In addition to the diagnostic work in the daily routine also a variety of research projects are conducted and supervised.
Two IZKF-funded projects are described here by way of example.
Constanze Pentzold - Fragiles Sites
Chromosomal fragile sites as markers of cancerogenic rearrangements – aspects of nuclear architecture and molecular localization
Chromosomal fragile sites (CFSs) are genomic regions prone to form gaps or breaks on metaphase chromosomes. As CFSs often appear as hot spots for gross chromosomal rearrangements in cancer cells, it is of high clinical relevance to map CFSs genome-wide for better understanding of complex aberrant karyotypes and to predict their clinical prognosis. For now, CFSs have mainly been analysed in human lymphocytes but the method is also established for other tissues and model systems. The mapping usually followed the traditional method by metaphase spreading and molecular cytogenetic definition. A new approach has become available recently to standardize this mapping to a high throughput and high resolution Next Generation Sequencing (NGS)-based genome-wide application. The aim of my junior research project is to establish this novel method in human cells, implement it for tumor material to overcome conventional metaphase spreading and morphological definition by a state-of-the-art NGS approach. To expand the view on CFSs by specific functional analyses in disease-derived cell lines, aspects of nuclear localization as well as molecular positioning of CFSs will be investigated. Overall, the project aims to identify the connection between the fragility of certain genomic regions and cancer predisposing and premature aging related disorders.
Early onset dystonia - a new genetic disorder or a new aspect of valproate fetopathy ?
Hereditary dystonia often starts in childhood, adolescence or in adulthood, while manifestation in the neonatal period is rare. Here we report a Syrian girl suffering from dystonia from birth onwards.
The girl is the second child of consanguineous Syrian parents (second degree cousins). Because of epilepsy the mother was on valproate treatment throughout pregnancy. The girl was delivered per Caesarean section in the 42th week of gestation because of refractory epilepsy of the mother. Soon after birth, the patient was admitted to the neonatal intensive care unit because of respiratory distress, ophisthotonus and hyperirritability.
Newborn screening for inborn metabolic diseases was normal. CMVDNA in urine was detected by PCR at 30 days of age.
evidence of epilepsy
No abnormalities. No evidence of abnormal signal intensities in basal ganglia
Treatment with L-dopa/Carbidopa did not alleviate symptoms, but the combination therapy with L-dopa/Carbidopa and Trazodon slightly reduced dystonic movements.
The mother suffers from epilepsy since childhood without intellectual disabilities. The 7 year old brother has a mild mental developmental delay with characteristic craniofacial features of fetal valproate syndrome but no dystonia.
The patient shows characteristic features of fetal valproate syndrome Micrognathia, high forehead, low nasal bridge with short nose, midface hypoplasia and long philtrum with a thin vermilion border.
Standard-chromosome analysis and array CGH: no abnormalities Exome sequencing in patient, both parents and unaffected brother - filtering: Common SNPs with minor allele frequency of < 0.01, intronic and synonymous variants, and ncRNA genes were excluded. Only homozygous variants in patient, heterozygous variants in both parents and wild type or heterozygous in brother were evaluated. - results: The exome identified 21 nonsynonymous homozygousvariants in our patient that were heterozygous in both parents. This did not include variants in known dystonia associated.
Discussion and Conclusion
We could not identify any disease causing mutation in one of the known 26 dystonia genes. Although we cannot exclude that the CMV infection or the valproate exposure may contribute to the phenotype, we rather suspect a rare autosomal recessive dystonic movement disorder.
Dr. Shoko Komatsuzaki
Fachärztin für Humangenetik,
Fachärztin für Kinder- und Jugendmedizin