Neu-Ulm, Germany
Neu-Ulm, Germany

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Deardorff M.A.,Children's Hospital of Philadelphia | Deardorff M.A.,University of Pennsylvania | Wilde J.J.,Children's Hospital of Philadelphia | Albrecht M.,University of Lübeck | And 31 more authors.
American Journal of Human Genetics | Year: 2012

The evolutionarily conserved cohesin complex was originally described for its role in regulating sister-chromatid cohesion during mitosis and meiosis. Cohesin and its regulatory proteins have been implicated in several human developmental disorders, including Cornelia de Lange (CdLS) and Roberts syndromes. Here we show that human mutations in the integral cohesin structural protein RAD21 result in a congenital phenotype consistent with a "cohesinopathy." Children with RAD21 mutations display growth retardation, minor skeletal anomalies, and facial features that overlap findings in individuals with CdLS. Notably, unlike children with mutations in NIPBL, SMC1A, or SMC3, these individuals have much milder cognitive impairment than those with classical CdLS. Mechanistically, these mutations act at the RAD21 interface with the other cohesin proteins STAG2 and SMC1A, impair cellular DNA damage response, and disrupt transcription in a zebrafish model. Our data suggest that, compared to loss-of-function mutations, dominant missense mutations result in more severe functional defects and cause worse structural and cognitive clinical findings. These results underscore the essential role of RAD21 in eukaryotes and emphasize the need for further understanding of the role of cohesin in human development. © 2012 by The American Society of Human Genetics. All rights reserved.


PubMed | University of Tübingen, St. Mary's University, Genetikum, University of Zürich and 4 more.
Type: | Journal: Journal of medical genetics | Year: 2016

Disruptions of the FOXP2 gene, encoding a forkhead transcription factor, are the first known monogenic cause of a speech and language disorder. So far, mainly chromosomal rearrangements such as translocations or larger deletions affecting FOXP2 have been reported. Intragenic deletions or convincingly pathogenic point mutations in FOXP2 have up to date only been reported in three families. We thus aimed at a further characterisation of the mutational and clinical spectrum.Chromosomal microarray testing, trio exome sequencing, multigene panel sequencing and targeted sequencing of FOXP2 were performed in individuals with variable developmental disorders, and speech and language deficits.We identified four different truncating mutations, two novel missense mutations within the forkhead domain and an intragenic deletion in FOXP2 in 14 individuals from eight unrelated families. Mutations occurred de novo in four families and were inherited from an affected parent in the other four. All index patients presented with various manifestations of language and speech impairment. Apart from two individuals with normal onset of speech, age of first words was between 4 and 7years. Articulation difficulties such as slurred speech, dyspraxia, stuttering and poor pronunciation were frequently noted. Motor development was normal or only mildly delayed. Mild cognitive impairment was reported for most individuals.By identifying intragenic deletions or mutations in 14 individuals from eight unrelated families with variable developmental delay/cognitive impairment and speech and language deficits, we considerably broaden the mutational and clinical spectrum associated with aberrations in FOXP2.


Huppke P.,University of Gottingen | Wegener E.,University of Gottingen | Bohrer-Rabel H.,Genetikum | Bolz H.J.,Center for Human Genetics Bioscientia | And 5 more authors.
European Journal of Human Genetics | Year: 2015

So far very few patients with sequence variants in the closely related tectonic genes TCTN1-3 have been described. By multi-gene panel next-generation sequencing (NGS) in patients with Joubert syndrome, we identified two more patients and summarize what is currently known about the phenotypes associated with sequence variants in these genes. In a boy aged 12 years with intellectual disability and the classical molar tooth sign on MRI, a homozygous splice-site sequence variant in TCTN3 leading to in-frame skipping of exon 7 was detected. A previously described non-truncating sequence variant in TCTN3 was also associated with Joubert syndrome, whereas four truncating sequence variants were detected in patients with Meckel-Gruber or Mohr-Majewski syndrome. The second patient, a boy aged 7 years with severe psychomotor retardation, was found to carry a homozygous canonic splice-site sequence variant in TCTN2. So far, only three sequence variants associated with Joubert syndrome and two with Meckel-Gruber syndrome have been described in this gene. Reviewing the clinical data on patients with sequence variants in the tectonic genes TCTN1-3 reveals that all of them have a neurological phenotype with vermis hypoplasia or occipital encephalocele associated with severe intellectual disability in the surviving patients. In contrast, other features frequently seen in patients with ciliopathies such as nephronophthisis, liver fibrosis, retinal dystrophy or coloboma have not been reported. Our patients emphasize the usefulness and efficacy of a comprehensive NGS panel approach. A concise genetic diagnosis may help to prevent unnecessary investigations and improve the clinical management of these patients. © 2015 Macmillan Publishers Limited All rights reserved.


PubMed | Ludwig Maximilians University of Munich, CeGaT GmbH, TU Munich and Genetikum
Type: | Journal: Muscle & nerve | Year: 2016

Mutations in the GDP-mannose pyrophosphorylase-B gene (GMPPB) have been identified in congenital muscular dystrophies (CMDs), limb-girdle muscular dystrophy (LGMD2T), and congenital myasthenic syndromes (CMSs); overall, 41 patients have been described.Two patients presented with a myasthenic syndrome (patient 1, 74-year-old) and rhabdomyolysis (patient 2, 23-year-old). Examinations included repetitive nerve stimulation, muscle biopsy and whole-body MRI (WBMRI); next generation sequencing facilitated diagnosis.We identified the following GMPPB mutations: c.79G>C/c.859C>T in the 23-yo man with LGMD2T-phenotype and c.79G>C homozygosity in the 74-yo woman with CMS-phenotype. WBMRI showed fatty degeneration of paraspinal, thigh adductor, and calf muscles in patient 1 and edematous changes of the soleus muscle in patient 2.This case of c.79G>C homozygosity causing a mild, late-onset CMS phenotype, confirms the mild nature of this common mutation. The descriptions of these 2 new GMPPB cases add to the knowledge regarding this recently discovered, heterogeneous disease. This article is protected by copyright. All rights reserved.


PubMed | Klinikum Oldenburg, University of Zürich, Institute of Mother and Child, University Pierre and Marie Curie and 18 more.
Type: Journal Article | Journal: Journal of medical genetics | Year: 2016

We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype-phenotype correlations.We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed.We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3 and 5 exons. Seizures in patients with mutations in exons 4-5 were more pharmacoresponsive than in patients with mutations in exons 8-15.SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.


PubMed | Heinrich Heine University Düsseldorf, Genetikum, University of Cologne and University of Gottingen
Type: Journal Article | Journal: American journal of medical genetics. Part A | Year: 2016

Heterozygous germline mutations in MTOR have been shown to underlie Smith-Kingsmore syndrome, a rare autosomal dominant syndrome characterized by macrocephaly, developmental delay, and dysmorphic facial features. Recently, two unrelated families with the MTOR mutation, c.5395G>A p.(Glu1799Lys), were reported. Here, we describe siblings from a non-consanguineous German family in whom we identified the same heterozygous missense mutation in MTOR. Remarkably, in all reported families with Smith-Kingsmore syndrome and the MTOR c.5395G>A mutation, including the family described herein, healthy parents of recurrently affected children do not have detectable levels of the mutation in tested tissues, lending credence to gonadal mosaicism as the underlying mechanism. Furthermore, the glutamic acid at position 1799 was shown to present a recurrent somatic mutation site in several cancers, including colon cancer, pointing to a somatic mutational hotspot in MTOR. Importantly, we highlight the occurrence of multiple intestinal polyps in the older sibling. Further patients are required to establish definitively whether polyp formation forms part of the SKS clinical spectrum. 2016 Wiley Periodicals, Inc.


Zechner U.,Johannes Gutenberg University Mainz | Hameister H.,Genetikum
Sexual Development | Year: 2011

It was noted only recently that the mammalian X/Y sex chromosome system originated late in our therian ancestors. The question is, what makes the X/Y sex chromosome system so special that it has replaced the original Z/W sex chromosome system? Two classes of genes are overrepresented on the X chromosome: sex and reproduction genes and brain-related genes. The X chromosome has acquired bursts of young male-biased genes engaged in sex and reproduction which exemplifies the dynamics of sex chromosome evolution. Brain genes are old genes and display the most conserved transcriptome. The new therian X chromosome was formed by fusion of chromosome building blocks already bearing the highest density of brain genes in the ancestral vertebrate karyotype. These building blocks constitute an X chromosome haplotype that undergoes strong selection and benefits both sexes by oscillating between males and females. We believe that this strategy is superior to male-driven Z/W sex chromosome evolution. Copyright © 2011 S. Karger AG, Basel.


Deschauer M.,Martin Luther University of Halle Wittenberg | Joshi P.R.,Martin Luther University of Halle Wittenberg | Glaser D.,Genetikum | Hanisch F.,Martin Luther University of Halle Wittenberg | And 2 more authors.
Nervenarzt | Year: 2011

Summary: Recessive mutations in the anoctamin 5 (ANO5) gene have been recently identified in families with limb girdle muscular dystrophy (LGMD2L) and distal non-dysferlin Miyoshi myopathy. Anoctamin 5 is supposed to be a putative calcium-activated chloride channel. We report five German patients (four index patients) with muscle dystrophy due to mutations in the ANO5 gene. Sequencing of the ANO5 exons 5, 13 and 20 was performed to screen for a common c.191dupA mutation and two other reported mutations (c.1295C>G and p.R758C). The whole coding region of the ANO5 gene was sequenced to identify new mutations. Phenotypically, three patients showed LGMD and one patient Miyoshi type distal myopathy. One sibling had asymptomatic hyperCKemia. The age at onset was 64, 38 and 40 years in patients with LGMD and 23 years in the patient with distal myopathy. The four symptomatic patients showed remarkable asymmetric muscle involvement. There was marked CK elevation (11 to 30 times). Electron microscopy showed multifocal gaps in the sarcolemmal membrane. All patients harboured the common c.191dupA mutation in at least one allele. Two patients with LGMD were homozygous and the third patient and his asymptomatic sister were compound heterozygous for the c.191dupA mutation and a novel p.T548I mutation. The patient with distal myopathy harboured the p.R758C mutation in the second allele. Mutations in the ANO5 gene seem to be a relatively common cause of muscular dystrophy in Germany. Cases with late onset or asymptomatic hyperCKemia can occur. Clinically, asymmetric manifestation is typical. © 2011 Springer-Verlag.


Joshi P.R.,Martin Luther University of Halle Wittenberg | Glaser D.,Genetikum | Dressel C.,Genetikum | Kress W.,University of Würzburg | And 2 more authors.
Neuromuscular Disorders | Year: 2014

We report a 45. year-old patient with an asymmetrical proximal muscle weakness affecting the quadriceps muscle of the right leg starting at the age of 32. years. CK was 25-fold increased. MRI of the legs showed signs of fatty degeneration more pronounced in the right side. Biopsy of a thigh muscle showed dystrophic pattern and amyloid deposition in blood vessel walls. The coding region and exon/intron boundaries of the ANO5 gene were amplified and sequenced. The common c.191dupA mutation and a silent novel p.Leu115Leu (c.345G>A) variant were identified. This silent variant was listed neither in the LOVD database nor in the SNP database. To evaluate the pathogenicity of the novel silent mutation in ANO5, cDNA analysis was performed that demonstrated skipping of exon 6. So far, no case with a silent mutation leading to abnormal splicing has been identified in Anoctamin 5 muscular dystrophy. Present findings emphasize that cDNA analysis should be done if a silent variant is not annotated in the databases. In Anoctamin 5 muscular dystrophy a molecular diagnosis is even more important as protein investigation through Western blotting or immunohistochemistry is not yet established. © 2013 Elsevier B.V.


PubMed | Ludwig Maximilians University of Munich, Martin Luther University of Halle Wittenberg and Genetikum
Type: Journal Article | Journal: Journal of neurology | Year: 2016

Limb-girdle muscular dystrophies (LGMDs) are genetically heterogeneous and the diagnostic work-up including conventional genetic testing using Sanger sequencing remains complex and often unsatisfactory. We performed targeted sequencing of 23 LGMD-related genes and 15 genes in which alterations result in a similar phenotype in 58 patients with genetically unclassified LGMDs. A genetic diagnosis was possible in 19 of 58 patients (33 %). LGMD2A was the most common form, followed by LGMD2L and LGMD2I. In two patients, pathogenic mutations were identified in genes that are not classified as LGMD genes (glycogen branching enzyme and valosin-containing protein). Thus, a focused next-generation sequencing-based gene panel is a rather satisfactory tool for the diagnosis in unclassified LGMDs.

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