Yorck Hellenbroich

Universität zu Lübeck, Lübeck Hansestadt, Schleswig-Holstein, Germany

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Publications (46)168.19 Total impact

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    ABSTRACT: Für Paare mit hohem Risiko der Nachkommen für eine monogen-erbliche oder chromosomal-bedingte Erkrankung kann die Präimplantationsdiagnostik (PID) heute eine Option einer verantwortlichen Familienplanung sein. Voraussetzung für eine PID ist die Befruchtung von Eizellen im Reagenzglas (In-vitro-Fertilisation, IVF). Die Behandlungsergebnisse entsprechen weitgehend denen einer normalen Kinderwunschbehandlung mit intrazytoplasmatischer Spermieninjektion (ICSI) ohne PID. Die Grenzen und Chancen, aber auch der hohe Aufwand, sind frühzeitig und ergebnisoffen in einer interdisziplinären Beratung zu thematisieren, um dem Paar eine informierte Entscheidung und Abwägung der PID gegenüber anderen Alternativen im Rahmen der Familienplanung zu ermöglichen. In diesem Beitrag werden der aktuelle internationale Kenntnisstand zur PID, einschließlich ihrer verschiedenen Anwendungsbereiche, sowie mögliche zukünftige Entwicklungen vorgestellt. Breiten Raum nimmt der rechtliche Rahmen für die eng begrenzte Durchführung einer PID in Deutschland ein, der durch den Deutschen Bundestag mit der Verabschiedung des Gesetzes zur Regelung der Präimplantationsdiagnostik (Präimplantationsdiagnostikgesetz, PräimpG) 2011 und der nachfolgenden Rechtsverordnung 2012 definiert wurde. Abschließend wird der derzeitige Stand der Umsetzung in Deutschland skizziert und eine nationale Koordination und Vernetzung der PID-Zentren angeregt, um zeitnah unter optimaler Nutzung der Ressourcen und Erfahrungen für ein möglichst breites Spektrum an seltenen Erkrankungen eine qualitätsgesicherte PID in Deutschland anbieten zu können.
    No preview · Article · Dec 2014 · Medizinische Genetik
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    ABSTRACT: Cerebral cavernous malformations (CCM) are prevalent vascular malformations occurring in familial autosomal dominantly inherited or isolated forms. Once CCM are diagnosed by magnetic resonance imaging, the indication for genetic testing requires either a positive family history of cavernous lesions or clinical symptoms such as chronic headaches, epilepsy, neurological deficits, and hemorrhagic stroke or the occurrence of multiple lesions in an isolated case. Following these inclusion criteria, the mutation detection rates in a consecutive series of 105 probands were 87% for familial and 57% for isolated cases. Thirty-one novel mutations were identified with a slight shift towards proportionally more CCM3 mutations carriers than previously published (CCM1: 60%, CCM2: 18%, CCM3: 22%). In-frame deletions and exonic missense variants requiring functional analyses to establish their pathogenicity were rare: An in-frame deletion within the C-terminal FERM domain of CCM1 resulted in decreased protein expression and impaired binding to the transmembrane protein heart of glass (HEG1). Notably, 20% of index cases carrying a CCM mutation were below age 10 and 33% below age 18 when referred for genetic testing. Since fulminant disease courses during the first years of life were observed in CCM1 and CCM3 mutation carriers, predictive testing of minor siblings became an issue.
    Full-text · Article · Mar 2014
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    ABSTRACT: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are major causes of blindness. They result from mutations in many genes which has long hampered comprehensive genetic analysis. Recently, targeted next-generation sequencing (NGS) has proven useful to overcome this limitation. To uncover "hidden mutations" such as copy number variations (CNVs) and mutations in non-coding regions, we extended the use of NGS data by quantitative readout for the exons of 55 RP and LCA genes in 126 patients, and by including non-coding 5' exons. We detected several causative CNVs which were key to the diagnosis in hitherto unsolved constellations, e.g. hemizygous point mutations in consanguineous families, and CNVs complemented apparently monoallelic recessive alleles. Mutations of non-coding exon 1 of EYS revealed its contribution to disease. In view of the high carrier frequency for retinal disease gene mutations in the general population, we considered the overall variant load in each patient to assess if a mutation was causative or reflected accidental carriership in patients with mutations in several genes or with single recessive alleles. For example, truncating mutations in RP1, a gene implicated in both recessive and dominant RP, were causative in biallelic constellations, unrelated to disease when heterozygous on a biallelic mutation background of another gene, or even non-pathogenic if close to the C-terminus. Patients with mutations in several loci were common, but without evidence for di- or oligogenic inheritance. Although the number of targeted genes was low compared to previous studies, the mutation detection rate was highest (70%) which likely results from completeness and depth of coverage, and quantitative data analysis. CNV analysis should routinely be applied in targeted NGS, and mutations in non-coding exons give reason to systematically include 5'-UTRs in disease gene or exome panels. Consideration of all variants is indispensable because even truncating mutations may be misleading.
    Full-text · Article · Nov 2013 · PLoS ONE
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    ABSTRACT: 5q14.3 deletions spanning and flanking MEF2C as well as intragenic MEF2C mutations have recently been described as a cause of severe intellectual disability, epilepsy, and muscular hypotonia, with variable brain and other anomalies. With an increasing number of patients described, the clinical presentation of the patients appears to be relatively uniform, however the structural brain phenotypes described are variable. We describe two unrelated patients with overlapping de novo interstitial deletions of 4.1 and 1.9 Mb, including MEF2C in 5q14.3, one of whom had a complex brain malformation which could be best described as microcephaly with simplified gyral pattern (MSG). Expression analysis in both patients confirmed haploinsufficiency for MEF2C, decreased MECP2 expression and increased C3ORF58 (DIA1) expression, which is a new finding. A detailed analysis of brain and white matter abnormalities reported in patients with 5q14.3 deletion syndrome to date revealed a greater number of reported abnormalities in patients with deletions not including MEF2C than those with deletions or mutations directly affecting MEF2C. Screening an additional 43 patients with malformations of cerebral cortical development (MCD) for mutations in MEF2C and/or deletions in 5q14.3q15, did not detect any additional mutations, allowing us to conclude that 5q14.3 deletion syndrome is a rare cause of microcephaly with simplified gyral pattern. © 2013 Wiley Periodicals, Inc.
    No preview · Article · Sep 2013 · American Journal of Medical Genetics Part A
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    ABSTRACT: We report on our experience with array CGH analysis on 1310 samples over the last 5 years. The number of copy number variants (CNV) rises as the resolution of the arrays increases; however, the relevance of some of these findings is difficult to evaluate. Deletion or duplication in 16p11.2 was the most frequently diagnosed pathogenic CNV. Clinically relevant findings which were not directly connected to the query were observed in about 0.2% of patients.
    No preview · Article · Jun 2012 · Medizinische Genetik
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    ABSTRACT: To report the first prenatal dopaminergic replacement therapy in autosomal recessive (AR) guanosine triphosphate cyclohydrolase 1 (GTPCH) deficiency without hyperphenylalaninemia. Case reports, literature review, and video presentation. University of Lübeck, Lübeck, Germany. Two boys from a consanguineous family. Physical and mental development as a function of replacement initiation. The older sibling presented with typical features of AR GTPCH deficiency due to a homozygous mutation in the GCH1 gene with proven pathogenicity. Levodopa treatment was initiated at age 10 months and resulted in a distinct motor improvement. However, mental development was delayed. In the younger sibling, prenatal replacement therapy was initiated after a prenatal diagnosis of AR GTPCH deficiency was made. At age 17 months, both motor and mental development were normal for his age. This report highlights the importance of an early diagnosis, including prenatal diagnosis, of complex dopa-responsive extrapyramidal syndromes. Prenatally initiated dopaminergic replacement therapy is beneficial and thus justified in AR GTPCH deficiency, allowing prevention of significant impairment of mental abilities.
    No preview · Article · Apr 2012 · Archives of neurology
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    ABSTRACT: Schwere und unheilbare genetische Erkrankungen stellen eine große Belastung für die betroffenen Paare dar. Bei der Anlage zu schweren genetischen Erkrankungen ist für die Betroffenen abzuwägen, eine Schwangerschaft einzugehen mit dem Risiko, ein genetisch schwer geschädigtes Kind zu bekommen (u. U. erneut) oder die Erkrankung des Kindes zu erkennen und die „Schwangerschaft auf Probe“ zu beenden. Nach langjährigen, teilweise kontroversen Diskussionen ist jetzt endlich im Bundestag eine Entscheidung gefallen: Die Präimplantationsdiagnostik (PID) an Embryonen soll künftig unter strengen Voraussetzungen zulässig sein. Darüber hat der Bundestag am 07.07.2011 nach einer langen Debatte abgestimmt. Für eine eingeschränkte Zulassung der PID haben sich 326 Abgeordnete ausgesprochen, 260 dagegen. Die PID ist für Paare mit einer Belastung für eine schwere genetische Erkrankung eine Alternative zur pränatalen Diagnostik. Nach dem Urteil des Bundesgerichtshofs zur Zulässigkeit der PID, bei strenger Indikationsstellung, wurde in der Universitätsfrauenklinik Lübeck mit der Anwendung begonnen. Erreicht wurde eine Schwangerschaft nach PID bei Veranlagung für das Desbuquois-Syndrom, eine monogenetisch vererbte Skelettanomalie, bei der sich Herz und Lunge nicht entwickeln können und die Kinder meist intrauterin oder früh postnatal sterben.
    No preview · Article · Jan 2012 · Der Gynäkologe
  • J Spiegler · I Stefanova · Y Hellenbroich · J Sperner
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    ABSTRACT: Alpers-Huttenlocher syndrome (AHS) is a very rare autosomal recessive disorder. AHS is caused by homozygous or compound heterozygous mutations in the nuclear gene encoding mitochondrial DNA polymerase gamma (POLG, chromosome 15q25). Most patients become symptomatic before the age of 2 years. We report 3 patients who were treated in our clinic between 2007 and 2010. All patients suffered from myoclonic seizures and had at least one refractory convulsive status which led to the diagnosis. All of them had varying degrees of developmental delay, 2 of them additionally ataxia. Gastrointestinal motility problems were severe in all patients despite only mildly deranged liver function. While in most aspects our patients present with typical AHS features, they also share intestinal problems, a feature that has not been recognized as typical for AHS before. AHS is a multisystem disorder that does affect all cell systems. Liver and brain are organs with the highest energy demand and are therefore usually affected early in the disease course of AHS. However, constipation and bowel obstruction should be regarded as typical complications in AHS and patients should be monitored and treated to improve quality of life. Regarding treatment options for epilepsy in AHS ketogenic diet as well as lacosamide might be considered.
    No preview · Article · Oct 2011 · Neuropediatrics
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    ABSTRACT: Autosomal dominant spinocerebellar ataxias (SCAs) are heterogeneous neurological disorders characterised by cerebellar dysfunction mostly due to Purkinje cell degeneration. Genetically, 30 different loci have been identified so far whereas the corresponding gene has not yet been determined for 12 of them. The chromosomal location for the spinocerebellar ataxia type 31 (SCA31) has been mapped to chromosome 16q22.1. This region is located within the candidate interval for the spinocerebellar ataxia type 4 (SCA4), for which the underlying mutation still has to be discovered. Recently, a complex (TGGAA)(n) containing repeat insertion within the SCA31 critical region was reported to be causative for SCA31. Although the presence of the pentanucleotide repeat component (TGGAA)(n) seems to be a specific feature of SCA31 patients' insertions, it is still unclear whether a large insertion lacking any (TGGAA) sequence remains nonpathogenic. In order to check whether the German SCA4 patients, belonging to one of the two currently known SCA4 families worldwide, exhibit a potential pathogenic mutation at the SCA31 locus, we performed molecular genetic analyses for affected as well as unaffected family members. Based on a nested-PCR approach and direct sequencing, a disease causing mutation at the SCA31 locus could be excluded for the German SCA4 kindred. However, our data impressively demonstrate the genetic instability in this chromosomal region.
    No preview · Article · Jul 2011 · Journal of Neurology
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    ABSTRACT: Joubert syndrome (JBTS) is characterized by a specific brain malformation with various additional pathologies. It results from mutations in any one of at least 10 different genes, including NPHP1, which encodes nephrocystin-1. JBTS has been linked to dysfunction of primary cilia, since the gene products known to be associated with the disorder localize to this evolutionarily ancient organelle. Here we report the identification of a disease locus, JBTS12, with mutations in the KIF7 gene, an ortholog of the Drosophila kinesin Costal2, in a consanguineous JBTS family and subsequently in other JBTS patients. Interestingly, KIF7 is a known regulator of Hedgehog signaling and a putative ciliary motor protein. We found that KIF7 co-precipitated with nephrocystin-1. Further, knockdown of KIF7 expression in cell lines caused defects in cilia formation and induced abnormal centrosomal duplication and fragmentation of the Golgi network. These cellular phenotypes likely resulted from abnormal tubulin acetylation and microtubular dynamics. Thus, we suggest that modified microtubule stability and growth direction caused by loss of KIF7 function may be an underlying disease mechanism contributing to JBTS.
    Full-text · Article · Jun 2011 · The Journal of clinical investigation
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    ABSTRACT: We report a 21-year-old patient with speech problems, autistic traits, dysmorphic facial features, broad thumbs with short distal phalanges and a pancreatic gastrinoma. Array-CGH demonstrated a 0.57 Mb de novo deletion in chromosome 11q13.1. The deleted region contains several genes which likely contribute to the patient's complex phenotype, including the MEN1 gene. The deletion of the MEN1 gene is causing multiple endocrine neoplasia type 1 (MEN1). The neurodevelopmental phenotype of the patient might be associated with the deletion of the genes NRXN2 and PPP2R5B which have been described to be involved in synaptogenesis and dendritic branching. According to our knowledge, we report for the first time a patient with the combination of a neurodevelopmental phenotype and MEN1 caused by a microdeletion on chromosome 11.
    No preview · Article · Apr 2011 · European journal of medical genetics
  • C. Zühlke · Y. Hellenbroich · G. Gillessen-Kaesbach
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    ABSTRACT: For paediatricians mental retardation/intellectual disability is a frequent question. Approximately 2% of our population show subaverage intellectual functioning that may be associated with dysmorphic signs or malformations, too. The degree of impairment from mental retardation varies widely, from profoundly impaired to mild or borderline retardation. Genetic defects or mutations are detectable in up to 40% of affected persons.
    No preview · Article · Mar 2011
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    ABSTRACT: Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked recessive disorder encompassing pre- and postnatal overgrowth and a variety of additional anomalies including craniofacial dysmorphism, macrocephaly, congenital heart defects and genitourinary anomalies. There is little published information regarding the prenatal presentation of SGBS in pregnancy. In the present report we describe the antenatal features of an affected fetus from 12 gestational weeks onwards, subsequently diagnosed with SGBS by molecular testing positive for GPC3 gene mutation.
    No preview · Article · Feb 2011 · European journal of medical genetics
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    ABSTRACT: DISORDERS OF SEXUAL DEVELOPMENT IN A GROUP OF SUDANESE: HARMONICAL DIAGNOSIS M. Ellaithi 1,2, R. Werner3, F. G. Riepe4, N. Krone5, A. E. Kulle4, A. Kamil6, D. Gissselsson 7,8, W. Alt5, P.-M. Holterhus4, O. Sabir1, O. Hiort3 1Al-Neelain University, Faculty of Medicine and Health Sciences, Khartoum, Sudan 2Ahfad University for Women, Faculty of Pharmacy, Omdurman, Sudan 3University of Lübeck, Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Lübeck, Germany 4University of Kiel, Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Kiel, Germany 5University of Birmingham, Centre for Endocrinology, Diabetes and Metabolism (CEDAM), School of Clinical and Experimental Medicine, Birmingham, United Kingdom 6National Health Centre, Human Genetics, Cairo, Egypt 7Lund University, Department of Clinical Genetics, Lund, Sweden 8Lund University, Department of Pathology, Regional and University Laboratories, Lund, Sweden Introduction: Given the high consanguineous marriage rate and the autosomal recessive inheritance of a large number of disorders of sexual development (DSDs), we can assume a significant problem of DSDs in the Sudanese society. Here we show systematic clinical, hormonal, and genetic diagnosis in some Sudanesecases. Materials: Twelve index cases, aged between 6 months - 33 years (median 13. 4 years old). Ten were raised as females, two as males; all were clinically diagnosed with DSD. Among the cases there were three families, one case with an extended family history of DSD and only one case with no family history. Consanguinity is recorded among all cases. Steroids were analyzed in urine and plasma; accordingly genes correlated were analyzed. Results: Seven cases had a 46, XY and five a 46, XX karyotype. In three cases, results from urine analysis and plasma steroid analysis were discrepant, later gene mutation analysis correlated with urinary steroids more than with plasma steroids. Both urine and plasma steroids were congruent with molecular genetic diagnosis in 6 cases. In three cases, no samples for steroid analyses were available. In the group of 46,XY, three patients had a pathologic HSD17B3 mutation, 4 cases a SRD5A2 mutation, in the group of 46,XX patients, 4 had a CYP21A2, and one case with a CYP11B1 mutation. All mutations are homozygous mutations except for two siblings who have compound heterozygous mutations in HSD17B3 gene. Conclusions: The abnormal steroid profiling was followed by detection of the disease causing genes mutation in all cases with suspected recessive inheritance. Therefore, a stringent and stepwise analysis will give a correct diagnosis. This is of high importance also for the Sudanese society, as most of the patients were quite old at medical investigations and diagnosis was lacking. http://www.dsdturk.org/documents/L%C3%BCbeck-DSD.pdf
    No preview · Conference Paper · Jan 2011
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    ABSTRACT: N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly Ca²(+)-permeable cation channels which are blocked by extracellular Mg²(+) in a voltage-dependent manner. Either GRIN2B or GRIN2A, encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy. Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations. In another cohort of 127 individuals with idiopathic epilepsy and/or mental retardation, we discovered a GRIN2A nonsense mutation in a three-generation family. In a girl with early-onset epileptic encephalopathy, we identified the de novo GRIN2A mutation c.1845C>A predicting the amino acid substitution p.N615K. Analysis of NR1-NR2A(N615K) (NR2A subunit with the p.N615K alteration) receptor currents revealed a loss of the Mg²(+) block and a decrease in Ca²(+) permeability. Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected.
    Full-text · Article · Oct 2010 · Nature Genetics
  • Y. Hellenbroich · S.-K. Frost · G. Gillessen-Kaesbach
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    ABSTRACT: Das Joubert-Syndrom ist ein überwiegend autosomal-rezessiv und sehr selten X-chromosomal erbliches Krankheitsbild, das durch eine muskuläre Hypotonie, ein irreguläres Atmungsmuster, Augenbewegungsstörungen, eine Ataxie, eine Entwicklungsverzögerung und ein „molar tooth sign“ in der Magnetresonanztomographie (MRT) als Ausdruck einer komplexen Klein- und Mittelhirnfehlbildung charakterisiert ist. Zahlreiche weitere klinische Auffälligkeiten können vorliegen, die häufigsten sind eine Nephronophthise, eine Retinopathie, Kolobome und eine Leberfibrose. Aufgrund der klinischen Variabilität und der Überlappung mit anderen Syndromen wurde der Begriff „Joubert syndrome and related disorders“ (JSRD) eingeführt. Bislang sind 10 Gene bekannt, deren Mutationen zu einem Joubert-Syndrom führen können. Die kodierten Proteine spielen alle eine funktionelle Rolle in Zilien. Joubert syndrome generally represents an autosomal recessive and rarely X-linked disorder characterized by hypotonia, an irregular breathing pattern, abnormal eye movements, ataxia, developmental delay and a complex mid-hindbrain malformation causing the molar tooth sign on magnetic resonance imaging (MRI). Many patients have additional features, with nephronophthisis, retinal dystrophy, coloboma and hepatic fibrosis representing the most frequent features. Due to its clinical variability and overlap with other syndromes, the term “Joubert syndrome and related disorders” (JSRD) was proposed. To date 10 genes are known to cause JSRD. The encoded proteins are localized to cilia, linking JSRD to other human ciliopathies. SchlüsselwörterJoubert-Syndrom-„Molar tooth sign“-Ziliopathie-Nephronophthise-Retinopathie KeywordsJoubert syndrome-Molar tooth sign-Ciliopathy-Kidney diseases, cystic-Retinopathy
    No preview · Article · Sep 2010 · Medizinische Genetik
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    ABSTRACT: Structural genome aberrations are frequently associated with highly variable congenital phenotypes involving mental retardation and developmental delay. Although some of these aberrations may result in recognizable phenotypes, a high degree of phenotypic variability often complicates a comprehensive clinical and genetic diagnosis. We describe four patients with overlapping deletions in chromosomal region 1q44, who show developmental delay, in particular of expressive speech, seizures, hypotonia, CNS anomalies, including variable thickness of the abnormal corpus callosum in three of them. High resolution oligonucleotide and SNP array-based segmental aneuploidy profiling showed that these three patients share a 0.440 Mb interstitial deletion, which does not overlap with previously published consensus regions of 1q44 deletions. Two copies of AKT3 and ZNF238, two previously proposed dosage sensitive candidate genes for microcephaly and agenesis of the corpus callosum, were retained in two of our patients. The deletion shared by our patients encompassed the FAM36A, HNRPU, EFCAB2 and KIF26B genes. Since HNRPU is involved in the regulation of embryonic brain development, this represents a novel plausible candidate gene for the combination of developmental delay, speech delay, hypotonia, hypo- or agenesis of the corpus callosum, and seizures in patients with 1q44 deletions. Since only one of the two patients with deletions including the ZNF124 gene showed a vermis hypoplasia, mere hemizygosity for this gene is not sufficient to cause this anomaly. Moreover, to reconcile the variability in the corpus callosum thickness, additional mechanisms, such as unmasking of hemizygous mutations, position effects and possible interactions with other loci need consideration.
    Full-text · Article · Apr 2010 · European journal of medical genetics
  • NW Guldner · Y Hellenbroich · PM Rumpf · T Hardel · C Kruse · HH Sievers

    No preview · Article · Feb 2010 · The Thoracic and Cardiovascular Surgeon
  • Y. Hellenbroich · S.-K. Frost · G. Gillessen-Kaesbach

    No preview · Article · Jan 2010
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    Guldner N W · Rumpf P M · Hellenbroich Y · Hardel T · Sievers H-H · Kruse C

    Preview · Article · Jan 2010 · Journal of Stem Cells and Regenerative Medicine

Publication Stats

903 Citations
168.19 Total Impact Points

Institutions

  • 2001-2014
    • Universität zu Lübeck
      • Institute of Human Genetics
      Lübeck Hansestadt, Schleswig-Holstein, Germany
  • 2010-2011
    • University Medical Center Schleswig-Holstein
      • Department of Pediatrics
      Kiel, Schleswig-Holstein, Germany
  • 2007
    • Universitätsklinikum Schleswig - Holstein
      Kiel, Schleswig-Holstein, Germany
    • University Hospital Essen
      • Institute of Human Genetics
      Essen, North Rhine-Westphalia, Germany