Oldenburg, Germany
Oldenburg, Germany

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Lemke J.R.,University of Bern | Hendrickx R.,Vlaams Institute for Biotechnology | Hendrickx R.,University of Antwerp | Geider K.,TU Darmstadt | And 25 more authors.
Annals of Neurology | Year: 2014

Objective To identify novel epilepsy genes using a panel approach and describe the functional consequences of mutations. Methods Using a panel approach, we screened 357 patients comprising a vast spectrum of epileptic disorders for defects in genes known to contribute to epilepsy and/or intellectual disability (ID). After detection of mutations in a novel epilepsy gene, we investigated functional effects in Xenopus laevis oocytes and screened a follow-up cohort. Results We revealed de novo mutations in GRIN2B encoding the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor in 2 individuals with West syndrome and severe developmental delay as well as 1 individual with ID and focal epilepsy. The patient with ID and focal epilepsy had a missense mutation in the extracellular glutamate-binding domain (p.Arg540His), whereas both West syndrome patients carried missense mutations within the NR2B ion channel-forming re-entrant loop (p.Asn615Ile, p.Val618Gly). Subsequent screening of 47 patients with unexplained infantile spasms did not reveal additional de novo mutations, but detected a carrier of a novel inherited GRIN2B splice site variant in close proximity (c.2011-5-2011-4delTC). Mutations p.Asn615Ile and p.Val618Gly cause a significantly reduced Mg2+ block and higher Ca2+ permeability, leading to a dramatically increased Ca2+ influx, whereas p.Arg540His caused less severe disturbance of channel function, corresponding to the milder patient phenotype. Interpretation We identified GRIN2B gain-of-function mutations as a cause of West syndrome with severe developmental delay as well as of ID with childhood onset focal epilepsy. Severely disturbed channel function corresponded to severe clinical phenotypes, underlining the important role of facilitated NMDA receptor signaling in epileptogenesis. ANN NEUROL 2014;75:147-154 © 2014 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of Child Neurology Society/American Neurological Association.


PubMed | CeGaT GmbH, Institute of Clinical Genetics, Germany 2 CeGaT GmbH and Hertie Institute for Clinical Brain Research
Type: Case Reports | Journal: European journal of human genetics : EJHG | Year: 2014

SATB2 is an evolutionarily highly conserved chromatin remodeling gene located on chromosome 2q33.1. Vertebrate animal models have shown that Satb2 has a crucial role in craniofacial patterning and osteoblast differentiation, as well as in determining the fates of neuronal projections in the developing neocortex. In humans, chromosomal translocations and deletions of 2q33.1 leading to SATB2 haploinsufficiency are associated with cleft palate (CP), facial dysmorphism and intellectual disability (ID). A single patient carrying a nonsense mutation in SATB2 has been described to date. In this study, we performed trio-exome sequencing in a 3-year-old girl with CP and severely delayed speech development, and her unaffected parents. Previously, the girl had undergone conventional and molecular karyotyping (microarray analysis), as well as targeted analysis for different diseases associated with developmental delay, including Angelman syndrome, Rett syndrome and Fragile X syndrome. No diagnosis could be established. Exome sequencing revealed a de novo nonsense mutation in the SATB2 gene (c.715C>T; p.R239*). The identification of a second patient carrying a de novo nonsense mutation in SATB2 confirms that this gene is essential for normal craniofacial patterning and cognitive development. Based on our data and the literature published so far, we propose a new clinically recognizable syndrome - the SATB2-associated syndrome (SAS). SAS is likely to be underdiagnosed and should be considered in children with ID, severe speech delay, cleft or high-arched palate and abnormal dentition with crowded and irregularly shaped teeth.


PubMed | CeGaT GmbH, Otto Von Guericke University of Magdeburg, 1 Institute of Clinical Genetics and Institute of Clinical Genetics
Type: Journal Article | Journal: European journal of human genetics : EJHG | Year: 2015

Megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth syndrome that is diagnosed by clinical criteria. Recently, somatic and germline variants in genes that are involved in the PI3K-AKT pathway (AKT3, PIK3R2 and PIK3CA) have been described to be associated with MCAP and/or other related megalencephaly syndromes. We performed trio-exome sequencing in a 6-year-old boy and his healthy parents. Clinical features were macrocephaly, cutis marmorata, angiomata, asymmetric overgrowth, developmental delay, discrete midline facial nevus flammeus, toe syndactyly and postaxial polydactyly--thus, clearly an MCAP phenotype. Exome sequencing revealed a pathogenic de novo germline variant in the PTPN11 gene (c.1529A>G; p.(Gln510Arg)), which has so far been associated with Noonan, as well as LEOPARD syndrome. Whole-exome sequencing (>100 coverage) did not reveal any alteration in the known megalencephaly genes. However, ultra-deep sequencing results from saliva (>1000 coverage) revealed a 22% mosaic variant in PIK3CA (c.2740G>A; p.(Gly914Arg)). To our knowledge, this report is the first description of a PTPN11 germline variant in an MCAP patient. Data from experimental studies show a complex interaction of SHP2 (gene product of PTPN11) and the PI3K-AKT pathway. We hypothesize that certain PTPN11 germline variants might drive toward additional second-hit alterations.


Ivaskevicius V.,University of Bonn | Biswas A.,University of Bonn | Bevans C.,University of Bonn | Schroeder V.,University of Bern | And 9 more authors.
Haematologica | Year: 2010

Background: Severe hereditary coagulation factor XIII deficiency is a rare homozygous bleeding disorder affecting one person in every two million individuals. In contrast, heterozygous factor XIII deficiencyis more common, but usually not associated with severe hemorrhage such as intracranialbleeding or hemarthrosis. In most cases, the disease is caused by F13A gene mutations. Causative mutations associated with the F13B gene are rarer. Design and Methods: We analyzed ten index patients and three relatives for factor XIII activity using a photometric assay and sequenced their F13A and F13B genes. Additionally, structural analysis of the wildtype protein structure from a previously reported X-ray crystallographic model identified potential structural and functional effects of the missense mutations. Results: All individuals except one were heterozygous for factor XIIIA mutations (average factor XIII activity 51%), while the remaining homozygous individual was found to have severe factor XIII deficiency (<5% of normal factor XIII activity). Eight of the 12 heterozygous patients exhibited a bleeding tendency upon provocation. Conclusions: The identified missense (Pro289Arg, Arg611His, Asp668Gly) and nonsense (Gly390X, Trp664X) mutations are causative for factor XIII deficiency. A Gly592Ser variant identified in three unrelated index patients, as well as in 200 healthy controls (minor allele frequency 0.005), and two further Tyr167Cys and Arg540Gln variants, represent possible candidates for rare F13A gene polymorphisms since they apparently do not have a significant influence on the structure of the factor XIIIA protein. Future in vitro expression studies of the factor XIII mutations are required to confirm their pathological mechanisms. © 2010 by Ferrata Storti Foundation.


Schanz J.,University of Gottingen | Haase D.,University of Gottingen | Steuernagel P.,Institute of Clinical Genetics | Shirneshan K.,University of Gottingen | Basecke J.,St Josefs Hospital
European Journal of Haematology | Year: 2015

A 62-yr-old man with two healthy daughters was diagnosed with osteomyelofibrosis. To our surprise, a female XX-karyotype was observed in bone marrow and confirmed in PHA-stimulated T-lymphocytes from peripheral blood. Further molecular genetic investigation revealed a submicroscopic translocation between the short arm of X and Y, which leads to an XX-male genotype based on an unbalanced translocation X;Y. This rare coincidence was further accentuated as the USP9Y gene, suspected to be to be involved in sperm cell production, was absent, but no azoospermia was present. In general, routine cytogenetics may result in findings that need to be further delineated and, as here, lead to a rare observation. © 2015 John Wiley & Sons A/S.


PubMed | St Josefs Hospital, Institute of Clinical Genetics and University of Gottingen
Type: Case Reports | Journal: European journal of haematology | Year: 2015

A 62-yr-old man with two healthy daughters was diagnosed with osteomyelofibrosis. To our surprise, a female XX-karyotype was observed in bone marrow and confirmed in PHA-stimulated T-lymphocytes from peripheral blood. Further molecular genetic investigation revealed a submicroscopic translocation between the short arm of X and Y, which leads to an XX-male genotype based on an unbalanced translocation X;Y. This rare coincidence was further accentuated as the USP9Y gene, suspected to be to be involved in sperm cell production, was absent, but no azoospermia was present. In general, routine cytogenetics may result in findings that need to be further delineated and, as here, lead to a rare observation.


Bogs T.,University of Bonn | Kipfmuller F.,University of Bonn | Kohlschmidt N.,Institute of Clinical Genetics | Gembruch U.,University of Bonn | And 2 more authors.
Journal of Medical Case Reports | Year: 2016

Background: Previous reports of chromosomal aberrations in different forms of congenital diaphragmatic hernia have been described as comprising aneuploidies (for example, trisomy 21), microdeletions, and duplications (for example, monosomy 15q24, 22q11.2). Case presentation: We describe the first association of a de novo partial tetrasomy 4q35.2 in a father with left-sided, isolated renal agenesis and left-sided, isolated congenital diaphragmatic hernia in his son, who inherited the chromosomal aberration from his father. Conclusions: Given that the aberration occurred de novo in the father and was transmitted to his son, with both presenting with unilateral left-sided developmental field defects, we suggest a gene dosage effect of the tetrasomic region to be involved in the phenotype of our two patients. Furthermore, we suggest performing a genetic workup in multiplex families with congenital malformations. © 2016 Bogs et al.


Neuhann T.M.,Institute of Clinical Genetics | Artelt J.,Institute of Clinical Genetics | Tinschert S.,Institute of Clinical Genetics | Rump A.,Institute of Clinical Genetics
Investigative Ophthalmology and Visual Science | Year: 2011

Purpose. The purpose of the study was to look for ADAMTSL4 mutations in a cohort of German patients with isolated ectopia lentis from nonconsanguineous families. Methods. Mutation screening was performed by PCR amplification of the coding exons of ADAMTSL4 and subsequent sequencing. Results. An identical homozygous deletion of 20 bp of coding sequence within exon 6 (NM_019032.4:c.759_778del20) was identified in eight individuals from seven unrelated families. In a screen of 360 ethnically matched, unaffected individuals, two heterozygous mutation carriers were found. The mutation was always accompanied by the identical haplotype, suggestive of a founder mutation. Conclusions. The results emphasize the association of ADAMTSL4 null mutations with isolated ectopia lentis and the presence of a founder mutation in the European population. Screening of ADAMTSL4 should be considered in all patients with isolated ectopia lentis, with or without family history. In patients from nonconsanguineous families, the authors propose a two-step diagnostic approach, starting with an examination of exon 6 before sequencing the entire coding region of ADAMTSL4. © 2011 The Association for Research in Vision and Ophthalmology, Inc.


PubMed | Institute of Clinical Genetics
Type: Journal Article | Journal: Investigative ophthalmology & visual science | Year: 2011

The purpose of the study was to look for ADAMTSL4 mutations in a cohort of German patients with isolated ectopia lentis from nonconsanguineous families.Mutation screening was performed by PCR amplification of the coding exons of ADAMTSL4 and subsequent sequencing.An identical homozygous deletion of 20 bp of coding sequence within exon 6 (NM_019032.4:c.759_778del20) was identified in eight individuals from seven unrelated families. In a screen of 360 ethnically matched, unaffected individuals, two heterozygous mutation carriers were found. The mutation was always accompanied by the identical haplotype, suggestive of a founder mutation.The results emphasize the association of ADAMTSL4 null mutations with isolated ectopia lentis and the presence of a founder mutation in the European population. Screening of ADAMTSL4 should be considered in all patients with isolated ectopia lentis, with or without family history. In patients from nonconsanguineous families, the authors propose a two-step diagnostic approach, starting with an examination of exon 6 before sequencing the entire coding region of ADAMTSL4.


PubMed | University of Bonn and Institute of Clinical Genetics
Type: | Journal: Journal of medical case reports | Year: 2016

Previous reports of chromosomal aberrations in different forms of congenital diaphragmatic hernia have been described as comprising aneuploidies (for example, trisomy 21), microdeletions, and duplications (for example, monosomy 15q24, 22q11.2).We describe the first association of a de novo partial tetrasomy 4q35.2 in a father with left-sided, isolated renal agenesis and left-sided, isolated congenital diaphragmatic hernia in his son, who inherited the chromosomal aberration from his father.Given that the aberration occurred de novo in the father and was transmitted to his son, with both presenting with unilateral left-sided developmental field defects, we suggest a gene dosage effect of the tetrasomic region to be involved in the phenotype of our two patients. Furthermore, we suggest performing a genetic workup in multiplex families with congenital malformations.

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