intellectual disability type Nascimento (MIM #300860), caused by mutations in UBE2A (MIM *312180), is characterized by craniofacial dysmorphism (synophrys, prominent supraorbital ridges, deep-set, almond-shaped eyes, depressed nasal bridge, prominent columella, hypoplastic alae nasi, and macrostomia), skin anomalies (hirsutism, myxedematous appearance, onychodystrophy), micropenis, moderate to severe intellectual disability (ID), motor delay, impaired/absent speech, and seizures. Hitherto only five familial point mutations and four different deletions including UBE2A have been reported in the literature.We present eight additional individuals from five families with UBE2A associated ID - three males from a consanguineous family, in whom we identified a small deletion of only 7.1 kb encompassing the first three exons of UBE2A, two related males with a UBE2A missense mutation in exon 4, a patient with a de novo nonsense mutation in exon 6, and two sporadic males with larger deletions including UBE2A. All affected male individuals share the typical clinical phenotype, all carrier females are unaffected and presented with a completely skewed X inactivation in blood. We conclude that 1.) X-linked intellectual disability type Nascimento is a clinically very distinct entity that might be underdiagnosed to date. 2.) So far, all females carrying a familial UBE2A aberration have a completely skewed X inactivation and are clinically unaffected. This should be taken in to account when counselling those families. 3.) The coverage of an array should be checked carefully prior to analysis since not all arrays have a sufficient resolution at specific loci, or alternative quantitative methods should be applied not to miss small deletions. © 2013 Czeschik et al.; licensee BioMed Central Ltd.
Canis M.,Ludwig Maximilians University of Munich |
Canis M.,University of Gottingen |
Lechner A.,Ludwig Maximilians University of Munich |
MacK B.,Ludwig Maximilians University of Munich |
And 5 more authors.
Cancer Biomarkers | Year: 2012
BACKGROUND: The pentaspan protein CD133 (Prominin-1) is a predictive marker and part of the signature of tumour-initiating cells (TICs) for various cancer entities. METHODS: The correlation of CD133 expression with clinical parameters was assessed in primary samples of head and neck squamous cell carcinomas (n=98) and normal mucosas (n=24). RESULTS: A gradual and inversely proportional correlation between CD133 expression in primary tumours and decreased overall survival was observed, along with a positive correlation with the presence of lymph node metastases. CONCLUSIONS: CD133 has the potential of being a novel clinically relevant prognostic marker for head and neck malignancies, which is possibly involved in regulation of tumourigenicity. © 2012/2013 - IOS Press and the authors. All rights reserved.
Seifert B.,KITZ KinderwunschTherapie im Zentrum |
Paulmann B.,KITZ KinderwunschTherapie im Zentrum |
Seifert D.,KITZ KinderwunschTherapie im Zentrum |
Brey S.,KITZ KinderwunschTherapie im Zentrum |
And 5 more authors.
Journal fur Reproduktionsmedizin und Endokrinologie | Year: 2014
On July 6th, 2010 the German Supreme Court (BGH) approved a case of Preimplantation Genetic Diagnosis (PGD) as conformable with the German Embryo Protection law, but highlighted several restrictions. Following this act, we conducted a prospective study to establish PGD after biopsy of trophectoderm from blastocysts. 40 treatment cycles from 29 nonparous couples were included. Of these, 15 had chromosomal translocations (reciprocal or Robertsonian), 12 patients presented recurrent miscarriages and 2 showed a positive family history for a monogenic disease. In total, 122 blastocysts underwent a biopsy of trophectoderm (n = 3/cycle). Of 109 biopsies for which array CGH has been scheduled, we were able to amplify and analyze DNA of 102 blastocysts (93.6%). Of these, 36 blastocysts (35.3%) were euploid or balanced and 66 blastocysts (64.7%) were aneuploid or unbalanced (as a result of the translocation in the couple or a numerical chromosome aberration). DNA amplifi cation failed for 7 blastocysts (6.4%). Blastocysts from the two patients with a positive family history for a monogenetic disease (SMA, gene SMN1) were analyzed using multiplex PCR and sequence analysis. After 26 transfers we counted 14 pregnancies (53.8%). No transfer took place in 8 of 29 patients (27.6%), as all embryos were affected. Exemplarily, we report the fi rst pregnancy in Germany after TEB in a patient with a positive family history for a monogenic disease.
PubMed | Ludwig Maximilians University of Munich, MGZ Medizinisch Genetisches Zentrum, TU Munich and Ohio State University
Type: Journal Article | Journal: European journal of human genetics : EJHG | Year: 2014
The hallmarks of Lynch syndrome (LS) include a positive family history of colorectal cancer (CRC), germline mutations in the DNA mismatch repair (MMR) genes, tumours with high microsatellite instability (MSI-H) and loss of MMR protein expression. However, in 10-15% of clinically suspected LS cases, MMR mutation analyses cannot explain MSI-H and abnormal immunohistochemistry (IHC) results. The highly variable phenotype of MUTYH-associated polyposis (MAP) can overlap with the LS phenotype, but is inherited recessively. We analysed the MUTYH gene in 85 unresolved patients with tumours showing IHC MMR-deficiency without detectable germline mutation. Biallelic p.(Tyr179Cys) MUTYH germline mutations were found in one patient (frequency 1.18%) with CRC, urothelial carcinoma and a sebaceous gland carcinoma. LS was suspected due to a positive family history of CRC and because of MSI-H and MSH2-MSH6 deficiency on IHC in the sebaceous gland carcinoma. Sequencing of this tumour revealed two somatic MSH2 mutations, thus explaining MSI-H and IHC results, and mimicking LS-like histopathology. This is the first report of two somatic MSH2 mutations leading to an MSI-H tumour lacking MSH2-MSH6 protein expression in a patient with MAP. In addition to typical transversion mutations in KRAS and APC, MAP can also induce tumourigenesis via the MSI-pathway.
Koehler U.,MGZ Medizinisch Genetisches Zentrum |
Schoen U.,MGZ Medizinisch Genetisches Zentrum |
Mayer V.,MGZ Medizinisch Genetisches Zentrum |
Holinski-Feder E.,MGZ Medizinisch Genetisches Zentrum
Journal fur Reproduktionsmedizin und Endokrinologie | Year: 2013
Since its dawn in the late 1980s, preimplantation genetic diagnosis (PGD, or Präimplantationsdiagnostik, PID) has evolved into a well-established technique, which can be offered to couples at risk of transmitting a mutation or a chromosomal aberration to their offspring. Polar bodies as well as day 3 blastomeres and day 5 blastocysts (trophectoderm) can be employed for the detection of a specific gene mutation or unbalanced karyotypes. For the latter, array comparative genomic hybridisation (array CGH) has replaced fluorescence in situ hybridisation (FISH) approaches. Furthermore, as blastocysts seem to exhibit less mosaicism compared to blastomeres, current PGD protocols focus on the analysis of blastocysts, however polar body testing is still applied for maternally derived conditions. In November 2011, the German embryo protection law (ESchG) has been supplemented by §3a, which defines the conditions for the legal implementation of PGD (PräimpG) in Germany.