13 research outputs found
The Nijmegen Breakage Syndrome - Frequency and Cancer Risk of Heterozygotes
No full textTitelblatt und Inhaltsverzeichnis
Einleitung
Patienten und Methoden
Ergebnisse
Diskussion
LiteraturverzeichnisDas Nijmegen Breakage Syndrom (NBS, OMIM 251260) ist eine seltene autosomal-
rezessive Krankheit aus der Gruppe der chromosomalen Instabilitätssyndrome.
Das klinische Erscheinungsbild ist gekennzeichnet durch eine Mikrozephalie und
einen Minderwuchs, ein vogelkopfartiges faziales Erscheinungsbild sowie eine
Defizienz des humoralen und zellulären Immunsystems. Krankheitsverursachend
sind Mutationen im NBS1-Gen auf Chromosom 8q21, das für ein Protein aus 754
Aminosäuren, Nibrin genannt, kodiert. Über 90 % der Patienten sind homozygot
für eine Deletion von 5 Basenpaaren, 657del5, im Exon 6. Hierbei handelt es
sich um eine slawische Gründer-Mutation, der überwiegende Anteil Betroffener
stammt daher aus Osteuropa. Nibrin ist Teil des
MRE11/RAD50/Nibrin-(MRN)-Proteinkomplexes, der in die DNA-Doppelstrangbruch-
Reparatur, die Zellzykluskontrolle und die Aufrechterhaltung der
Telomerstabilität einbezogen ist. NBS-Patienten weisen daher eine erhöhte
Empfindlichkeit gegenüber ionisierender Strahlung und eine hohe Prädisposition
für maligne Tumoren, insbesondere Lymphome, auf. Eine erhöhte Tumordisposition
konnte auch für heterozygote Genträger nachgewiesen werden. Gegenstand der
Arbeit ist (1.) die Ermittlung der Prävalenz heterozygoter Genträger in zwei
Gegenden Deutschlands mit hohem bzw. niedrigen Anteil slawischer Bevölkerung,
(2.) die Ermittlung der Häufigkeit Heterozygoter unter Krebspatienten und (3.)
die Bestimmung der NBS1-Genkonstitution in den Tumoren heterozygoter
Individuen. 1\. Patienten mit dem Nijmegen Breakage Syndrom finden sich in
Deutschland gehäuft in Oberfranken und der Oberpfalz. Es wurde daher ein
Kollektiv Neugeborener aus der Region Bayreuth in Oberfranken auf Mutationen
im NBS1-Gen gescreent sowie als Kontrolle ein Kollektiv aus Berlin. Dabei
konnten unter 1056 Neugeborenen aus dem Raum Bayreuth 6 heterozygote Träger
der Mutation 657del5 (Frequenz 1:176) und 2 Individuen mit der Mutation R215W
(Frequenz 1:528) identifiziert werden. Unter den 990 Neugeborenen aus Berlin
fanden sich jeweils 1 heterozygoter Träger der Mutationen 657del5 und R215W
(Frequenzen jeweils 1:990). Insgesamt konnte damit ein ausgeprägter
Häufigkeitsunterschied Heterozygoter für die slawische Mutation 657del5 in
den beiden untersuchten deutschen Neugeborenenkollektiven festgestellt werden.
Die hohe Frequenz dieser Mutation unter den Bayreuther Neugeborenen entsprach
dabei dem hohen Bevölkerungsanteil slawischer Abstammung. 2\. Um
herauszufinden, ob heterozygote Träger von NBS1-Mutationen eine erhöhte
Disposition für maligne Tumore aufweisen, wurden insgesamt 589 erwachsene
polnische Tumorpatienten auf eine Heterozygotie für NBS1-Genmutationen im Exon
6 untersucht und mit einer Kontrollgruppe verglichen. Hierbei konnten 5
heterozygote Träger der Mutation 657del5 und 4 Heterozygote der Mutation R215
identifiziert werden. Es wurde ein signifikant erhöhtes Risiko heterozygoter
657del5-Genträger für maligne Melanome nachgewiesen. Zudem war die Anzahl
heterozygoter Träger der Mutation R215W mit kolorektalem Karzinom und Hodgkin-
Lymphom signifikant erhöht. 3\. Um die Bedeutung der NBS1-Mutation 657del5 für
die Carcinogenese zu untersuchen, wurden in Tumorgeweben 8 Heterozygoter die
Anteile an Wildtyp- und 657del5-Allelen bestimmt. Das Vorliegen erhöhter
657del5-Allelanteile konnte durch die in der Mehrzahl der Tumoren
nachgewiesenen Polysomien der Chromosomen 8 erklärt werden, die bevorzugt das
657del5-Allel trugen. Als Folge davon liegt ein höherer Anteil des verkürzten
p70-Nibrin-Fragmentes vor, das zu einem funktionell eingeschränkten
MRN(p70)-Proteinkomplex führt. Die betreffenden Zellen sollten eine erhöhte
genomische Instabilität und damit eine höhere Wahrscheinlichkeit einer
malignen Entartung aufweisen.The Nijmegen Breakage Syndrome (NBS, OMIM #251260) is a rare autosomal
recessive disease that belongs to the group of chromosomal instability
syndromes. This syndrome is clinically characterized by microcephaly and
growth retardation, a bird-like facial appearance as well as
immunodeficiency involving the humoral and cellular systems. Mutations in the
NBS1 gene located on chromosome 8q21 are responsible for NBS. This gene
encodes a 754 amino acid protein called nibrin. More than 90 % of the patients
are homozygous for a 5-base pair deletion in exon 6 (657del5). This founder
mutation of Slavic origin affects mostly individuals from Eastern Europe.
Nibrin is part of the MRE11/RAD50/nibrin (MRN) protein complex, which is
involved in DNA double-strand break repair, cell cycle control, and
maintenance of telomere stability. Therefore, NBS patients show
hypersensitivity to ionizing radiation and predisposition for cancer,
especially lymphomas. A higher risk for tumors was also demonstrated for
heterozygous individuals. The aims of this study were: (1.) to determine the
prevalence of heterozygous carriers in two regions of Germany with a high and
a low percentage of Slavic population, respectively; (2.) to determine the
frequency of heterozygous individuals among cancer patients and (3.) to define
the NBS1 genotype of tumors from heterozygous individuals. 1\. Patients with
Nijmegen Breakage Syndrome are more frequently found in Upper Franconia and
Upper Palatinate than in other parts of Germany. Therefore, a newborn
screening for NBS1 mutations was performed for one group from Bayreuth (Upper
Franconia) and for a control group from Berlin. This revealed that 6
heterozygous carriers of the 657del5 mutation (frequency 1/176) and 2
individuals with the R215W mutation (frequency 1/528) were identified from
1056 newborns in the Bayreuth area. Only 1 heterozygous carrier of each
mutation 657del5 and R215W was found (frequencies 1/990 each) among the
990 newborns from Berlin. Comparing the two collectives of newborns, a marked
difference in the frequency of heterozygous carriers of the Slavic mutation ,
657del5, was detected. The high frequency of this mutation among the newborns
in the Bayreuth area corresponds to the large proportion of Slavic origin in
the population. 2\. To analyze if heterozygous carriers of the NBS1 mutations
show a higher predisposition for cancer, 589 adult Polish cancer patients were
studied to detect heterozygosity for NBS1 mutations in exon 6 and were
compared with a control group. As a result 5 heterozygous carriers of the
657del5 mutation and 4 heterozygous carriers of the R215 mutation were
identified. The risk for malignant melanomas was significantly higher for
heterozygous carriers of the 657del5 mutation. Furthermore, the incidence of
colorectal carcinoma and Hodgkin s lymphoma was significantly increased among
the heterozygous carriers of the R215W mutation. 3\. To study the significance
of the 657del5 mutation in the NBS1 gene in carcinogenesis, wild type and
657del5 alleles of tumor samples from 8 heterozygous patients were determined.
The majority of the tumors showed polysomy of chromosome 8, preferentially
carrying the 657del5 alleles, explaining the increased frequency of 657del5
alleles. Consequently the proportion of the truncated p70-nibrin fragment is
increased, leading to a reduced functionality of the MRN (p70) protein
complex. The affected cells should have a higher genomic instability and,
therefore, a predisposition to malignant degeneration
Isolation of a 370 kb YAC fragment spanning a translocation breakpoint at 3p14.1 associated with holoprosencephaly
No full textIdentification of pathogenic YY1AP1 splice variants in siblings with Grange syndrome by whole exome sequencing.
No full textGrange syndrome is an autosomal recessive condition characterized by arterial occlusions and hypertension. Syndactyly, brachydactyly, bone fragility, heart defects, and learning disabilities have also been reported. Loss-of-function variants in YY1AP1 have only recently been associated with Grange syndrome. YY1AP1 encodes for the transcription coactivator yin yang 1-associated protein 1 which regulates smooth muscle cell proliferation and differentiation. We here report on three siblings with steno-occlusive arterial disorder and syndactyly in two of them. Whole exome sequencing including near-splice regions led to the identification of two intronic YY1AP1 variants which were predicted to interfere with normal splicing. Sanger sequencing demonstrated compound-heterozygosity in all affected siblings. RT-PCR analyses confirmed skipping of exon 6 on one allele and exonization of 22bp in intron 6 on the other. This is the first report of biallelic YY1AP1 variants in noncoding regions and just the second family with multiple affected siblings. Therefore, our report further delineates the phenotypic spectrum of Grange syndrome
Targeted enrichment sequencing in two midterm pregnancies with severe abnormalities on ultrasound
No full textCommunity acquired Staphylococcus aureus meningitis and cerebral abscesses in a patient with a Hyper-IgE and a Dubowitz-like syndrome
No full textDNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber’s hereditary optic neuropathy and optic atrophy
No full textBACKGROUND: Leber’s hereditary optic neuropathy (LHON) has been considered a prototypical mitochondriopathy and a textbook example for maternal inheritance linked to certain disease-causing variants in the mitochondrial genome. Recently, an autosomal recessive form of LHON (arLHON) has been described, caused by disease-causing variants in the nuclear encoded gene DNAJC30. METHODS AND RESULTS: In this study, we screened the DNAJC30 gene in a large Central European cohort of patients with a clinical diagnosis of LHON or other autosomal inherited optic atrophies (OA). We identified likely pathogenic variants in 35/1202 patients, corresponding to a detection rate of 2.9%. The previously described missense variant c.152A>G;p.(Tyr51Cys) accounts for 90% of disease-associated alleles in our cohort and we confirmed a strong founder effect. Furthermore, we identified two novel pathogenic variants in DNAJC30: the nonsense variant c.610G>T;p.(Glu204*) and the in-frame deletion c.230_232del;p.(His77del). Clinical investigation of the patients with arLHON revealed a younger age of onset, a more frequent bilateral onset and an increased clinically relevant recovery compared with LHON associated with disease-causing variants in the mitochondrial DNA. CONCLUSION: This study expands previous findings on arLHON and emphasises the importance of DNAJC30 in the genetic diagnostics of LHON and OA in European patients
Molecular Karyotyping as a relevant diagnostic tool in children with growth retardation with Silver-Russell features
No full textOBJECTIVE: To determine the contribution of submicroscopic chromosomal imbalances to the etiology of Silver-Russell syndrome (SRS) and SRS-like phenotypes. STUDY DESIGN: We performed molecular karyotyping in 41 patients with SRS or SRS-like features without known chromosome 7 and 11 defects using the Affymetrix SNP Array 6.0 system (Affymetrix, High Wycombe, United Kingdom). RESULTS: In 8 patients, pathogenic copy number variations with sizes ranging from 672 kb to 9.158 Mb were identified. The deletions in 1q21, 15q26, 17p13, and 22q11 were associated with known microdeletion syndromes with overlapping features with SRS. The duplications in 22q13 and Xq25q27 represent unique novel copy number variations but have an obvious influence on the phenotype. In 5 additional patients, the pathogenetic relevance of the detected variants remained unclear. CONCLUSION: Pathogenic submicroscopic imbalances were detectable in a significant proportion of patients with short stature and features reminiscent of SRS. Therefore, molecular karyotyping should be implemented in routine diagnostics for growth-retarded patients with even slight dysmorphisms suggestive for SRS
Familial Mental Retardation Syndrome ATR-16 Due to an Inherited Cryptic Subtelomeric Translocation, t(3;16)(q29;p13.3)
No full textSummaryIn the search for genetic causes of mental retardation, we have studied a five-generation family that includes 10 individuals in generations IV and V who are affected with mild-to-moderate mental retardation and mild, nonspecific dysmorphic features. The disease is inherited in a seemingly autosomal dominant fashion with reduced penetrance. The pedigree is unusual because of (1) its size and (2) the fact that individuals with the disease appear only in the last two generations, which is suggestive of anticipation. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal the cause of the mental retardation. Therefore, a whole-genome scan was performed, by linkage analysis, with microsatellite markers. The phenotype was linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. This case reinforces the role of cryptic (cytogenetically invisible) subtelomeric translocations in mental retardation, which is estimated by others to be implicated in 5%–10% of cases
New mutations in the ATM gene and clinical data of 25 AT patients
No full textAtaxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, oculocutaneous telangiectasias, chromosomal instability, radiosensitivity, and cancer predisposition. The gene mutated in the patients, ATM, encodes a member of the phosphatidylinositol 3-kinase family proteins. The ATM protein has a key role in the cellular response to DNA damage. Truncating and splice site mutations in ATM have been found in most patients with the classical AT phenotype. Here we report of our extensive ATM mutation screening on 25 AT patients from 19 families of different ethnic origin. Previously unknown mutations were identified in six patients including a new homozygous missense mutation, c.8110T > C (p.Cys2704Arg), in a severely affected patient. Comprehensive clinical data are presented for all patients described here along with data on ATM function generated by analysis of cell lines established from a subset of the patients
Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy
No full textVici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 affected individuals. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies showed a severe block in autophagosomal clearance in muscle and fibroblasts from individuals with mutant EPG5, resulting in the accumulation of autophagic cargo in autophagosomes. These findings position Vici syndrome as a paradigm of human multisystem disorders associated with defective autophagy and suggest a fundamental role of the autophagy pathway in the immune system and the anatomical and functional formation of organs such as the brain and hear
