The Heritability of Frontotemporal Lobar Degeneration: Validation of Pedigree Classification Criteria in a Northern Italy Cohort

Abstract

A large portion of frontotemporal lobar degeneration (FTLD) patients has a family history of disease and the presence of a pathogenic mutation confirms the clinical diagnosis. Recently, standardized criteria to evaluate FTLD pedigree, based on first- and second-degree affected relatives, their age at onset, and clinical phenotype, were proposed and validated in an American cohort. Herein we applied these criteria to 402 Italian FTLD pedigrees and assessed mutation frequencies in GRN, C9orf72, and MAPT genes with the aim of validating these criteria. Moreover, we evaluated whether genetic counseling requests reflect the estimated family risk. 12.4% of pedigrees had high family history, 6.5% medium, 15.4% low; 39% were apparent sporadic cases and 26.6% had family history of unknown significance. Mutations frequencies were in line with the categorization proposed: the highest rate was found in the most at-risk families (74%) and decreased in other categories (medium: 15.4%; low: 9.7%; sporadic: 1.3%). Mutation carriers with unknown family history (5.6%) were mostly early-onset patients. Detected mutation frequency was comparable with the US-cohort (13.7%), but mutations distribution among genes was different, with higher frequency of GRN mutations (9.4%) in our cohort. An elevated proportion of FTLD patients belonging to “high risk” pedigrees asked for genetic counseling (42%); requests decreased according to the estimated family risk (medium: 26.9%; low: 17.7%; sporadic: 5.1%). In conclusion, the proposed pedigree classification criteria, herein further validated, should be incorporated in the FTLD diagnostic work-up. Moreover, our data suggest to extend genetic screening to early-onset patients with unknown family history.

Keywords

C9orf72 frontotemporal lobar degeneration genetic counseling GRN MAPT mutation pedigree

INTRODUCTION

Frontotemporal lobar degeneration (FTLD) is a common cause of early-onset dementia with a mean age of presentation under 65 years old [1, 2]. FTLD is characterized by progressive degeneration of frontal and anterior temporal lobes of the brain with two main clinical presentations: deterioration of behavior or language disorders. The behavioral variant frontotemporal dementia (bvFTD) presents behavioral disorders and change in personality (e.g., apathy, disinhibition, loss of empathy, ritualistic behavior, hyperorality) [3], while the phenotype with language disorders can be classified as primary progressive aphasia (PPA), with loss of grammar and motor speech, or semantic dementia (SD), with anomia and loss of word comprehension [4]. Moreover, FTLD can clinically overlap with motor disorders: corticobasal syndrome, progressive supranuclear palsy, and motor neuron disease [5 –7]. It is well known that most FTLD cases are sporadic but up to 50% of FTLD patients has a family history of the disease and 15% to 40% of these cases are due to single gene mutations [8]. Recently, the presence of a pathogenic mutation was introduced in the bvFTD diagnostic criteria to confirm the clinical diagnosis [3]. The microtubule associated protein tau gene (MAPT) was the first FTLD gene identified in 1998 [9, 10] followed by the progranulin gene (GRN) in 2006 [11, 12] and lastly, in 2011, the chromosome 9 open reading frame 72 (C9orf72) [13, 14]. Mutations in these three genes have been identified as the most frequent genetic cause of FTLD (https://www.molgen.ua.ac.be/ADMutations/). The obvious progress in the genetic of FTLD and the possibility, for mutation carriers, of targeted pharmacological trials have raised the interest of clinicians and researchers to identify FTLD families. Moreover, it opened the possibility also for the at-risk family members to know their risk of developing the disease. This has implications both from an ethical, psychological, legal, or social point of view and this is why accurate genetic counseling protocols are evolving in dementia [15].

Previously, inheritance trait of FTLD has been largely investigated and different criteria for pedigree classification in FTLD were proposed [16 –20]. An accurate pedigree classification is important since 1) it provides clinicians information on the real need to carry out diagnostic genetic testing and on the priority on which gene or genes to test; and 2) it provides information about the family-risk.

In this study, we applied the criteria to classify FTLD pedigrees recently proposed by Wood and colleagues [19] in a memory center clinical setting and rated the mutation frequencies with the aim of further validating these criteria as a tool to support genetic testing decisions in clinical settings.

MATERIALS AND METHODS

Participants

A total of 402 patients (one proband for each pedigree) with a clinical diagnosis of FTLD, according to international guidelines, were included in this study [3 , 21]. All patients were serially recruited at the MAC Memory Clinic of the IRCCS Fatebenefratelli Centro San Giovanni di Dio in Brescia, Italy. At recruitment, a blood sample for DNA extraction were collected and pedigrees information were acquired with a Family History Questionnaire [22]. All participants signed an informed consent for the blood collection as approved by the local ethics committee (approval number 2/1992; 26/2014). Patients and families also had the opportunity to ask to be informed about the genetic testing following an experimental genetic counseling protocol; to adhere to genetic counseling protocol, a specific informed consent was signed (Local Ethics Committee approval number 34/2003).

Pedigrees classification

Depending on information acquired with the Family History Questionnaire, probands families were classified using Wood’s pedigrees classifications. The criteria include 5 categories: high, medium, low family history of dementia, apparent sporadic, and unknown significance. Classification is based on the number of first-degree relatives (FDR) and second-degree relatives (SDR), their age at onset of the disease and their clinical phenotype, as described in [19]. Criteria for family history category “high” were: 1) one or more FDR with FTLD or amyotrophic lateral sclerosis (ALS); 2) one SDR with FTLD or ALS and one or more FDR or SDR with FTLD, ALS, Parkinson’s disease (PD), Alzheimer’s disease (AD), or dementia not otherwise specified (NOS); 3) two FDRs with PD, AD, or dementia NOS with onset at ≤65 years. Criteria for family history category “medium” were: 1) one SDR with FTLD or ALS; 2) one FDR with PD, AD, or dementia NOS with onset at ≤65 years; 3) three or more FDRs or SDRs with PD, AD, or dementia NOS. Criteria for family history category “low” were: one FDR with PD, AD, or dementia NOS with onset at >65 years. Criteria for sporadic cases: 1) two or more SDRs with PD, AD, or dementia NOS at any age of onset; 2) no other affected FDRs or SDRs. The category of unknown significance included pedigrees with information that was too limited or uncertain for categorization (e.g., small family size or lack of information regarding key relatives due early death from an unrelated cause, diagnosis or clinical details not welldocumented).

Biochemical and genetic analyses

The presence of null mutations in GRN gene was first investigated by plasma dosage of progranulin, employing a commercially available ELISA assay (Human Progranulin ELISA Kit, Adipo-Gen Inc., Liestal, Switzerland) [23]: if the level was <61.55 ng/ml, the presence of the common Italian Leu271LeufsX10 mutation was assessed; if this mutation was not found, all other exons were sequenced as described [24]. MAPT mutations were investigated by direct sequencing of all exons and flanking regions [24]. The GGGGCC repeat in the C9orf72 gene was amplified by PCR and allele identification was performed by agarose gel electrophoresis. To provide a qualitative assessment of the presence of an expanded repeat, we performed a repeat-primed PCR. Number of repeat units were estimated based on the length of PCR amplified fragments or by Peak scanner software analysis of the traces deriving from the repeat-primed PCR reaction. A value equal or higher than 30 repeat units was classified as pathological expansion [25].

Statistical analyses

The SPSS 20.0 software for Windows (IBM) was used for statistical analysis. The Kolmogorov-Smirnov test was performed in all continuous variables to define the presence of normality. One way ANOVA with post-hoc test with Sidak correction was used for groups comparisons of normally distributed continuous variables. The KruskalWallis test and pair wise comparison with Bonferroni correction was used for groups comparisons of skewed variables. Categorical variables were performed with the chi-square test; non-parametric binomial test was applied to compare mutation rate found in the Italian-cohort and the onespublished on the US-cohort [19]. Two tailed p value equal or less than 0.05 was considered statisticallysignificant.

RESULTS

A total of 402 FTLD families were classified using the recently proposed FTLD pedigree classification criteria [19]: according to these criteria, 12.4% were classified as pedigrees with high family history of dementia, 6.5% with medium family history of dementia, 15.4% with low family history of dementia, 39% apparent sporadic, and 26.6% with family history of dementia of unknown significance (Table 1). Compared to the American cohort— where these criteria were first applied (US-cohort)— we found: 1) less families classified as medium family history pedigrees (6.5% versus 10.1%, p = 0.008); 2) more probands classified as apparent sporadic (39% versus 29.7%, p < 0.001); 3) less pedigrees with family history of dementia of unknown significance (26.6% versus 32.4%, p = 0.011). Sex of probands belonging to these families was equally distributed among the 5 categories. Age at the disease onset was significantly lower in probands belonging to families with high family history of dementia (ANOVA test, p < 0.001; post hoc: high versus medium, p = 0.006; high versus low, p < 0.001; high versus apparent sporadic, p < 0.001; high versus unknown significance, p < 0.001), while there were no differences between other groups (Table 1).

Table 1

Clinical and demographic characteristics of probands of the Italian FTLD-cohort

	Whole Cohort	Family History Category					p-values
		High	Medium	Low	Apparent Sporadic	Unknown significance
Number of families, n (%)	402	50 (12.4%)	26 (6.5%)	62 (15.4%)	157 (39%)	107 (26.6%)	–
Female, n (%)	227 (56.5%)	26 (52%)	14 (53.8%)	36 (58.1%)	86 (54.8%)	65 (60.7%)	P = 0.823^*
Age at onset of the disease (y, mean±SD)	64.7±9.9	57.2±8.2	66.5±9	66.9±9.1	64.8±10.7	67.1±8	P < 0.001^**
Age at blood sampling (y, mean±SD)	67.9±10.2	60.6±8.4	68.4±9.8	69.8±9.4	67.4±10	70.9±10	p < 0.001^**

^*Chi-square test; ^**ANOVA test; y, years.

All probands were tested for GRN, C9orf72, and MAPT mutations, the three most commonly mutated genes in FTLD: pathogenic mutations were found in 55 patients (13.7%) which include 38 GRN, 14 C9orf72, and 3 MAPT. The highest percentage of identified mutations is among probands belonging to pedigree classified as high family history of dementia and decreases in the other categories (Fisher exact test: high versus medium, low, apparentsporadic, unknown significance, p < 0.001): in probands belonging to pedigrees classified high family history of dementia a pathological mutation was identified in 74% of cases; mutations were present in 15.4% of medium family history cases, in 9.7% of low family history cases, and in 1.3% of apparent sporadic cases. The percentage of presence of mutation in unknown significance cases was 5.6% (Table 2). Mutations in GRN were the most common genetic determinant, with a mutation frequency up to 50% in pedigrees with high family history (Table 2). Compared to Wood’s US-cohort, globally we have found a comparable mutation detection rate in the whole sample as well as in the family history category subgroups (Table 3); in the two cohorts, we found differences in the distribution of mutations in the three genes: GRN mutations were 2.35-fold more frequent in the Italian cohort, while C9orf72 and MAPT mutations were significantly less frequent (Table 4). In addition, we analyzed the rate of FTLD families deciding to undertake the genetic counseling protocol within the 5 categories.

Table 2

Mutation rate divided by genes

Mutated gene	Pedigrees with mutation/ total pedigrees (%)	Family History Category
		High	Medium	Low	Apparent Sporadic	Unknown Significance
GRN	38/402 (9.4%)	25/50 (50%)	3/26 (11.5%)	3/62 (4.8%)	2/157 (1.3%)	5/107 (4.7%)
C9ORF72	14/402 (3.5%)	9/50 (18%)	1/26 (3.8%)	3/62 (4.8%)	0/157 (0%)	1/107 (0.9%)
MAPT	3/402 (0.7%)	3/50 (6%)	0/26 (0%)	0/62 (0%)	0/157 (0%)	0/107 (0%)
Total	55/402 (13.7%)	37/50 (74%)	4/26 (15.4%)	6/62 (9.7%)	2/157 (1.3%)	6/107 (5.6%)

Table 3

Comparison between mutation detection rate in categories in US-cohort and Italian-cohort

Family History category	Mutation rate (US-cohort)	Mutation rate (Italian-cohort)	p-values
High	25 (64.1%)	37 (74%)	p = 0.090^†
Medium	9 (29%)	4 (15.4%)	p = 0.089^†
Low	5 (10.9%)	6 (9.7%)	p = 0.470^†
Apparent Sporadic	1 (1.1%)	2 (1.3%)	p = 0.466^†
Unknown Significance	7 (7.1%)	6 (5.6%)	p = 0.372^†
Total	47 (15.4%)	55 (13.7%)	p = 0.254^†

^†Binomial test.

Table 4

Comparison between mutations in US-cohort and Italian-cohort

Mutated gene	Mutation rate		p-values
	US-cohort	Italian-cohort
GRN	12 (4%)	38 (9.4%)	p < 0.001^†
C9ORF72	25 (8.2%)	14 (3.5%)	p < 0.001^†
MAPT	10 (3.3%)	3 (0.7%)	p = 0.002^†
Total	47 (15.3%)	55 (13.7%)	p = 0.254^†

^†Binomial test.

Forty-two percent of families classified as high family history of dementia pedigrees requested the genetic counseling protocol; 26.9% of medium family history pedigrees; 17.7% of low family history pedigrees, 5.1% of apparent sporadic patients, and 0% of patients with family history of unknown significance (Table 5). Patients acceding to the genetic counseling had comparable ages among the family history categories (Table 5); however, apparent sporadic patients acceding to the genetic counseling protocol were significantly younger than the sporadic patients that did not request genetic counseling (56.1±6.4 versus 68.0±9.8, p = 0.001).

Table 5

Rate and age of probands acceding to genetic counseling protocol

	Family History Category					p-values
	High	Medium	Low	Apparent Sporadic	Unknown significance
Access to genetic counseling (families in counseling/total)	21/50 (42%)	7/26 (26.9%)	11/62 (17.7%)	8/157 (5.1%)	0/107 (0%)	p < 0.001^*
Age of patients acceding to genetic counseling (years, mean±SD)	60.5±8.8	63.3±7.3	65.6±7.8	56.1±6.4	–	p = 0.082^**

^*Chi-square test; ^**ANOVA test.

DISCUSSION

The constant changes in the field of FTLD with new discoveries in molecular pathogenic pathways and the evidence of a strong genetic causative component have brought a growing interest to this pathology [26]. Interestingly, updated diagnostic criteria for bvFTD includes the presence of a pathogenic mutation: thus, genetic testing can be employed to confirm the clinical diagnosis [3]. Moreover, the progress in the genetic of FTLD open the opportunity, both for affected and pre-symptomatic mutation carriers, of targeted pharmacological trials. Despite its utility, the genetic testing is not economically feasible for every individual with FTLD. Thus, in recent years, new pedigree classification criteria have been developed to favor the identification of families with a likelihood of carrying a pathogenic mutation [17 –20]. The FTLD-specific criteria proposed by Wood et al., incorporating first- and second-degree affected relatives’ essential clinical information, such as diagnoses and ages at onset, were demonstrated to be more efficient to classify pedigrees according to the likelihood of carrying a pathogenic mutation, as compared with criteria using classic descriptions of inheritance [19]. In this study, we applied these criteria to classify FTLD pedigrees in a memory center clinical setting in Northern Italy and we validated the criteria with mutation screening in the whole cohort for the three most common FTLD-associated genes (GRN, C9orf72, and MAPT). Moreover, we evaluated whether genetic counseling requests reflect the family risk, estimated by these criteria. Based on Wood’s criteria, we found 12.4% of FTLD pedigrees with high family history; this frequency is similar to the one found in the American cohort (13.0%) and to what reported in previous studies for FTLD with autosomal dominant inheritance [8, 20]. Unlike previous criteria, Wood’s ones can be employed to classify pedigrees with high family history also in the absence of a clear autosomal dominant inheritance pattern, that is often difficult to trace in late onset diseases. Compared to the US-cohort, we found less families classified as medium family history pedigrees, more probands classified as apparent sporadic and less pedigrees with family history of dementia of unknown significance. In our cohort probands belonging to pedigrees with high family history had a significant lower age at onset as compared with patients belonging to other categories.

The mutations frequencies that we detected is in line with the categorization proposed, since the highest mutation rate was found in the most at-risk families. Thus, we confirmed that the proposed criteria are effective at detecting potentially mutated cases.

The mutation rate in our FTLD population was comparable with the rate found in the US cohort (13.7%); however, we found a different contributionof the investigated genes. A strong variability in mutation prevalence across different geographical regions is reported for MAPT, GRN and C9orf72 genes[8 , 28]. The variation of the relative mutation frequency in the investigated genes is often due to founder effects, resulting in a regionally high occurrence of one or limited number of specific mutations, e.g., the +16 exon 10 splice mutation of MAPT in the United Kingdom [29], the GRN p.Arg493X (c.1477C>T) in US [30], the GRN p.0 (c.138+1G>C) in Belgium [31], and the GRN p.Leu271LeufsX10 (c.813-816delCTCA) in Italy [32]. In the present study, we confirmed that the most frequent genetic cause in our cohort are mutations in the GRN gene, explaining 69% of all detected mutations. The majority of probands herein analyzed carried the p.Leu271Leufsx10 mutation, a founder mutation [24 , 33]. Thus, our hypothesis is that a founder effect might be responsible for the local differences observed. Of note, mutations in MAPT gene were found only in probands belonging to pedigrees with high family history. Differently from the US-cohort, the C9orf72 gene expansion was detected also in families with low family history but not in sporadic cases even if an incomplete penetrance was described for this mutation [34]. GRN mutation were found in all categories, including apparently sporadic patients and patients with family history of unknown significance. GRN mutations are associated with a strong variability in the age of onset and an age-dependent penetrance, with 50–60% of the mutation carriers being affected by the age of 60 and 90–95% by the age of 70 years [24 , 35]; thus, family history is not always apparent for GRN mutations carriers and sporadic carriers has been often reported.

Thus the present validation study indicates that Wood’s criteria can be equally applied to US and Italian patients to capture potentially mutated cases; however the priority on which gene should be tested first should be adapted for local differences. Next generation Sequencing (NGS) panels are already available for quick and efficient mutation search and appear as the upcoming technology for mutation analysis. However, a step-by-step algorithm for guiding genetic screening on the basis of mutation regional occurrence might be applied to reduce time and cost of the laboratory analysis [15] in clinical centers where NGS analysis is not available.

A limitation of the proposed criteria is the presence of mutations in more than 5% of patients belonging to families classified as “of unknown significance”. According to the proposed classification criteria, these patients might escape from genetic analysis, since there are not specific indications for genetic testing in this category [19]. Since we observed that the 83.3% of mutated patients with family history of unknown significance developed the disease before 65 years (data not shown), we suggest to include in the genetic screening patients with age at onset lower than 65 years, when the family history is of unknown significance. In addition, we observed that five out of six mutated patients belonging to unclassified families were carrying GRN mutations. Given the high prevalence of GRN mutations in these cases and the opportunity to catch mutation employing plasma progranulin dosage [23, 36], our suggestion is to apply this quick and not expensive test in all FTLD patient, especially in populations where the founder effect was described [12 , 31].

In this study we also investigated if, in our cohort, families requested to access genetic counseling protocol according to their risk. More than 40% of families classified as high family history of dementia pedigrees requested to accede to the genetic counseling protocol; this rate decreases in other categories according to the estimated genetic risk. Of note, apparent sporadic patients that requested to enter the genetic counseling protocol were significantly younger than patients that did not request it. We have previously investigated the willingness of dementia patients’ relatives to undergo genetic testing in different hypothetical scenario and we have found a high interest in genetic testing (more than 70%) independently of test accuracy or availability of a successful treatment, suggesting poor criticism [37]. In the investigated cohort, a significantly lower percentage of families (11.7%) actually requested to accede to the genetic counseling protocol, and the requests depended on the estimated family risk, indicating a more informed decision.

The ideal time to treat neurodegenerative diseases is before clinical presentation, when neuronal degeneration has only partially occurred. The best prospect of achieving this lies with FTLD, where pathogenic mutation carriers are frequent and may benefit from molecularly targeted disease modifying or disease-delaying therapies. Therapeutic opportunities are especially needed in pre-symptomatic carriers, where markers of neurodegeneration can be detected even a decade before the expected onset of clinical symptoms [38, 39]. Herein, we validated the pedigree classification criteria proposed by Wood et al. These criteria represent an important tool to rate for known common genetic causes of FTLD and should be incorporated in the FTLD diagnostic work-up. In addition, our data suggest to extend genetic screening to early-onset patients when family history is unknown. Mutation screening of the described cohort suggests that there are other genetic determinants yet to be discovered: in the next future, next generation sequencing and genome-wide approaches will complete the picture of heritability and genetics in FTLD.

Footnotes

ACKNOWLEDGMENTS

This work was supported by the Italian Ministry of Health (Ricerca Corrente) and by the EU Joint Programme –Neurodegenerative Disease Research (JPND PreFrontAls).

Authors’ disclosures available online ().

References

Ratnavalli

, Brayne

, Dawson

, Hodges

(2002) The prevalence of frontotemporal dementia. Neurology 58, 1615–1621.

Onyike

, Diehl-Schmid

(2013) The epidemiology of frontotemporal dementia. Int Rev Psychiatry 25, 130–137.

Rascovsky

, Hodges

, Knopman

, Mendez

, Kramer

, Neuhaus

, van Swieten

, Seelaar

, Dopper

, Onyike

, Hillis

, Josephs

, Boeve

, Kertesz

, Seeley

, Rankin

, Johnson

, Gorno-Tempini

, Rosen

, Prioleau-Latham

, Lee

, Kipps

, Lillo

, Piguet

, Rohrer

, Rossor

, Warren

, Fox

, Galasko

, Salmon

, Black

, Mesulam

, Weintraub

, Dickerson

, Diehl-Schmid

, Pasquier

, Deramecourt

, Lebert

, Pijnenburg

, Chow

, Manes

, Grafman

, Cappa

, Freedman

, Grossman

, Miller

(2011) Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134, 2456–2477.

Gorno-Tempini

, Hillis

, Weintraub

, Kertesz

, Mendez

, Cappa

, Ogar

, Rohrer

, Black

, Boeve

, Manes

, Dronkers

, Vandenberghe

, Rascovsky

, Patterson

, Miller

, Knopman

, Hodges

, Mesulam

, Grossman

(2011) Classification of primary progressive aphasia and its variants. Neurology 76, 1006–1014.

Lomen-Hoerth

, Anderson

, Miller

(2002) The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 59, 1077–1079.

Josephs

, Petersen

, Knopman

, Boeve

, Whitwell

, Duffy

, Parisi

, Dickson

(2006) Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP. Neurology 66, 41–48.

Burrell

, Kiernan

, Vucic

, Hodges

(2011) Motor neuron dysfunction in frontotemporal dementia. Brain 134, 2582–2594.

Rohrer

, Guerreiro

, Vandrovcova

, Uphill

, Reiman

, Beck

, Isaacs

, Authier

, Ferrari

, Fox

, Mackenzie

, Warren

, de Silva

, Holton

, Revesz

, Hardy

, Mead

, Rossor

(2009) The heritability and genetics of frontotemporal lobar degeneration. Neurology 73, 1451–1456.

Poorkaj

, Bird

, Wijsman

, Nemens

, Garruto

, Anderson

, Andreadis

, Wiederholt

, Raskind

, Schellenberg

(1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 43, 815–825.

10.

Hutton

, Lendon

, Rizzu

, Baker

, Froelich

, Houlden

, Pickering-Brown

, Chakraverty

, Isaacs

, Grover

, Hackett

, Adamson

, Lincoln

, Dickson

, Davies

, Petersen

, Stevens

, de Graaff

, Wauters

, van Baren

, Hillebrand

, Joosse

, Kwon

, Nowotny

, Che

, Norton

, Morris

, Reed

, Trojanowski

, Basun

, Lannfelt

, Neystat

, Fahn

, Dark

, Tannenberg

, Dodd

, Hayward

, Kwok

, Schofield

, Andreadis

, Snowden

, Craufurd

, Neary

, Owen

, Oostra

, Hardy

, Goate

, van Swieten

, Mann

, Lynch

, Heutink

(1998) Association of missense and 5’-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705.

11.

Baker

, Mackenzie

, Pickering-Brown

, Gass

, Rademakers

, Lindholm

, Snowden

, Adamson

, Sadovnick

, Rollinson

, Cannon

, Dwosh

, Neary

, Melquist

, Richardson

, Dickson

, Berger

, Eriksen

, Robinson

, Zehr

, Dickey

, Crook

, McGowan

, Mann

, Boeve

, Feldman

, Hutton

(2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442, 916–919.

12.

Cruts

, Gijselinck

, van der Zee

, Engelborghs

, Wils

, Pirici

, Rademakers

, Vandenberghe

, Dermaut

, Martin

, van Duijn

, Peeters

, Sciot

, Santens

, De Pooter

, Mattheijssens

, Van den Broeck

, Cuijt

, Vennekens

, De Deyn

, Kumar-Singh

, Van Broeckhoven

(2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442, 920–924.

13.

Renton

, Majounie

, Waite

, Simon-Sanchez

, Rollinson

, Gibbs

, Schymick

, Laaksovirta

, van Swieten

, Myllykangas

, Kalimo

, Paetau

, Abramzon

, Remes

, Kaganovich

, Scholz

, Duckworth

, Ding

, Harmer

, Hernandez

, Johnson

, Mok

, Ryten

, Trabzuni

, Guerreiro

, Orrell

, Neal

, Murray

, Pearson

, Jansen

, Sondervan

, Seelaar

, Blake

, Young

, Halliwell

, Callister

, Toulson

, Richardson

, Gerhard

, Snowden

, Mann

, Neary

, Nalls

, Peuralinna

, Jansson

, Isoviita

, Kaivorinne

, Holtta-Vuori

, Ikonen

, Sulkava

, Benatar

, Wuu

, Chio

, Restagno

, Borghero

, Sabatelli

, ITALSGEN Consortium, Heckerman

, Rogaeva

, Zinman

, Rothstein

, Sendtner

, Drepper

, Eichler

, Alkan

, Abdullaev

, Pack

, Dutra

, Pak

, Hardy

, Singleton

, Williams

, Heutink

, Pickering-Brown

, Morris

, Tienari

, Traynor

(2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268.

14.

DeJesus-Hernandez

, Mackenzie

, Boeve

, Boxer

, Baker

, Rutherford

, Nicholson

, Finch

, Flynn

, Adamson

, Kouri

, Wojtas

, Sengdy

, Hsiung

, Karydas

, Seeley

, Josephs

, Coppola

, Geschwind

, Wszolek

, Feldman

, Knopman

, Petersen

, Miller

, Dickson

, Boylan

, Graff-Radford

, Rademakers

(2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256.

15.

Bocchetta

, Mega

, Bernardi

, Di Maria

, Benussi

, Binetti

, Borroni

, Colao

, Di Fede

, Fostinelli

, Galimberti

, Gennarelli

, Ghidoni

, Piaceri

, Pievani

, Porteri

, Redaelli

, Rossi

, Suardi

, Babiloni

, Scarpini

, Tagliavini

, Padovani

, Nacmias

, Sorbi

, Frisoni

, Bruni

, SINdem Collaborators (2016) Genetic counseling and testing for Alzheimer’s disease and frontotemporal lobar degeneration: An Italian consensus protocol. J Alzheimers Dis 51, 277–291.

16.

Stevens

, van Duijn

, Kamphorst

, de Knijff

, Heutink

, van Gool

, Scheltens

, Ravid

, Oostra

, Niermeijer

, van Swieten

(1998) Familial aggregation in frontotemporal dementia. Neurology 50, 1541–1545.

17.

Chow

, Miller

, Hayashi

, Geschwind

(1999) Inheritance of frontotemporal dementia. Arch Neurol 56, 817–822.

18.

Goldman

, Farmer

, Wood

, Johnson

, Boxer

, Neuhaus

, Lomen-Hoerth

, Wilhelmsen

, Lee

, Grossman

, Miller

(2005) Comparison of family histories in FTLD subtypes and related tauopathies. Neurology 65, 1817–1819.

19.

Wood

, Falcone

, Suh

, Irwin

, Chen-Plotkin

, Lee

, Xie

, Van Deerlin

, Grossman

(2013) Development and validation of pedigree classification criteria for frontotemporal lobar degeneration. JAMA Neurol 70, 1411–1417.

20.

Loy

, Schofield

, Turner

, Kwok

(2014) Genetics of dementia. Lancet 383, 828–840.

21.

Neary

, Snowden

, Gustafson

, Passant

, Stuss

, Black

, Freedman

, Kertesz

, Robert

, Albert

, Boone

, Miller

, Cummings

, Benson

(1998) Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria. Neurology 51, 1546–1554.

22.

Farrer

, Myers

, Connor

, Cupples

, Growdon

(1991) Segregation analysis reveals evidence of a major gene for Alzheimer disease. Am J Hum Genet 48, 1026–1033.

23.

Ghidoni

, Stoppani

, Rossi

, Piccoli

, Albertini

, Paterlini

, Glionna

, Pegoiani

, Agnati

, Fenoglio

, Scarpini

, Galimberti

, Morbin

, Tagliavini

, Binetti

, Benussi

(2012) Optimal plasma progranulin cutoff value for predicting null progranulin mutations in neurodegenerative diseases: A multicenter Italian study. Neurodegener Dis 9, 121–127.

24.

Benussi

, Ghidoni

, Pegoiani

, Moretti

, Zanetti

, Binetti

(2009) Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide. Neurobiol Dis 33, 379–385.

25.

Benussi

, Rossi

, Glionna

, Tonoli

, Piccoli

, Fostinelli

, Paterlini

, Flocco

, Albani

, Pantieri

, Cereda

, Forloni

, Tagliavini

, Binetti

, Ghidoni

(2014) C9ORF72 hexanucleotide repeat number in frontotemporal lobar degeneration: A genotype-phenotype correlation study. J Alzheimers Dis 38, 799–808.

26.

Bang

, Spina

, Miller

(2015) Frontotemporal dementia. Lancet 386, 1672–1682.

27.

Binetti

, Nicosia

, Benussi

, Ghidoni

, Feudatari

, Barbiero

, Signorini

, Villa

, Mattioli

, Zanetti

, Alberici

(2003) Prevalence of TAU mutations in an Italian clinical series of familial frontotemporal patients. Neurosci Lett 338, 85–87.

28.

van der Zee

, Gijselinck

, Dillen

, Van Langenhove

, Theuns

, Engelborghs

, Philtjens

, Vandenbulcke

, Sleegers

, Sieben

, Baumer

, Maes

, Corsmit

, Borroni

, Padovani

, Archetti

, Perneczky

, Diehl-Schmid

, de Mendonca

, Miltenberger-Miltenyi

, Pereira

, Pimentel

, Nacmias

, Bagnoli

, Sorbi

, Graff

, Chiang

, Westerlund

, Sanchez-Valle

, Llado

, Gelpi

, Santana

, Almeida

, Santiago

, Frisoni

, Zanetti

, Bonvicini

, Synofzik

, Maetzler

, Vom Hagen

, Schols

, Heneka

, Jessen

, Matej

, Parobkova

, Kovacs

, Strobel

, Sarafov

, Tournev

, Jordanova

, Danek

, Arzberger

, Fabrizi

, Testi

, Salmon

, Santens

, Martin

, Cras

, Vandenberghe

, De Deyn

, Cruts

, Van Broeckhoven

, van der Zee

, Gijselinck

, Dillen

, Van Langenhove

, Theuns

, Philtjens

, Sleegers

, Baumer

, Maes

, Corsmit

, Cruts

, Van Broeckhoven

, van der Zee

, Gijselinck

, Dillen

, Van Langenhove

, Philtjens

, Theuns

, Sleegers

, Baumer

, Maes

, Cruts

, Van Broeckhoven

, Engelborghs

, De Deyn

, Cras

, Engelborghs

, De Deyn

, Vandenbulcke

, Borroni

, Padovani

, Archetti

, Perneczky

, Diehl-Schmid

, Synofzik

, Maetzler

, Muller Vom Hagen

, Schols

, Synofzik

, Maetzler

, Muller Vom Hagen

, Schols

, Heneka

, Jessen

, Ramirez

, Kurzwelly

, Sachtleben

, Mairer

, de Mendonca

, Miltenberger-Miltenyi

, Pereira

, Firmo

, Pimentel

, Sanchez-Valle

, Llado

, Antonell

, Molinuevo

, Gelpi

, Graff

, Chiang

, Westerlund

, Graff

, Kinhult Stahlbom

, Thonberg

, Nennesmo

, Borjesson-Hanson

, Nacmias

, Bagnoli

, Sorbi

, Bessi

, Piaceri

, Santana

, Santiago

, Santana

, Helena Ribeiro

, Rosario Almeida

, Oliveira

, Massano

, Garret

, Pires

, Frisoni

, Zanetti

, Bonvicini

, Sarafov

, Tournev

, Jordanova

, Tournev

, Kovacs

, Strobel

, Heneka

, Jessen

, Ramirez

, Kurzwelly

, Sachtleben

, Mairer

, Jessen

, Matej

, Parobkova

, Danel

, Arzberger

, Maria Fabrizi

, Testi

, Ferrari

, Cavallaro

, Salmon

, Santens

, Cras

, European Early-Onset Dementia Consortium (2013) A pan-European study of the C9orf72 repeat associated with FTLD: Geographic prevalence, genomic instability, and intermediate repeats. Hum Mutat 34, 363–373.

29.

Pickering-Brown

, Baker

, Bird

, Trojanowski

, Lee

, Morris

, Rossor

, Janssen

, Neary

, Craufurd

, Richardson

, Snowden

, Hardy

, Mann

, Hutton

(2004) Evidence of a founder effect in families with frontotemporal dementia that harbor the tau +16 splice mutation. Am J Med Genet B Neuropsychiatr Genet 125B, 79–82.

30.

Rademakers

, Baker

, Gass

, Adamson

, Huey

, Momeni

, Spina

, Coppola

, Karydas

, Stewart

, Johnson

, Hsiung

, Kelley

, Kuntz

, Steinbart

, Wood

, Yu

, Josephs

, Sorenson

, Womack

, Weintraub

, Pickering-Brown

, Schofield

, Brooks

, Van Deerlin

, Snowden

, Clark

, Kertesz

, Boylan

, Ghetti

, Neary

, Schellenberg

, Beach

, Mesulam

, Mann

, Grafman

, Mackenzie

, Feldman

, Bird

, Petersen

, Knopman

, Boeve

, Geschwind

, Miller

, Wszolek

, Lippa

, Bigio

, Dickson

, Graff-Radford

, Hutton

(2007) Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C⟶ T (Arg493X) mutation: An international initiative. . Lancet Neurol 6, 857–868.

31.

van der Zee

, Rademakers

, Engelborghs

, Gijselinck

, Bogaerts

, Vandenberghe

, Santens

, Caekebeke

, De Pooter

, Peeters

, Lubke

, Van den Broeck

, Martin

, Cruts

, De Deyn

, Van Broeckhoven

, Dermaut

(2006) A Belgian ancestral haplotypes harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD. Brain 129, 841–852.

32.

Benussi

, Rademakers

, Rutherford

, Wojtas

, Glionna

, Paterlini

, Albertini

, Bettecken

, Binetti

, Ghidoni

(2013) Estimating the age of the most common Italian GRN mutation: Walking back to Canossa times. J Alzheimers Dis 33, 69–76.

33.

Benussi

, Ghidoni

, Binetti

(2010) Progranulin mutations are a common cause of FTLD in Northern Italy. Alzheimer Dis Assoc Disord 24, 308–309.

34.

Galimberti

, Arosio

, Fenoglio

, Serpente

, Cioffi

, Bonsi

, Rossi

, Abbate

, Mari

, Scarpini

(2014) Incomplete penetrance of the C9ORF72 hexanucleotide repeat expansions: Frequency in a cohort of geriatric non-demented subjects. J Alzheimers Dis 39, 19–22.

35.

Gass

, Cannon

, Mackenzie

, Boeve

, Baker

, Adamson

, Crook

, Melquist

, Kuntz

, Petersen

, Josephs

, Pickering-Brown

, Graff-Radford

, Uitti

, Dickson

, Wszolek

, Gonzalez

, Beach

, Bigio

, Johnson

, Weintraub

, Mesulam

, White

3rd , Woodruff

, Caselli

, Hsiung

, Feldman

, Knopman

, Hutton

, Rademakers

(2006) Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 15, 2988–3001.

36.

Ghidoni

, Benussi

, Glionna

, Franzoni

, Binetti

(2008) Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration. Neurology 71, 1235–1239.

37.

Binetti

, Benussi

, Roberts

, Villa

, Pasqualetti

, Sheu

, Gigola

, Lussignoli

, Dal Forno

, Barbiero

, Corbellini

, Green

, Rossini

, Ghidoni

(2006) Areas of intervention for genetic counselling of dementia: Cross-cultural comparison between Italians and Americans. Patient Educ Couns 64, 285–293.

38.

Pievani

, Paternico

, Benussi

, Binetti

, Orlandini

, Cobelli

, Magnaldi

, Ghidoni

, Frisoni

(2014) Pattern of structural and functional brain abnormalities in asymptomatic granulin mutation carriers. Alzheimers Dement 10, S354–S363.e1.

39.

Rohrer

, Nicholas

, Cash

, van Swieten

, Dopper

, Jiskoot

, van Minkelen

, Rombouts

, Cardoso

, Clegg

, Espak

, Mead

, Thomas

, De Vita

, Masellis

, Black

, Freedman

, Keren

, MacIntosh

, Rogaeva

, Tang-Wai

, Tartaglia

, Laforce

Jr , Tagliavini

, Tiraboschi

, Redaelli

, Prioni

, Grisoli

, Borroni

, Padovani

, Galimberti

, Scarpini

, Arighi

, Fumagalli

, Rowe

, Coyle-Gilchrist

, Graff

, Fallstrom

, Jelic

, Stahlbom

, Andersson

, Thonberg

, Lilius

, Frisoni

, Pievani

, Bocchetta

, Benussi

, Ghidoni

, Finger

, Sorbi

, Nacmias

, Lombardi

, Polito

, Warren

, Ourselin

, Fox

, Rossor

, Binetti

(2015) Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: A cross-sectional analysis. Lancet Neurol 14, 253–262.