Clinical trial NCT02363062: Identification of New FTLD Genes
Official title: Identification of New Genes Causing Frontotemporal Lobar Degeneration by Whole Exome Sequencing and Characterization of the Associated Phenotypes
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Frontotemporal Lobar Degeneration
Keywords: frontotemporal lobar degeneration
genes
whole exome sequencing
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2015-02-13
Enrollment: 440
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients affected by FTLD±ALS according to the international diagnosis criteria and their relatives

Brief summary: The major objective of the project is to map/identify new loci/genes, by a combination of whole exome sequencing and genome-wide linkage in autosomal dominant FTLD families excluded for known mutations.

Several secondary goals will be attained in the course of during the project:

For each novel gene identified in this project, we will determine the spectrum of mutations, evaluate their frequency and characterize the associated phenotypes. This will allow us to establish genotype-phenotype correlations in a large number of families, which will improve the nosology of these disorders and the diagnostic procedures;

Detailed description: Background and justification of the research. In France, 6,000 to 8,000 patients are affected by frontotemporal lobar degeneration (FTLD). FTLD are degenerative dementias related to Alzheimer's disease, characterized by behavioural, language and cognitive disorders beginning in the sixth decade. The genetic forms of FTLD are frequent (30-50% of the patients), but the genes responsible for 30-40% of familial FTLD are still unknown. At present, no molecular diagnosis can be proposed for 30% of the FTLD families and patients, for which the responsible genes are still unknown. No presymptomatic testing can be proposed either to at-risk relatives in these families.

Objectives.

1. The principal objective of this proposal is to identify one or several genes responsible for FTLD.
2. The secondary objectives are to:

   * evaluate the relative frequency of identified genes;
   * describe the phenotypes associated with the mutations in these genes;
   * establish phenotype-genotype correlations in order to improve the diagnostic procedures and strategies;
   * develop new genetic diagnostic analyses in the near future.

Project The patients will be recruited in three hospitals (Paris Salpetriere, Limoges, Lille). These three centers are partners of a national clinico-genetic network of 20 french centers experts in FTLD/FTLD-ALS, coordinated by Dr. I Le Ber. The participants in this network have collaborated for the last 15 years, and have already recruited over 1,000 patients with FTLD. Sequencing of known genes in these families allowed the identification of 150 families with an autosomal dominant form of FTLD not associated with a known mutation. Through the network, we aim to recruit 400 new patients with FTLD during the 4 years of the project. This estimation is based on the annual recruitment of the network during the last two years.

In this project, the 30 most informative families will be extended (440 patients and relatives sampled).

The combination of whole exome sequencing with genetic linkage studies in FTLD families without known mutations, and the large number of families included in this project, are two major points that should lead to the identification of several new genes. When causative genes are identified, we will establish the frequencies of mutations, extend the mutational spectrum, describe the clinical phenotypes and establish phenotype-genotype correlations. Genetic parameters such as penetrance will be analyzed.

Eligibility criteria: Patients are included if they:

i) are affected by FTLD±ALS according to the international diagnosis criteria and ii) Have (or their legal representatives have) given signed written informed consent for the research.

iii) are affiliated to social security or beneficiary of such régime

Relatives are included if they:

i) are aged \>18 years and ii) Have signed an informed consent for the research. are affiliated to social security or beneficiary of such

Primary outcomes:
measure: whole exome sequencing
timeFrame: Day 1
Secondary outcomes:
Other outcomes:
Locations:
city: Paris
country: France
facility: Pitié Salpetriere Hospital
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Isabelle LE BER, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ceslis A, Argall R, Henderson RD, McCombe PA, Robinson GA. The spectrum of language impairments in amyotrophic lateral sclerosis. Cortex. 2020 Nov;132:349-360. doi: 10.1016/j.cortex.2020.09.003. Epub 2020 Sep 18.
citation: Didic M, Aglieri V, Tramoni-Negre E, Ronat L, Le Ber I, Ceccaldi M, Belin P, Felician O. Progressive phonagnosia in a telephone operator carrying a C9orf72 expansion. Cortex. 2020 Nov;132:92-98. doi: 10.1016/j.cortex.2020.05.022. Epub 2020 Aug 10.