Thomas Schwarzbraun

Publications of Thomas Schwarzbraun

• MODY type 2 in Greig cephalopolysyndactyly syndrome (GCPS) as part of a contiguous gene deletion syndrome.

  Authors: Amnon Zung, Erwin Petek, Bruria Ben-Zeev, Thomas Schwarzbraun, Sagi Josefsberg Ben-Yehoshua

  American journal of medical genetics. Part A. 10/2011; 155A(10):2469-72.

  Maturity-onset diabetes of the young type 2 (MODY2) is a form of monogenic diabetes, characterized by mild fasting hyperglycemia. MODY2 is caused by heterozygous mutations in the GCK gene thatMaturity-onset diabetes of the young type 2 (MODY2) is a form of monogenic diabetes, characterized by mild fasting hyperglycemia. MODY2 is caused by heterozygous mutations in the GCK gene that encodes the glucokinase enzyme. We describe the clinical features and the underlying genetic defect of MODY2 in a patient with atypical Greig cephalopolysyndactyly syndrome (GCPS). The patient presented with the limb formation and the craniofacial developmental abnormalities typical to GCPS, in addition to mental retardation and epilepsy (assigned as atypical syndrome). Fasting hyperglycemia in the diabetic range, impaired glucose tolerance, and lack of diabetes autoantibodies were compatible with MODY2. In order to delineate the genetic aberrations relevant both to MODY2 and Greig syndrome in this patient, we performed cytogenetic analysis, real-time PCR of the GCK gene, and comparative genomic hybridization (CGH) array. Cytogenetic study has shown a microscopic detectable deletion in the 7p13-15 chromosomal region. Real-time PCR demonstrated a deletion of the GCK gene in the patient but not her parents, and CGH array revealed a deleted region of approximately 12 Mb in the 7p13-15 region. This deleted region included GLI3 and GCK genes (where heterozygous mutations cause GCPS and MODY2, respectively), and many other contiguous genes. Our patient manifests a unique form of MODY2, where GCK gene deletion is part of a large deleted segment in the 7p13-15 chromosomal region.

• Combined molecular genetic and cytogenetic analysis from single cells after isothermal whole-genome amplification.

  Authors: Thomas Kroneis, Jochen B Geigl, Amin El-Heliebi, Martina Auer, Peter Ulz, Thomas Schwarzbraun, Gottfried Dohr, Peter Sedlmayr

  Clinical chemistry. 05/2011; 57(7):1032-41.

  Analysis of chromosomal aberrations or single-gene disorders from rare fetal cells circulating in the blood of pregnant women requires verification of the cells' genomic identity. We have developed aAnalysis of chromosomal aberrations or single-gene disorders from rare fetal cells circulating in the blood of pregnant women requires verification of the cells' genomic identity. We have developed a method enabling multiple analyses at the single-cell level that combines verification of the genomic identity of microchimeric cells with molecular genetic and cytogenetic diagnosis. We used a model system of peripheral blood mononuclear cells spiked with a colon adenocarcinoma cell line and immunofluorescence staining for cytokeratin in combination with DNA staining with the nuclear dye TO-PRO-3 in a preliminary study to define candidate microchimeric (tumor) cells in Cytospin preparations. After laser microdissection, we performed low-volume on-chip isothermal whole-genome amplification (iWGA) of single and pooled cells. DNA fingerprint analysis of iWGA aliquots permitted successful identification of all analyzed candidate microchimeric cell preparations (6 samples of pooled cells, 7 samples of single cells). Sequencing of 3 single-nucleotide polymorphisms was successful at the single-cell level for 20 of 32 allelic loci. Metaphase comparative genomic hybridization (mCGH) with iWGA products of single cells showed the gains and losses known to be present in the genomic DNA of the target cells. This method may be instrumental in cell-based noninvasive prenatal diagnosis. Furthermore, the possibility to perform mCGH with amplified DNA from single cells offers a perspective for the analysis of nonmicrochimeric rare cells exhibiting genomic alterations, such as circulating tumor cells.

• Further evidence for the pathogenicity of 15q24 microduplications distal to the minimal critical regions.

  Authors: Katharina M Roetzer, Thomas Schwarzbraun, Anna C Obenauf, Erwin Hauser, Michael R Speicher

  American journal of medical genetics. Part A. 12/2010; 152A(12):3173-8.

  DNA copy number alterations in 15q24 have repeatedly been reported in patients exhibiting mild to moderate developmental delay and dysmorphic features. To date, mainly microdeletions have beenDNA copy number alterations in 15q24 have repeatedly been reported in patients exhibiting mild to moderate developmental delay and dysmorphic features. To date, mainly microdeletions have been described, and comparison of overlapping regions allowed the definition of minimal critical regions (MCRs) for microdeletions as well as microduplications. These MCRs are associated with distinct phenotypes. Recently, a family with a new microduplication distal to these MCRs was reported. However, for this alteration the typical phenotypical consequences could not yet be determined. Here we present another family with a nearly identical microduplication exhibiting a broad clinical spectrum including developmental delay, autistic traits and dysmorphic features. Our data suggest that microduplications adjacent and distal to the known MCRs are variable in expressivity and are associated with distinct features. They might represent a novel and recurrent microduplication syndrome.

• Androgen receptor expression in breast cancer patients tested for BRCA1 and BRCA2 mutations.

  Authors: Gunda Pristauz, Edgar Petru, Elvira Stacher, Jochen B Geigl, Thomas Schwarzbraun, Oleksiy Tsybrovskyy, Raimund Winter, Farid Moinfar

  Histopathology. 12/2010; 57(6):877-84.

  To assess the expression of receptors for androgen (AR), oestrogen (ER) and progesterone (PR) as well as human epidermal growth factor receptor type 2 (Her-2/neu) status of breast carcinomas inTo assess the expression of receptors for androgen (AR), oestrogen (ER) and progesterone (PR) as well as human epidermal growth factor receptor type 2 (Her-2/neu) status of breast carcinomas in breast cancer susceptibility gene (BRCA) BRCA1/2 mutation carriers and BRCA1/2 negative tested women. One hundred and thirty-five breast cancers in women tested for BRCA1/2 mutations. Screening for BRCA1 and BRCA2 mutations was performed by direct sequencing of all BRCA1 and BRCA2 exons as well as the surrounding intronic sequences. Additionally, BRCA genes were analysed with multiplex ligation-dependent probe amplification. Consecutive paraffin sections were examined immunohistochemically for AR, ER, PR and Her-2/neu. Of the 135 tumours, 43 (32%) were BRCA1-related, 18 (13%) were BRCA2-related and 74 (55%) were BRCA1/2-negative. Seventy-two per cent of the BRCA1-related, 22% of the BRCA2-related and 12% of the BRCA1/2-negative tumours were triple (ER, PR, Her2neu)-negative. Eighty-four per cent of BRCA1 mutated cancers were high-grade (G3) tumours. ARs were expressed in 30% (13 of 43) of BRCA1-related, in 78% (14 of 18) in BRCA2-related tumours and in 76% (56 of 74) in BRCA1/2 negative tumours. Twenty-one per cent of ER-negative BRCA1-related tumours expressed androgen receptors. Approximately one in five BRCA1 mutated breast cancers negative for ER and PR express androgen receptors. Modulation of AR might open a new avenue for treating these high-risk cancers.

• Altered bone matrix mineralization in a patient with Rett syndrome.

  Authors: Jochen G Hofstaetter, Katharina M Roetzer, Petra Krepler, Kamilla Nawrot-Wawrzyniak, Thomas Schwarzbraun, Klaus Klaushofer, Paul Roschger

  Bone. 09/2010; 47(3):701-5.

  Rett syndrome (RTT) is a common X-linked neurodevelopmental disorder caused by mutations in the coding region of methyl-CpG-binding 2 (MECP2) gene. Patients with RTT have a low bone mineral densityRett syndrome (RTT) is a common X-linked neurodevelopmental disorder caused by mutations in the coding region of methyl-CpG-binding 2 (MECP2) gene. Patients with RTT have a low bone mineral density and increased risk of fracture. However, very little is known if bone matrix mineralization is altered in RTT. A 17-year-old girl with a classical form of RTT with a heterozygous nonsense mutation in exon 3 in the MECP2-gene was treated in our hospital. Her femoral neck BMD is 43.3% below the 3rd percentile when compared to age and sex-matched controls. She underwent surgery for correction of her scoliosis, which provided a unique opportunity to obtain bone tissue to study bone matrix mineralization (Bone Mineralization Density Distribution-BMDD) using quantitative backscattered electron imaging (qBEI) and histomorphometry. BMDD outcomes were compared to recently published normative reference data for young individuals. qBEI analysis showed a significant shift to lower matrix mineralization despite histomorphometric indices indicate a low bone turnover. There was a reduction in CaMean (-7.92%) and CaPeak (-3.97%), which describe the degree of mineralization. Furthermore the fraction of low mineralized matrix (CaLow: +261.84%) was dramatically increased, which was accompanied with an increase in the heterogeneity of mineralization (CaWidth: +86.34%). Our findings show a significantly altered bone matrix mineralization of a typical patient with RTT. This may partly explain the low bone density seen in these patients. These results also warrant further studies on the molecular role of MECP2 in bone matrix mineralization.

• Mapping of balanced chromosome translocation breakpoints to the basepair level from microdissected chromosomes.

  Authors: Anna C Obenauf, Thomas Schwarzbraun, Martina Auer, Eva M Hoffmann, Julie Waldispuehl-Geigl, Peter Ulz, Barbara Günther, Hans-Christoph Duba, Michael R Speicher, Jochen B Geigl

  Journal of cellular and molecular medicine. 08/2010; 14(8):2078-84.

  The analysis of structural variants associated with specific phenotypic features is promising for the elucidation of the function of involved genes. There is, however, at present no approach allowingThe analysis of structural variants associated with specific phenotypic features is promising for the elucidation of the function of involved genes. There is, however, at present no approach allowing the rapid mapping of chromosomal translocation breakpoints to the basepair level from a single chromosome. Here we demonstrate that we have advanced both the microdissection and the subsequent unbiased amplification to an extent that breakpoint mapping to the basepair level has become possible. As a case in point we analysed the two breakpoints of a t(7;13) translocation observed in a patient with split hand/foot malformation (SHFM1). The amplification products of the der(7) and of the der(13) were hybridized to custom-made arrays, enabling us to define primers at flanking breakpoint regions and thus to fine-map the breakpoints to the basepair level. Consequently, our results will also contribute to a further delineation of causative mechanisms underlying SHFM1 which are currently unknown.

• The G-protein coupled receptor associated sorting protein GASP-1 regulates the signalling and trafficking of the viral chemokine receptor US28.

  Authors: Pia Tschische, Elisabeth Moser, Dawn Thompson, Henry F Vischer, Gerald P Parzmair, Veronika Pommer, Wolfgang Platzer, Thomas Schwarzbraun, Helmut Schaider, Martine J Smit, Lene Martini, Jennifer L Whistler, Maria Waldhoer

  Traffic (Copenhagen, Denmark). 05/2010; 11(5):660-74.

  Human cytomegalovirus (HCMV) encodes the seven transmembrane(7TM)/G-protein coupled receptor (GPCR) US28, which signals and endocytoses in a constitutive, ligand-independent manner. Here we showHuman cytomegalovirus (HCMV) encodes the seven transmembrane(7TM)/G-protein coupled receptor (GPCR) US28, which signals and endocytoses in a constitutive, ligand-independent manner. Here we show that, following endocytosis, US28 is targeted to the lysosomes for degradation as a consequence of its interaction with the GPCR-associated sorting protein-1 (GASP-1). We find that GASP-1 binds to US28 in vitro and that disruption of the GASP-1/US28 interaction by either (i) overexpression of dominant negative cGASP-1 or by (ii) shRNA knock-down of endogenous GASP-1 is sufficient to inhibit the lysosomal targeting of US28 and slow its post-endocytic degradation. Furthermore, we found that GASP-1 affects US28-mediated signalling. The knock-down of endogenous GASP-1 impairs the US28-mediated Galphaq/PLC/inositol phosphate (IP) accumulation as well as the activation of the transcription factors Nuclear Factor-kappaB (NF-kappaB) and cyclic AMP responsive element binding protein (CREB). Overexpression of GASP-1 enhances both IP accumulation and transcription factor activity. Thus, GASP-1 is an important cellular determinant that not only regulates the post-endocytic trafficking of US28, but also regulates the signalling capacities of US28.

• Sporadic gastric Peutz-Jeghers polyp with intraepithelial neoplasia.

  Authors: Lars Harbaum, Jochen B Geigl, Hildegard Volkholz, Thomas Schwarzbraun, Harald Oschmautz, Michael Vieth, Cord Langner

  APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. 12/2009; 117(12):941-3.

• Predictive diagnosis of the cancer prone Li-Fraumeni syndrome by accident: new challenges through whole-genome array testing.

  Authors: Thomas Schwarzbraun, Anna Obenauf, Andrea Langmann, Ursula Gruber-Sedlmayr, Klaus Wagner, Michael Speicher, Peter Kroisel

  Journal of medical genetics. 04/2009;

  Li-Fraumeni syndrome greatly increases the risk of developing several types of cancer and is usually caused by TP53 germline mutations. Predictive testing of at-risk family members is only offeredLi-Fraumeni syndrome greatly increases the risk of developing several types of cancer and is usually caused by TP53 germline mutations. Predictive testing of at-risk family members is only offered after a complex genetic counseling process. Recently the clinical implementation of array comparative genomic hybridization (CGH) has revolutionized the diagnosis of patients with syndromic or nonsyndromic mental retardation and has evolved to a routinely performed high-resolution whole-genome scan. When using array-CGH to identify the cause for mental retardation in a seven-year-old child we found a submicroscopic de novo deletion of chromosome 17p13.1, which includes several genes likely to be causative for her phenotype, and also of TP53. Thus, array-CGH resulted in an unintended predictive diagnosis of an increased tumor susceptibility as observed in Li-Fraumeni syndrome.

• Identification and in silico analysis of 14 novel GJB1, MPZ and PMP22 gene mutations.

  Authors: Gabriel Miltenberger-Miltenyi, Thomas Schwarzbraun, Wolfgang N Löscher, Julia Wanschitz, Christian Windpassinger, Hans-Christoph Duba, Rainer Seidl, Gerhard Albrecht, Helga Weirich-Schwaiger, Heinz Zoller, Gerd Utermann, Michaela Auer-Grumbach, Andreas R Janecke

  European journal of human genetics : EJHG. 04/2009;

  Duplication within the chromosome 17p11.2 (CMT1Adup), peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and gap junction beta1-protein (GJB1) gene mutations are frequent causes of theDuplication within the chromosome 17p11.2 (CMT1Adup), peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and gap junction beta1-protein (GJB1) gene mutations are frequent causes of the Charcot-Marie-Tooth disease (CMT). A large number of mutations in these genes are listed in databases. Sequence variants identified in patients are frequently reported as mutations without further evaluation. We analyzed 250 consecutively recruited unrelated Austrian CMT patients for CMT1Adup by microsatellite marker typing, real-time PCR or MLPA, and found 79 duplications (31.6%). The coding regions of the PMP22, MPZ and GJB1 genes were analyzed by direct sequencing in the remaining patients; 28 patients showed mutations, 14 of which were novel. We scored the pathogenicity of novel missense mutations by segregation studies and by their exclusion in control samples. Our comprehensive literature study found that up to 60% of the reported mutations in these genes had not been evaluated regarding their pathogenicity, and the PANTHER bioinformatics tool was used to score novel and published missense variants. The PANTHER program scored known polymorphisms as such, but scored approximately 82-88% only of the published and novel mutations as most likely deleterious. Mutations associated with axonal CMT were less likely to be classified as deleterious, and the PMP22 S72L mutation repeatedly associated with severe CMT was classified as a polymorphism using default parameters. Our data suggest that this in silico analysis tool could be useful for assessing the functional impact of DNA variations only as a complementary approach. The CMT1Adup, GJB1, MPZ and PMP22 mutation frequencies were in the range of those described in other CMT patient collectives with different ethnical backgrounds.European Journal of Human Genetics advance online publication, 4 March 2009; doi:10.1038/ejhg.2009.29.

• Characterization of a de novo translocation t(5;18)(q33.1;q12.1) in an autistic boy identifies a breakpoint close to SH3TC2, ADRB2, and HTR4 on 5q, and within the desmocollin gene cluster on 18q.

  Authors: John B Vincent, Abdul Noor, Christian Windpassinger, Peter J Gianakopoulos, Thomas Schwarzbraun, Simon E Alfred, Beata Stachowiak, Stephen W Scherer, Wendy Roberts, Klaus Wagner, Peter M Kroisel, Erwin Petek

  American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 01/2009;

  We have recently reported the identification of a de novo balanced translocation t(5;18)(q33.1;q12.1) in a boy with autism. Here we discuss the identification of the breakpoints on chromosomes 5 andWe have recently reported the identification of a de novo balanced translocation t(5;18)(q33.1;q12.1) in a boy with autism. Here we discuss the identification of the breakpoints on chromosomes 5 and 18, and subsequent genomic and candidate gene analyses. The 18q breakpoint lies between desmocollin genes DSC1 and DSC2. The chromosome 5 breakpoint lies at the 3' end of the SH3TC2 gene and distal to beta-adrenergic receptor gene ADRB2 and serotonin receptor gene HTR4. We hypothesized that the transcription of one (or more) of these genes is affected by the translocation by position effect. Looking at allele-specific gene expression for the genes at the 5q locus, we were able to determine that ADRB2 is expressed from both the normal and derivative alleles. Due to the lack of expression in available tissues or lack of available informative transcribed SNPs, we were unable to exclude the involvement of SH3TC2 and HTR4 due to position effect. However, we determined that both DSC1 and DSC2 are only transcribed from the normal chromosome 18 in lymphocytes from the proband. This monoallelic expression of DSC2 may put the patient at risk for arrythmogenic right ventricular cardiomyopathy. Desmocollin genes encode cell-adhesion molecules, and are also highly expressed in brain regions, and thus may also be important for normal neuronal functioning. While a role for SH3TC2, ADRB2, and HTR4 as putative candidate genes for autism cannot be discounted, a role for the desmocollin genes at the 18q breakpoint should also be considered. (c) 2008 Wiley-Liss, Inc.

• Persistence of DNA threads in human anaphase cells suggests late completion of sister chromatid decatenation.

  Authors: Lily Hui-Ching Wang, Thomas Schwarzbraun, Michael R Speicher, Erich A Nigg

  Chromosoma. 05/2008; 117(2):123-35.

  PICH (Plk1-interacting checkpoint helicase) was recently identified as an essential component of the spindle assembly checkpoint and shown to localize to kinetochores, inner centromeres, and thinPICH (Plk1-interacting checkpoint helicase) was recently identified as an essential component of the spindle assembly checkpoint and shown to localize to kinetochores, inner centromeres, and thin threads connecting separating chromosomes even during anaphase. In this paper, we have used immuno-fiber fluorescence in situ hybridization and chromatin-immunoprecipitation to demonstrate that PICH associates with centromeric chromatin during anaphase. Furthermore, by careful analysis of PICH-positive anaphase threads through FISH as well as bromo-deoxyurdine and CREST labeling, we strengthen the evidence that these threads comprise mainly alphoid centromere deoxyribonucleic acid. Finally, by timing the addition of ICRF-193 (a specific inhibitor of topoisomerase-II alpha) to cells synchronized in anaphase, we demonstrate that topoisomerase activity is required specifically to resolve PICH-positive threads during anaphase (as opposed to being required to prevent the formation of such threads during earlier cell cycle stages). These data indicate that PICH associates with centromeres during anaphase and that most PICH-positive threads evolve from inner centromeres as these stretch in response to tension. Moreover, they show that topoisomerase activity is required during anaphase for the resolution of PICH-positive threads, implying that the complete separation of sister chromatids occurs later than previously assumed.

• Defining 'chromosomal instability'.

  Authors: Jochen B Geigl, Anna C Obenauf, Thomas Schwarzbraun, Michael R Speicher

  Trends in genetics : TIG. 03/2008; 24(2):64-9.

  Most scientists agree that the majority of human solid malignant tumors are characterized by chromosomal instability (CIN) involving gain or loss of whole chromosomes or fractions of chromosomes. CINMost scientists agree that the majority of human solid malignant tumors are characterized by chromosomal instability (CIN) involving gain or loss of whole chromosomes or fractions of chromosomes. CIN is thought to be an early event during tumorigenesis and might therefore be involved in tumor initiation. Despite its frequent occurrence in tumors and its potential importance in tumor evolution, CIN is poorly defined and is used inconsistently and imprecisely. Here, we provide criteria to define CIN and argue that few experimental approaches are capable of assessing the presence of CIN. Accurate assessment of CIN is crucial to elucidate whether CIN is a driving force for tumorigenesis and whether a chromosomally unstable genome is necessary for tumor progression.

• An X-linked myopathy with postural muscle atrophy and generalized hypertrophy, termed XMPMA, is caused by mutations in FHL1.

  Authors: Christian Windpassinger, Benedikt Schoser, Volker Straub, Sonja Hochmeister, Abdul Noor, Birgit Lohberger, Natalie Farra, Erwin Petek, Thomas Schwarzbraun, Lisa Ofner, Wolfgang N Löscher, Klaus Wagner, Hanns Lochmüller, John B Vincent, Stefan Quasthoff

  American journal of human genetics. 02/2008; 82(1):88-99.

  We have identified a large multigenerational Austrian family displaying a novel form of X-linked recessive myopathy. Affected individuals develop an adult-onset scapulo-axio-peroneal myopathy withWe have identified a large multigenerational Austrian family displaying a novel form of X-linked recessive myopathy. Affected individuals develop an adult-onset scapulo-axio-peroneal myopathy with bent-spine syndrome characterized by specific atrophy of postural muscles along with pseudoathleticism or hypertrophy and cardiac involvement. Known X-linked myopathies were excluded by simple-tandem-repeat polymorphism (STRP) and single-nucleotide polymorphism (SNP) analysis, direct gene sequencing, and immunohistochemical analysis. STRP analysis revealed significant linkage at Xq25-q27.1. Haplotype analysis based on SNP microarray data from selected family members confirmed this linkage region on the distal arm of the X chromosome, thereby narrowing down the critical interval to 12 Mb. Sequencing of functional candidate genes led to the identification of a missense mutation within the four and a half LIM domain 1 gene (FHL1), which putatively disrupts the fourth LIM domain of the protein. Mutation screening of FHL1 in a myopathy family from the UK exhibiting an almost identical phenotype revealed a 3 bp insertion mutation within the second LIM domain. FHL1 on Xq26.3 is highly expressed in skeletal and cardiac muscles. Western-blot analysis of muscle biopsies showed a marked decrease in protein expression of FHL1 in patients, in concordance with the genetic data. In summary, we have to our knowledge characterized a new disorder, X-linked myopathy with postural muscle atrophy (XMPMA), and identified FHL1 as the causative gene. This is the first FHL protein to be identified in conjunction with a human genetic disorder and further supports the role of FHL proteins in the development and maintenance of muscle tissue. Mutation screening of FHL1 should be considered for patients with uncharacterized myopathies and cardiomyopathies.

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• A new 3p interstitial deletion including the entire MITF gene causes a variation of Tietz/Waardenburg type IIA syndromes.

  Authors: Thomas Schwarzbraun, Lisa Ofner, Gabriele Gillessen-Kaesbach, Barbara Schaperdoth, Karl-Heinz Preisegger, Christian Windpassinger, Klaus Wagner, Erwin Petek, Peter M Kroisel

  American journal of medical genetics. Part A. 04/2007; 143(6):619-24.

• Molecular and genomic studies of IMMP2L and mutation screening in autism and Tourette syndrome.

  Authors: Erwin Petek, Thomas Schwarzbraun, Abdul Noor, Megha Patel, Kazuhiko Nakabayashi, Sanaa Choufani, Christian Windpassinger, Mara Stamenkovic, Mary M Robertson, Harald N Aschauer, Hugh M D Gurling, Peter M Kroisel, Klaus Wagner, Stephen W Scherer, John B Vincent

  Molecular genetics and genomics : MGG. 02/2007; 277(1):71-81.

  We recently reported the disruption of the inner mitochondrial membrane peptidase 2-like (IMMP2L) gene by a chromosomal breakpoint in a patient with Gilles de la Tourette syndrome (GTS). In theWe recently reported the disruption of the inner mitochondrial membrane peptidase 2-like (IMMP2L) gene by a chromosomal breakpoint in a patient with Gilles de la Tourette syndrome (GTS). In the present study we sought to identify genetic variation in IMMP2L, which, through alteration of protein function or level of expression might contribute to the manifestation of GTS. We screened 39 GTS patients, and, due to the localization of IMMP2L in the critical region for the autistic disorder (AD) locus on chromosome 7q (AUTS1), 95 multiplex AD families; however, no coding mutations were found in either GTS or AD patients. In addition, no parental-specific expression of IMMP2L was detected in somatic cell hybrids containing human chromosome 7 and human cell lines carrying a maternal uniparental disomy for chromosome 7 (mUPD7). Despite the fact that no deleterious mutations in IMMPL2 (other than the inverted duplication identified previously) were identified in either GTS or AD, this gene cannot be excluded as a possible rare cause of either disorder.

• Phenotypic and molecular characterisation of a de novo 5q deletion that includes the APC gene.

  Authors: Lisa Ofner, Jochen Raedle, Christian Windpassinger, Thomas Schwarzbraun, Peter M Kroisel, Klaus Wagner, Erwin Petek

  Journal of human genetics. 02/2006; 51(2):141-6.

  We report on a 12-year-old female patient with mild dysmorphic signs, including bilateral epicanthal folds, low-set dysplastic ears, a short nose with anteverted nostrils, conically shaped fingers,We report on a 12-year-old female patient with mild dysmorphic signs, including bilateral epicanthal folds, low-set dysplastic ears, a short nose with anteverted nostrils, conically shaped fingers, generalised increase of subcutaneous fat, multiple fine venous teleangiectasia on her back, mild pectus carinatum, and a general muscular hypotonia. Cytogenetic analysis and fluorescence in situ hybridisation (FISH) studies using region-specific BAC and YAC clones indicated a de novo interstitial deletion of the long arm of chromosome 5, resulting in monosomy 5q21.1-q23.1. Molecular analysis of polymorphic markers helped to narrow down the breakpoints and demonstrated that the derivative chromosome 5 is of paternal origin. By using the same panel of polymorphic markers, a reinvestigation of a similar, already published, 5q deletion case [Raedle et al. (2001) Am J Gastroenterol 96:3016-3020] was performed, allowing a more detailed genotype-phenotype correlation. Phenotypic classification was also carried out. Several known genes, including APC and MCC, were found to map to the common deleted genomic segment. Genetic counselling based on the molecular analysis data was performed for the index family.

• Cloning, genomic structure, and expression profiles of TULIP1 (GARNL1), a brain-expressed candidate gene for 14q13-linked neurological phenotypes, and its murine homologue.

  Authors: Thomas Schwarzbraun, John B Vincent, Axel Schumacher, Daniel H Geschwind, Joao Oliveira, Christian Windpassinger, Lisa Ofner, Michael K Ledinegg, Peter M Kroisel, Klaus Wagner, Erwin Petek

  Genomics. 10/2004; 84(3):577-86.

  Previously, we have described the clinical and molecular characterization of a de novo 14q13.1-q21.1 microdeletion, less than 3.5 Mb in size, in a patient with severe microcephaly, psychomotorPreviously, we have described the clinical and molecular characterization of a de novo 14q13.1-q21.1 microdeletion, less than 3.5 Mb in size, in a patient with severe microcephaly, psychomotor retardation, and other clinical anomalies. Here we report the characterization of the genomic structure of the human tuberin-like protein gene 1 (TULIP1; approved gene symbol GARNL1), a CpGisland-associated, brain-expressed candidate gene for the neurological findings in our patient, and its murine homologue. The human TULIP1 gene was mapped to chromosome band 14q13.2 by fluorescence in situ hybridization of BAC clone RP11-355C3 (GenBank Accession No. AL160231), containing the 3' region of the gene. TULIP1 spans about 271 kb of human genomic DNA and is divided into 41 exons. An untranscribed, processed pseudogene of TULIP1 was found on human chromosome band 9q31.1. The active locus TULIP1, encoding a predicted protein of 2036 amino acids, is expressed ubiquitously in pre- and postnatal human tissues. The murine homologue Tulip1 spans about 220 kb of mouse genomic DNA and is also divided into 41 exons, encoding a predicted protein of 2035 amino acids. No pseudogene could be found in the available mouse sequence data. Several splicing variants were found. Considering the location, expression profile, and predicted function, TULIP1 is a strong candidate for several neurological features seen in 14q deletion patients. Additionally we searched for mutations in the coding region of TULIP1 in subjects from a family with idiopathic basal ganglia calcification (IBGC; Fahr disease), previously linked to chromosome 14q. We identified two novel SNPs in the intron-exon boundaries; however, they did not segregate only with affected subjects in the predicted model of an autosomal dominant disease such as IBGC.

• Genomic analysis of five chromosome 7p deletion patients with Greig cephalopolysyndactyly syndrome (GCPS).

  Authors: Thomas Schwarzbraun, Christian Windpassinger, Lisa Ofner, John B Vincent, Joseph Cheung, Stephen W Scherer, Klaus Wagner, Peter M Kroisel, Erwin Petek

  European journal of medical genetics. 49(4):338-45.

  Chromosomal deletions on chromosome 7p are associated with Greig cephalopolysyndactyly syndrome (GCPS, OMIM 175700) a syndrome affecting the development of the skull, face, and limbs. We haveChromosomal deletions on chromosome 7p are associated with Greig cephalopolysyndactyly syndrome (GCPS, OMIM 175700) a syndrome affecting the development of the skull, face, and limbs. We have compared data from molecular cytogenetic and genetic analyses with clinical symptoms from five previously published GCPS deletion patients, including a pair of monozygotic twins. The genomic DNA of the probands and their parents, as well as the DNA from monoallelic cell lines of two patients, was analyzed using microsatellite markers. In some cases (e.g. where the microsatellite studies were uninformative) we also used fluorescence in situ hybridization (FISH) with bacterial artificial chromosomes (BAC) probes. The fine mapping results of the deletions and genomic data from chromosome 7, were compared to the clinical symptoms. Common breakpoint sequences or mutation hotspots were not observed. Mutation screening for PGAM2, which is responsible for a form of myopathy with recessive inheritance, was performed in all patients. Loss of heterozygosity for known genes with dominant inheritance, such as the glucokinase gene (GCK), which, when mutated or haploinsufficient, is responsible for maturity-onset diabetes of the young, type II (MODY2, OMIM 125851), was identified and included in a genetic counseling of the patients' families.

• Genomic analysis of five chromosome 7p deletion patients with Greig cephalopolysyndactyly syndrome (GCPS)

  Authors: Thomas Schwarzbraun, Christian Windpassinger, Lisa Ofner, John B. Vincent, Joseph Cheung, Stephen W. Scherer, Klaus Wagner, Peter M. Kroisel, Erwin Petek

  European Journal of Medical Genetics.

  Chromosomal deletions on chromosome 7p are associated with Greig cephalopolysyndactyly syndrome (GCPS, OMIM 175700) a syndrome affecting the development of the skull, face, and limbs. We haveChromosomal deletions on chromosome 7p are associated with Greig cephalopolysyndactyly syndrome (GCPS, OMIM 175700) a syndrome affecting the development of the skull, face, and limbs. We have compared data from molecular cytogenetic and genetic analyses with clinical symptoms from five previously published GCPS deletion patients, including a pair of monozygotic twins. The genomic DNA of the probands and their parents, as well as the DNA from monoallelic cell lines of two patients, was analyzed using microsatellite markers. In some cases (e.g. where the microsatellite studies were uninformative) we also used fluorescence in situ hybridization (FISH) with bacterial artificial chromosomes (BAC) probes. The fine mapping results of the deletions and genomic data from chromosome 7, were compared to the clinical symptoms. Common breakpoint sequences or mutation hotspots were not observed. Mutation screening for PGAM2, which is responsible for a form of myopathy with recessive inheritance, was performed in all patients. Loss of heterozygosity for known genes with dominant inheritance, such as the glucokinase gene (GCK), which, when mutated or haploinsufficient, is responsible for maturity-onset diabetes of the young, type II (MODY2, OMIM 125851), was identified and included in a genetic counseling of the patients' families.