Jenssen, Sönke Elisabeth
[VerfasserIn]
;
Felbor, Ute
[AkademischeR BetreuerIn];
Hübner, Christian
[AkademischeR BetreuerIn]Universität Greifswald
Zerebrale Kavernomatose - Identifizierung tief-intronischer Varianten in den genomischen Regionen von CCM1, CCM2 und CCM3 mittels Hochdurchsatzsequenzierung
Sie können Bookmarks mittels Listen verwalten, loggen Sie sich dafür bitte in Ihr SLUB Benutzerkonto ein.
Medientyp:
E-Book;
Hochschulschrift
Titel:
Zerebrale Kavernomatose - Identifizierung tief-intronischer Varianten in den genomischen Regionen von CCM1, CCM2 und CCM3 mittels Hochdurchsatzsequenzierung
Cerebral cavernous malformations (CCMs) are vascular malformations of the central nervous system which can lead to headaches, seizures and hemorrhagic strokes. Familial forms are inherited in an autosomal dominant manner with incomplete penetrance. So far, three genes have been associated with CCM: CCM1 (KRIT1), CCM2 (malcavernin) and CCM3 (PDCD10). Despite stringent inclusion criteria about 40% of non-familial CCM cases remain mutation-negative in standard molecular genetic diagnostics. The aim of this study was to investigate the previously unexplored, non-coding regions of the three genes by high-throughput sequencing for the presence of putative pathogenic variants. For target enrichment, a long-range PCR (LR-PCR) approach was established. Its practicability and reliability was confirmed by sequencing of several mutation-positive control samples. With this approach, 20 mutation-negative probands were re-analyzed on the MiSeq® platform. During this, 36 previously unknown or rare heterozygous variants could be detected. After a filter strategy 14 of the detected variants were prioritized as putative pathogenic. Segregation analyses could not support a causality of these variants. Also transcript analyses in five of ten probands with prioritized variants did not prove the functional relevance. For the remaining five cases, RNA samples were not available and further analyses have to follow to evaluate the causality of detected variants. In summary, the reliability of the ...