Perinnöllisyyslääkärin osuus syövän geenidiagnostiikassa - kokemukset Tyksistä ja muualta

Geeniohjatun syövän hoidon työryhmän (MTB) tiimityöskentelyssä perinnöllisyyslääkärien rooliin kuuluu erityisesti geenivarianttien eli geenimuutosten merkitysten tulkinta siitä näkökulmasta, voisiko todettu variantti olla perinnöllinen ituradassa esiintyvä variantti (germline variant) somaattisen sijasta. Uusimpien raporttien mukaan kasvainnäytetutkimusten tulokset viittaavat siihen, että perinnöllisten syöpien osuus kaikista syövistä on aikaisemmin ymmärrettyä suurempi. Esittelemme Tyksin MTB:n päätösten pohjalta kahden vuoden aikana hoidetut 20 potilasta perinnöllisyyslääkärin näkökulmasta. Pilottiaineistossa todettujen perinnöllisten patogeenisten geenivarianttien osuus oli 15 \%, mikä on linjassa uusimpaan kirjallisuustietoon nähden

Perinnöllisyyslääkärin osuus syövän geenidiagnostiikassa - kokemukset Tyksistä ja muualta

Vertaisarvioitu. Teema : geeniohjatun syövän hoidon työryhmä.Geeniohjatun syövän hoidon työryhmän (MTB) tiimityöskentelyssä perinnöllisyyslääkärien rooliin kuuluu erityisesti geenivarianttien eli geenimuutosten merkitysten tulkinta siitä näkökulmasta, voisiko todettu variantti olla perinnöllinen ituradassa esiintyvä variantti (germline variant) somaattisen sijasta. Uusimpien raporttien mukaan kasvainnäytetutkimusten tulokset viittaavat siihen, että perinnöllisten syöpien osuus kaikista syövistä on aikaisemmin ymmärrettyä suurempi. Esittelemme Tyksin MTB:n päätösten pohjalta kahden vuoden aikana hoidetut 20 potilasta perinnöllisyyslääkärin näkökulmasta. Pilottiaineistossa todettujen perinnöllisten patogeenisten geenivarianttien osuus oli 15 %, mikä on linjassa uusimpaan kirjallisuustietoon nähden.Peer reviewe

Clinical features and spectrum of NOTCH3 variants in Finnish patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Objectives Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by pathogenic variants in the NOTCH3 gene. In Finland, the majority of CADASIL patients carry the pathogenic founder variant c.397C>T, (p.Arg133Cys), but the spectrum of other NOTCH3 variants has not been investigated previously. The aim of the study was to investigate the spectrum and prevalence of NOTCH3 variants Finnish CADASIL patients and to examine the clinical features associated with them. Materials and Methods The spectrum of NOTCH3 variants and the clinical features associated with them were retrospectively examined in 294 Finnish CADASIL patients tested during January 1996 to October 2021 in the Medical Genetics laboratory of Department of Genomics of Turku University Hospital, where practically all samples of patients with suspected CADASIL in Finland are investigated. Results The most common NOTCH3 variants in the study cohort were c.397C>T, (p.Arg133Cys) (68%) and c.3206A>G p.(Tyr1069Cys) (18%), but other less common NOTCH3 variants were detected in as many as 14% of the patients. Eight of the detected NOTCH3 variants were novel: c.520T>A,p.(Cys174Ser), c.836A>G,p.(Gln279Arg), c.1369T>G,p.(Cys457Gly), c.1338C>G,p.(Cys446Trp), c.1564T>G,p.(Cys522Gly), c.2848T>G,p.(Cys950Gly), c.6102dup,p.(Gly2035Argfs*60), and c.2410+6C>G. Other NOTCH3 variants than p.Arg133Cys and p.Tyr1069Cys were more often associated with more severe clinical features. Conclusion This study revealed the genetic and clinical spectrum of CADASIL in the Finnish population. Sequencing of the whole NOTCH3 gene performing a gene-panel or exome sequencing is recommended when suspecting CADASIL.Peer reviewe

Bringing ecosystem thinking to sustainability-driven wooden construction business

Lowering environmental impacts by material choices is proposed as a way to promote urban sustain ability transition, and one solution is building more wooden multi-storey constructions (WMCs). In the construction industry, however, there is a strong path dependency towards applying well-established construction materials and methods, as well as partnerships. To gain understanding of network-based collaboration, learning and end-user involvement in novel wooden construction business, the study uses qualitative methods and employs business ecosystem approach in the analysis. The studied WMC business case revealed that barriers of collaborative business ecosystem development include both the lack of clarity in the shared goals between actors and weak end-user involvement. Moreover, neither companies nor end-users fully recognize sustainability aspects around WMC. Enabling factors such as smooth communication and building trust among business actors during planning and building were recognised. The study suggests that a broader business ecosystem approach, including the living and use of the building, offers a mindset shift for developing sustainability-driven logic alongside profitable construction business and creating value for consumers. (c) 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Peer reviewe

Milloin konsultoin perinnöllisyyslääkäriä?

English summaryPeer reviewe

Potilaalla on perinnöllinen rintasyöpäalttius - miten seuraan?

Vertaisarvioitu. Näin hoidan.Rintasyövistä noin 10 %:n arvioidaan johtuvan perinnöllisistä yksittäisen geenin mutaatioista. Selvästi yleisimpiä näistä ovat virheet geeneissä BRCA1, BRCA2 ja PALB2. Perinnöllistä rintasyöpäalttiutta kantavien naisten riskiä sairastua rintasyöpään voidaan vähentää huomattavasti kirurgisin keinoin, ennen kaikkea mastektomialla. Jos riskiryhmään kuuluva nainen ei ole halukas riskiä vähentävään kirurgiaan, hänelle tarjotaan seurantaa. Vuosittainen rintojen magneettikuvaus, usein yhdistettynä mammografiaan, on osoitettu vaikuttavaksi kuvausmenetelmäksi seurannassa, erityisesti suuren riskin geenivirheen kantajien osalta. Verikokeiden ottamisesta seurantakäyntien yhteydessä ei ole hyötyä, ja myös lääkkeiden rooli rintasyövän ehkäisyssä on vähäinen. Usein perinnölliseen rintasyöpäalttiuteen liittyy suurentunut riski sairastua muihin syöpiin, etenkin munasarjasyöpään, mikä huomioidaan seurannoissa

Chorea-acanthocytosis associated with two novel heterozygous mutations in the VPS13A gene

Non peer reviewe

Constitutional mosaicism for aBRCA2mutation as a cause of early-onset breast cancer

Germline mutations in theBRCA1andBRCA2genes cause hereditary breast and ovarian cancer syndrome (HBOC). Mutations in these genes are usually inherited, and reports ofde novo BRCA1/2mutations are rare. To date, only one patient with low-levelBRCA1mutation mosaicism has been published. We report on a breast cancer patient with constitutional somatic mosaicism of aBRCA2mutation.BRCA2mutation c.9294C>G, p.(Tyr3098Ter) was detected in 20% of reads in DNA extracted from peripheral blood using next-generation sequencing (NGS). TheBRCA2mutation was subsequently observed at similar levels in normal breast tissue, adipose tissue, normal right fallopian tube tissue and ovaries of the patient, suggesting that this mutation occurred early in embryonic development. This is the first case to report constitutional mosaicism for aBRCA2mutation and shows thatBRCA2mosaicism can underlie early-onset breast cancer. NGS forBRCA1/2should be considered for patients whose tumors harbor aBRCA1/2mutation and for individuals suggestive of genetic predisposition but without a family history of HBO.Peer reviewe

Platelet function and filamin A expression in two families with novel FLNA gene mutations associated with periventricular nodular heterotopia and panlobular emphysema

Pathogenic variants of the X-linked FLNA gene encoding filamin A protein have been associated with a wide spectrum of symptoms, including the recently described pulmonary phenotype with childhood-onset panlobular emphysema. We describe three female patients from two families with novel heterozygous FLNA variants c.5837_2del and c.508C > T. Analysis of immunofluorescence of peripheral blood smears and platelet function was performed for all patients. FLNA-negative platelets were observed, suggesting that these variants result in the loss of a functional protein product. All three patients also had periventricular nodular heterotopia and panlobular emphysema. However, they had considerably milder symptoms and later age of onset than in the previously reported cases. Therefore, patients with pathogenic FLNA variants should be studied actively for lung involvement even in the absence of pronounced respiratory symptoms. Conversely, any patient with unexplained panlobular emphysema should be analyzed for pathogenic FLNA variants. We also suggest that immunofluorescence analysis is a useful tool for investigating the pathogenicity of novel FLNA variants.Peer reviewe