PROMO-GENODE: a PROspective study of MOnoGEnic causes Of DEmentia


Genetisch onderzoek bij dementie: een studie in de dagelijkse praktijk. Eén verandering in één gen kan dementie veroorzaken. Deze zogenaamde monogene oorzaken van dementie zorgen ervoor dat dementie in sommige families heel vaak voorkomt. Toch weten we niet hoe vaak monogene oorzaken van dementie voorkomen, omdat slechts sommige patiënten voor genetisch onderzoek in aanmerking komen. Ook is er weinig aandacht voor wat de emotionele gevolgen zijn van het vinden en het vertellen over een monogene oorzaak van dementie op patiënten. Ik zal onderzoeken bij alle patiënten die een geheugenpolikliniek bezoeken, hoe vaak monogene oorzaken écht voorkomen bij patiënten en welke patiënten willen de uitslag van het erfelijksonderzoek weten. Daarnaast wordt emotionele belasting van het vertellen over een genetisch risico aan patiënten onderzocht.

Titel: Genome-wide association study of frontotemporal dementia identifies a C9ORF72 haplotype with a median of 12-G4C2 repeats that predisposes to pathological repeat expansions
Auteur: Lianne M. Reus,corresponding author1 Iris E. Jansen,1,2 Merel O. Mol,3 Fred van Ruissen,4 Jeroen van Rooij,3 Natasja M. van Schoor,5 Niccolò Tesi,1,6,7 Marcel J. T. Reinders,7 Martijn A. Huisman,5,8 Henne Holstege,1,6 Pieter Jelle Visser,1,9,10 Sterre C. M. de Boer,1 Marc Hulsman,1,6 Shahzad Ahmad,11 Najaf Amin,11 Andre G. Uitterlinden,12 Arfan Ikram,11 Cornelia M. van Duijn,11 Harro Seelaar,3 Inez H. G. B. Ramakers,9 Frans R. J. Verhey,9 Aad van der Lugt,13 Jurgen A. H. R. Claassen,14 Geert Ja
Magazine: Translational psychiatry
Titel: New insights into the genetic etiology of Alzheimer's disease and related dementias
Auteur: Céline Bellenguez # 1, Fahri Küçükali # 2 3 4, Iris E Jansen # 5 6, Luca Kleineidam # 7 8 9, Sonia Moreno-Grau # 10 11, Najaf Amin # 12 13, Adam C Naj # 14 15, Rafael Campos-Martin # 8, Benjamin Grenier-Boley 16, Victor Andrade 7 8, Peter A Holmans 17, Anne Boland 18, Vincent Damotte 16, Sven J van der Lee 5 19, Marcos R Costa 16 20, Teemu Kuulasmaa 21, Qiong Yang 22 23, Itziar de Rojas 10 11, Joshua C Bis 24, Amber Yaqub 12, Ivana Prokic 12, Julien Chapuis 16, Shahzad Ahmad 12 25, Vilmantas
Magazine: Nature Genetics
Titel: Letter to the editor on a paper by Kaivola et al. (2020): carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is not associated with amyotrophic lateral sclerosis or frontotemporal dementia
Auteur: Sterre C M de Boer 1 2, Lauren Woolley 3, Merel O Mol 4, Maria Serpente 5, Lianne M Reus 6 7 8, Rick van Minkelen 9, Joke F A van Vugt 10, Federica Sorrentino 5 11, Jan H Veldink 10, Harro Seelaar 4, Daniela Galimberti 5 11, Fred van Ruissen 12, Simon Mead 3, Ekaterina Rogaeva 13, Yolande A L Pijnenburg 6 7, Sven J van der Lee 6 7 14
Magazine: Acta Neuropathologica communications
Titel: Mapping the genetic landscape of early-onset Alzheimer's disease in a cohort of 36 families
Auteur: Merel O. Mol, Sven J. van der Lee, Marc Hulsman, Yolande A. L. Pijnenburg, Phillip Scheltens, Netherlands Brain Bank, Harro Seelaar, John C. van Swieten, Laura Donker Kaat, Henne Holstege & Jeroen G. J. van Rooij
Magazine: Alzheimer's research & therapy
Titel: Genetics of Dementia: novel discoveries, risk stratification and personalized prediction
Auteur: Sven van der Lee
Titel: Quality of life in the memory clinic setting and associated factors
Auteur: Jetske van der Schaar, MSc*1, Sven J. van der Lee, MD, PhD1,2, Wiesje M. van der Flier, PhD1,3, Yolande, A.L. Pijnenburg, MD, PhD1, Ellen M.A. Smets, PhD4 and Leonie N.C. Visser, PhD4,5
Titel: Genetische diagnostiek bij dementie: wanneer en hoe?
Auteur: Sven van der Lee
Titel: The majority of the patients with a monogenic predisposition for dementia did not fulfill current criteria for genetic testing
Auteur: Sven J. van der Lee, Marc Hulsman, Rosalina M.L. van Spaendonk, Petra E. Cohn-Hokke, Wiesje M. van der Flier, Henne Holstege, and Philip Scheltens
Titel: Genetica van dementie: toepassing in de klinische zorg
Auteur: Sven van der Lee
Titel: Lunch and Learn
Auteur: Sven van der Lee
Titel: Het onderzoek naar missende erfelijkheidsfactoren
Auteur: Sven van der Lee
Titel: Alzheimer Actueel
Auteur: Sven van der Lee
Titel: Runner up: Young Outstanding research award

Samenvatting van de aanvraag
Background Dementia can be caused by a single variation in a single gene. This type of dementia is therefore called monogenic dementia. These variations can explain disease that runs in families. In the past, screening a gene for a variation was expensive and time-consuming. Due to the costs and the absence of treatment genetic analysis was only offered to patients that fulfilled strict patient criteria. The criteria include a strong family history or a very early onset of dementia (<65 years). This increased the a-priori chance to find a causal mutation, but only a small number of patients fulfilled the criteria. In addition to costs, clinicians were hesitant to genetic testing as disclosing a monogenic cause is seen as a very difficult message in the absence of treatment. Due to these practices monogenic types of dementia are likely understudied in daily clinical practice. Recent developments warrant that this should change. First, the development of next-generation-sequencing (NGS) decimated costs and tests all genes in a single test. Second, the discovery of more genes that can contain monogenic causes of dementia (now > 50 genes are known). Third, researchers found that also in those patients without a very clear family history causal variants can be found and even if family history is absent, it has been shown that new (‘de novo’) mutations can occur. In other words: NGS techniques enable us to affordably screen all patients for all causes of monogenic dementia. In the setting of research, it has recently been shown that in up to 12.6% of patients with dementia a monogenic cause can be found. This suggests monogenic causes are far more common than expected, but a study in the setting of daily clinical care is missing. The questions that need to be answered are: • How often do monogenic causes in the known genes really occur? • How often do monogenic causes of dementia occur in relation to current clinical guidelines? • Do patients want to know their genetic risk and can it be safely disclosed to those that want to know? To answer these questions, I propose PROMO-GENODE: A prospectively study monogenic causes of dementia in the setting of clinical care. The objectives of PROMO-GENODE are to: 1) Determine the unselected incidence of monogenic causes of dementia in clinical care; 2) Evaluate how often monogenic causes of dementia occur in those not fulfilling current criteria for genetic screening and evaluate patterns of disease in families; 3) Study the psychological impact of disclosing a monogenic cause to patients. Strategy: To initiate a prospective study embedded in the Amsterdam dementia Cohort (ADC). The ADC protocol includes genetic research and is approved by the local Medical Ethics Committee. For objective (1) I will screen 500 consecutive individuals (no selection criteria) included in the ADC for monogenic causes of dementia. Screening will be performed with NGS exome-sequencing (coding part of all genes) and by determining hexanucleotide repeat lengths of C9ORF (an important genetic cause of FTD). A clinical geneticist will evaluate the >50 known genes for monogenic causes of dementia. I will calculate the incidence of monogenic causes of dementia in the setting of clinical care. For objective (2) I will determine the age at onset, study the family history, and make family trees of all patients. I will study how often monogenic causes of dementia occur in those not fulfilling criteria for screening and compare the clinical presentation within a family. For object (3) I will study the psychological impact of disclosure of genetic risk to patients. Patients will be informed that genetic tests will be performed in the setting of research (objective 1). I will ask participants if they want to be informed about the results. Those that want their genetic risk disclosed will be counselled. Prior to disclosure I will ask for their reason to participate and study with questionnaires: worries related to dementia, levels of anxiety and depression and sense of control. Then genetic screening results will be disclosed. Those screened positive will be offered further counselling and three months after disclosure I will ask for understanding of their genetic risk and the same questionnaires. Ethics approval has to be obtained for objective (3). Expected results and innovations: An unselected estimate of the incidence of monogenic causes of dementia in new patients from a memory clinic, an estimate how often monogenic causes of dementia occur outside current criteria, and estimates of the psychological impact of disclosing genetic risk on patients. If successful, PROMO-GENODE will take the first steps to wider use of personalized genetic risk profiling in memory clinics.
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
dr. S.J. van der Lee MD PhD