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Stuttgart Mühlhausen, Germany

Amrhein P.,Klinik fur Hals Nasen Ohrenkrankheiten | Sittel C.,Klinik fur Hals Nasen Ohrenkrankheiten | Spaich C.,Institute For Klinische Genetik | Kohlhase J.,Praxis fur Humangenetik | And 3 more authors.
HNO | Year: 2014

Branchio-oto-renal (BOR) syndrome is characterized by ear malformations associated with sensorineural or mixed hearing loss. In addition, preauricular tags, preauricular pits, branchial cleft fistulas and cysts, as well as renal dysplasia are seen. A genetic mutation on chromosome 8, either autosomal dominantly inherited or occuring as a spontaneous mutation, is the cause in the majority of cases. Using array-based comparative genomic hybridization (CGH), it is possible to detect even the smallest genetic changes. Salivary gland choristoma in the middle ear is very rare. Surgical removal and histological clarification are required. © 2013 Springer-Verlag Berlin Heidelberg.


Molecular karyotyping of array-based genomic hybridization (microarrays) not only detects copy number variations, genomic gains and losses but also provides the assessment of specific mosaicism. This article gives an overview on parameters influencing the detection of mosaicism and different cases with mosaicism detected by comparative genomic hybridization (CGH) arrays and by single nucleotide polymorphism (SNP) arrays. Furthermore, a possibility is provided to calculate the percentage of a given mosaicism. © 2014, Springer-Verlag Berlin Heidelberg.


Bartholdi D.,Institute For Klinische Genetik | Miny P.,University of Basel
Therapeutische Umschau | Year: 2013

New key technologies such as arraybased molecular karyotyping and high throughput sequencing are currently introduced in pre- and postnatal diagnostic testing. These greatly improved genomic testing approaches are beginning to fundamentally change diagnostic strategies in the clinical setting. Molecular karyotyping in the fetus is now routinely performed in high risk situations or on parental request. It will replace the conventional microscopic approach in the near future. Non-invasive prenatal testing to exclude common trisomies is probably the most significant recent achievement and has the potential to dramatically reduce invasive testing. Multiple congenital malformations and intellectual disability (ID) occur in up to 3 % of the general population. A correct diagnosis at an early age is important for clinical management of the patients and for counselling the families with regard to recurrence risk. Conventional karyotyping has been replaced by molecular karyotyping (microarray analysis, Array-CGH), increasing the diagnostic yield up to 15 - 20 % in this population. This approach can be challenging with regard to interpretation of copy number variants of uncertain significance or variants with reduced penetrance. If the clinical assessment leads to the suspicion of a specific syndrome or a leading symptom like epilepsy or microcephaly is present, genetic testing might be directed towards single-gene analysis. However, increasing knowledge indicates that many of these conditions are genetically heterogeneous. The availability of next-generation sequencing techniques has led to the implementation of testing panels in the diagnostic setting, by which multiple genes are analyzed in parallel. This approach allows for increased diagnostic yield in monogenic disorders and defining of more detailed genoptype- phenotype correlations. In addition, whole-exome or whole-genome sequencing has led to the identification of the genetic basis of many known genetic disorders and to the identification and delineation of novel disorders thus allowing a diagnosis in more patients. Fulfilling the potential of the increasing number of options for genetic testing for accurate diagnosis requires close collaboration between clinical geneticists and paediatricians. © 2013 Verlag Hans Huber, Hogrefe AG, Bern.


Blatter R.H.E.,University of Basel | Plasilova M.,University of Basel | Plasilova M.,Institute For Klinische Genetik | Wenzel F.,University of Basel | And 4 more authors.
Genes Chromosomes and Cancer | Year: 2015

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder predisposing to gastrointestinal hamartomatous polyps and cancer with a pathogenic SMAD4 or BMPR1A germline mutation (1st-hit) being identified in about 40-50% of patients. Little is known, however, about the occurrence and nature of somatic alterations (2nd-hit) in SMAD4-/BMPR1A-related juvenile polyps. In this study, we screened 25 polyps from three patients carrying either a pathogenic SMAD4 (c.1244-1247delACAG) or BMPR1A (c.583C>T; p.Gln195*) germline mutation for somatic alterations. The SMAD4-related polyps were also analyzed for SMAD4 protein expression by immunohistochemistry. Despite comprehensive screening for loss of heterozygosity (LOH), mutations in the coding sequence, chromosomal rearrangements, and promoter methylation, no somatic alterations could be identified in 14 SMAD4-related polyps. SMAD4 protein expression, however, was lost in 8 (57%) of 14 juvenile polyps with 6 showing concomitant loss in both, the epithelial and stromal, compartments. In the BMPR1A-related polyps, five out of nine (56%) displayed LOH. Further analysis of selected polyps revealed that LOH was gene copy number neutral and had occurred in the epithelial compartment. The heterogeneity of genetic mutations and protein expression levels indicates that different modes of gene inactivation can be operational in SMAD4- and BMPR1A-related polyp formation. Our observation, that about half of BMPR1A-related polyps displayed LOH, predominantly in the epithelial compartment, is compatible with BMPR1A acting as a tumour suppressor gene. Still, it remains to be determined whether juvenile polyp development generally requires loss of BMPR1A expression or, as observed in some SMAD4-related polyps, can occur despite normal protein expression. © 2015 Wiley Periodicals, Inc.


Kohl S.,Forschungsinstitut For Augenheilkunde | Biskup S.,Institute For Klinische Genetik | Biskup S.,CeGaT GmbH
Klinische Monatsblatter fur Augenheilkunde | Year: 2013

Inherited retinal dystrophies are clinically and genetically highly heterogeneous. They can be divided according to the clinical phenotype and course of the disease, as well as the underlying mode of inheritance. Isolated retinal dystrophies (i.e., retinitis pigmentosa, Lebers congenital amaurosis, cone and cone-rod dystrophy, macular dystrophy, achromatopsia, congenital stationary nightblindness) and syndromal forms (i.e., Usher syndrome, Bardet-Biedl syndrome) can be differentiated. To date almost 180 genes and thousands of distinct mutations have been identified that are responsible for the different forms of these blinding illnesses. Until recently, there was no adequate diagnostic genetic testing available. With the development of the next generation sequencing technologies, a comprehensive genetic screening analysis for all known genes for inherited retinal dystrophies has been established at reasonable costs and in appropriate turn-around times. Depending on the primary clinical diagnosis and the presumed mode of inheritance, different diagnostic panels can be chosen for genetic testing. Statistics show that in 55-80 % of the cases the genetic defect of the inherited retinal dystrophy can be identified with this approach, depending on the initial clinical diagnosis. The aim of any genetic diagnostics is to define the genetic cause of a given illness within the affected patient and family and thereby i) confirm the clinical diagnosis, ii) provide targeted genetic testing in family members, iii) enable therapeutic intervention, iv) give a prognosis on disease course and progression and v) in the long run provide the basis for novel therapeutic approaches and personalised medicine. © Georg Thieme Verlag KG Stuttgart · New York.

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