59 research outputs found
Constitutional de novo and postzygotic mutations in isolated cases of cerebral cavernous malformations
No full textBackgroundCerebral cavernous malformations (CCM) are vascular lesions of the central nervous system that can be found in sporadic or autosomal dominantly inherited forms and manifest with headaches, seizures, and hemorrhagic stroke. The precise proportion of de novo mutations in the CCM1, CCM2, and CCM3 genes remains unknown. MethodsWe here present a series of six trios with de novo mutations that have been analyzed by amplicon deep sequencing to differentiate between constitutional and postzygotic mutations. ResultsIn one case, allelic ratios clearly indicated mosaicism for a CCM3 splice site mutation found in blood and buccal mucosa of a 2-year-old boy with multiple CCMs. The remaining five de novo mutations proved to be constitutional. In addition to three CCM3, two CCM1, and one CCM2 de novo point mutations, a deletion of the entire CCM3 gene was identified in an index case that most likely originated from an early postzygotic event. These are the first high-level mosaic mutations reported in blood samples of isolated CCM cases. ConclusionOur data demonstrate that de novo mutations in CCM1-3 might be more frequent than previously thought. Furthermore, amplicon deep sequencing is useful to discriminate between patients with constitutional and postzygotic mutations, and thereby improves genetic counseling
Evaluierung von Ergebnissen der Array-CGH-Untersuchungen bei Kindern mit psychomotorischer Retardierung und assoziierter Symptomatik aus Sichtweise der klinisch-genetischen Praxis
No full textIn der Dissertation ist der Stellenwert der Array-CGH im Rahmen der ursächlichen Abklärung unklarer Intelligenzminderung und Entwicklungsverzögerung bei Kindern und Jugendlichen im Alter von 5 Monaten bis 19 Jahren herausgearbeitet worden. Dabei liegt der Schwerpunkt auf der Beurteilung der Effizienz und Sensitivität eines solchen Testverfahrens in einem Klinikum der Maximalversorgung, wo sich die Patienten ungefiltert und ohne entsprechende Vordiagnostik in der klinisch-genetischen Sprechstunde vorstellen. Bei den in dieser Dissertation beschriebenen Patienten handelt es sich um 50 Kinder mit psychomotorischer Entwicklungsverzögerung und Intelligenzminderung unterschiedlichen Ausmaßes sowie zusätzlichen phänotypischen Auffälligkeiten wie craniofazialen Dysmorphien, Verhaltensauffälligkeiten, neurologischen und/oder orthopädische Auffälligkeiten. Die bisher durchgeführten genetischen Untersuchungen (u.a. Chromosomenanalyse, FISH) dieser Patienten ließen keine kausale Diagnose des klinischen Erscheinungsbildes zu, sodass die Array-CGH zur Diagnosestellung zum Einsatz kam. Dabei wurde die Frage nach Kausalität der entsprechend detektierten Aberration in Bezug auf den vorliegenden Phänotyp mit Hilfe der Datenbanken UCSC, Decipher und ISCA sowie geeigneter Reviews analysiert, um die bis zu sechs Jahre alten Befunde zu reevaluieren. Dabei konnte herausgearbeitet werden, dass in 12% Prozent der Fälle die Array-CGH tatsächlich eine ursächliche Deletion/Duplikation im Genom der Patienten detektierte. Kinder mit pathologischen CNVs zeigten hierbei deutlich häufiger craniofaziale Dysmorphien als Kinder mit normalem Array-CGH Befund
RASSENBIOLOGIE UND VERERBUNGSWISSENSCHAFT IN DER MEDIZINISCHEN FAKULTAT DER UNIVERSITAT WURZBURG, 1937-1945
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Cerebral Cavernous Malformations: An Update on Prevalence, Molecular Genetic Analyses, and Genetic Counselling
No full textBased on the latest gnomAD dataset, the prevalence of symptomatic hereditary cerebral cavernous malformations (CCMs) prone to cause epileptic seizures and stroke-like symptoms was re-evaluated in this review and calculated to be 1:5,400-1:6,200. Furthermore, state-of-the-art molecular genetic analyses of the known CCM loci are described which reach an almost 100% mutation detection rate for familial CCMs if whole genome sequencing is performed for seemingly mutation-negative families. An update on the spectrum of CCM1, CCM2, and CCM3 mutations demonstrates that deep-intronic mutations and submicroscopic copy-number neutral genomic rearrangements are rare. Finally, this review points to current guidelines on genetic counselling, neuroimaging, medical as well as neurosurgical treatment and highlights the formation of active patient organizations in various countries
High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one-third of probands are minors
No full textCerebral cavernous malformations (CCM) are prevalent vascular malformations occurring in familial autosomal dominantly inherited or isolated forms. Once CCM are diagnosed by magnetic resonance imaging, the indication for genetic testing requires either a positive family history of cavernous lesions or clinical symptoms such as chronic headaches, epilepsy, neurological deficits, and hemorrhagic stroke or the occurrence of multiple lesions in an isolated case. Following these inclusion criteria, the mutation detection rates in a consecutive series of 105 probands were 87% for familial and 57% for isolated cases. Thirty-one novel mutations were identified with a slight shift towards proportionally more CCM3 mutations carriers than previously published (CCM1: 60%, CCM2: 18%, CCM3: 22%). In-frame deletions and exonic missense variants requiring functional analyses to establish their pathogenicity were rare: An in-frame deletion within the C-terminal FERM domain of CCM1 resulted in decreased protein expression and impaired binding to the transmembrane protein heart of glass (HEG1). Notably, 20% of index cases carrying a CCM mutation were below age 10 and 33% below age 18 when referred for genetic testing. Since fulminant disease courses during the first years of life were observed in CCM1 and CCM3 mutation carriers, predictive testing of minor siblings became an issue
Hereditary Breast and Ovarian Cancer Service in Sparsely Populated Western Pomerania
No full textThe German Consortium Hereditary Breast and Ovarian Cancer (GC-HBOC) consists of 23 academic centers striving to provide high-quality regional care for affected individuals and healthy at-risk family members. According to the standard operating procedures defined by the GC-HBOC, a Familial Breast and Ovarian Cancer Center was implemented at the University Medicine Greifswald over a four-year period from 2018 to 2021, despite the COVID-19 pandemic. Genetic analyses were performed in a total of 658 individuals, including 41 males, which paved the way to local annual risk-adapted breast cancer surveillance for 91 women and prophylactic surgery for 34 women in 2021. Our experience in the North Eastern part of Germany demonstrates that it is possible to establish a high-risk breast and ovarian cancer service even in a sparsely populated region. Major facilitators are the interdisciplinary collaboration of dedicated local experts, the support of the GC-HBOC, fruitful clinical and scientific cooperations and the use of technical improvements. As a blueprint, our project report may help to further expand the network of specialized and knowledge-generating care for HBOC families
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