Genetic counselling and testing for inherited dementia: single-centre evaluation of the consensus Italian DIAfN protocol

Alzheimer’s disease (AD) is the most common form of dementia and accounts for 60–70% of all dementia cases [1]. Frontotemporal dementia (FTD) represents an estimated 10–20% of all dementia cases and one of the most common presenile dementias [2]. In fewer than 5% of AD cases [3] and about 10% of FTD cases [4], these diseases are inherited as an autosomal dominant trait, by mutations in presenilin-1 (PSEN1), presenilin-2 (PSEN2) and the amyloid precursor protein (APP) genes, for AD [3], and microtubule-associated protein tau (MAPT), granulin (GRN) and chromosome 9 open reading frame 72 (C9orf72) genes, for FTD [5].

Although inherited AD and FTD represent a minority of all dementia cases, they constitute a critically important area of study, because the pathological features of genetic forms are similar to the more common sporadic ones, and research in the field contributes to advances in the basic scientific understanding of these diseases. Moreover, families with inherited dementia represent an ideal population for clinical trials with putative disease-modifying drugs, which have the potential to delay or even prevent dementia in asymptomatic individuals, in addition to slowing progression in those with symptoms.

The identification of deterministic genes associated to inherited AD and FTD enables members of families with a positive history for dementia to consider to undergo the relevant genetic test. When the family history is suggestive for inherited dementia, it is important to allow the patient and the family to understand the genetic risk and the possible options [6]. Being a carrier of a genetic variant causing familial dementia implies a risk for the relatives, especially for the offspring, with a remarkable burden also in spouses. When a disease-associated mutation is identified in a family, the consequences are not limited to the psychological outcomes caused by the unfavourable genetic test result. Finding an inherited form of dementia in a family impacts on all family members, including those who would have chosen not to know about the genetically determined risk [7]. Moreover, the disclosure of a genetically determined disease in a family is expected to raise ethical, legal and social issues [6]. In fact, the assessment of any genetic test, in order to be transferred in the clinical practice, should include safety and utility as well as the users’ perspective [8, 9].

A limited number of studies addressed genetic counselling and testing for inherited dementia (namely AD and FTD), as compared to the large body of literature focussed on Huntington’s disease (HD) and, more recently, amyotrophic lateral sclerosis (ALS). As recommended by the current guidelines for AD and the other inherited dementias [10], genetic counselling should always precede genetic testing to avoid negative outcomes, in both affected individuals and healthy at-risk relatives. However, a handful of papers addressed genetic counselling and testing for dementia to date. In the 5 years’ experience of a genetic counselling program in Spain, genetic testing was performed in 87 affected individuals from 72 families with suspected familial AD, FTD or prion disease, and in 23 at-risk relatives from the 22 families with an identified pathogenic mutation [11]. The program implemented a structured genetic counselling protocol only for at-risk relatives [11]. The other published papers report the experience with genetic counselling and testing in at-risk relatives for AD and FTD [12‐14].

In Italy, a network of research centres with expertise in hereditary dementia developed a consensus research protocol for genetic counselling and testing of affected individuals and healthy at-risk relatives with familial AD and FTD within the Italian Dominantly Inherited Alzheimer’s and Frontotemporal Network (IT-DIAfN) project [15]. The IT-DIAfN protocol has been implemented within a research environment in centres participating into the IT-DIAfN project.

The aim of this study was to evaluate feasibility and acceptability of the genetic counselling and testing process for familial dementia, as undertaken according to the IT-DIAfN protocol. We appraised the 4 years’ experience in one IT-DIAfN research centre to determine whether the procedures set out in each phase of the protocol can be implemented in a research setting and offered to both affected individuals and at-risk relatives; this appraisal may provide a ground of evidence for future improvements.

Seventy-six families requested genetic counselling. The main reason was the concerns of either a spouse or a first-degree relative of an affected individual about a possible genetic aetiology of the disease suggested by an early onset of dementia or by the presence of more than a family member affected by dementia. About 50% of the families were excluded because the diagnosis was dementia other than AD or FTD (i.e. vascular dementia or dementia of uncertain aetiology) and/or the proband was deceased. Twenty affected individuals from 17 of these families satisfied the family history criteria of the IT-DIAfN protocol for suspected inherited dementia (17 for AD, 2 for FTD, 1 for inclusion body myopathy with Paget disease of bone and frontotemporal dementia, IBMPFD) and were included. The affected individual with suspected IBMPFD was not symptomatic for FTD or dementia, but for Paget disease of the bone and was included considering the family history highly suggestive for IBMPFD. Three additional families with a previously ascertained inherited dementia were also included.

This study describes the experience of a research centre with specific expertise in dementia with the IT-DIAfN protocol, a structured genetic counselling and testing protocol for familial AD and FTD. The IT-DIAfN protocol was implemented in both affected individuals and healthy at-risk family members, according to the current guidelines of the American College of Medical Genetics and the National Society of Genetic Counsellors [10], which state that genetic testing for AD should only occur in the context of genetic counselling, for both affected individuals and at-risk relatives.

The current guidelines, in turn, were mainly based on the large body of evidence produced during the decades of experience with HD, making the HD genetic counselling and testing protocol the gold standard for late-onset neurodegenerative diseases. However, clinical and genetic differences between HD and dementia (prominent movement disorder usually not associated with early dementia and single-gene mutation in HD), the expansion of genetic tests for dementia and the availability of clinical trials for prevention and treatment, raised new issues requiring specific guidelines and protocols for dementia [30].

Experiences of genetic counselling and testing protocol implementation in affected individuals were not reported in the literature. In the genetic counselling program for dementia in Spain [11], a genetic study was offered to 87 patients with suspected familial AD and FTD or genetically determined prion diseases, directly after obtaining a written consent. A specific counselling protocol was applied only to at-risk relatives [11]. The reasons for genetic testing in affected individuals were not reported.

In our experience, the genetic testing for affected individuals was mainly requested by either a spouse or a first-degree relative who was concerned about the occurrence of a possible familial form of dementia. Only two patients with early-onset dementia (< 50 years) were included in the IT-DIAfN protocol upon clinical indication. In common practice, in fact, genetic testing in dementia is requested for affected individuals with a family history strongly indicative of early-onset autosomal dominant dementia, in whom the identification of a mutation may result in definitive diagnosis. This request was done within a clinical diagnostic work-up, and the patient unlikely had access to a research program including genetic counselling. Nonetheless, the increased awareness in genetics of dementias increased requests for information. The public dissemination of the IT-DIAfN research project of genetic counselling and testing allowed the individuals concerned about own genetic risk to ask for the genetic test. Of note, in a previous study on FTD, we revealed that a high proportion of patients belonging to high-risk pedigrees asked for genetic counselling; requests decreased according to the estimated family risk [31].

In the present series, one affected individual left the IT-DIAfN protocol after the pre-test consultation, because of the turned awareness of not being ready to cope with a potential unfavourable result. This occurrence underlines that, in the context of genetic counselling, the uptake of genetic testing should not be considered the final aim. When genetic testing of an affected individual was requested by a relative, genetic counselling was critical to explore attitudes towards pursuing genetic testing [10], the potential impact on the family and possible lack of interest of the patient to know the result of the genetic test. In this context, the multidisciplinary counselling team ensured a comprehensive care of the entire family including affected individuals, caregivers and at-risk relatives. According to the most acknowledged definition of genetic counselling [32], all family members involved were offered an open communication process, structured to allow the comprehension of medical and genetic facts, their implications and the meaning of each available option, with the aim of the best adjustment with the illness or the risk status.

The high rate of lost-to-follow-up suggested that a revision of the IT-DIAfN protocol for affected individuals would be considered. The lack of psychological assessments—most are self-administered scales—is not astonishing. Psychological assessment included in the IT-DIAfN protocol was developed in order to have a comprehensive evaluation of emotional and psychological conditions of the participant, and monitor the impact of the test result on the personal, family and social balance of the person. At the time of the protocol development, we had not included an evaluation of psychological state of mind of caregiver. However, patient and caregiver represent a dyad with a synergistic relationship and mutual psychological influence [33]. The active participation of the caregiver in assessing and reviewing the psychological impact of the genetic test procedure could facilitate the involvement of the family and allow to reveal mutual psychological influences within the patient-caregiver dyad. Should the follow-up visits be perceived too demanding, remote meetings could be offered to families in which geographical distance from the research centre limits in-person follow-up visits, as suggested by preliminary evidence [34].

We identified 5 genetic mutations in 6 families. These mutations had been reported as “pathogenic” in the dedicated mutation database for AD and FTD [35]. We already reported the genetic mutations identified in families 1 thru 4 elsewhere [29]. In families 1 and 4, the Met239Ile mutation was identified in the PSEN2 gene. It was first reported in an Italian family [36] and then in two additional Italian families [37, 38]. No common ancestor has been established, and a specific search was beyond the scope of this study. In the family 2, the R93C mutation was identified in the VCP gene. It was first reported in a family of unknown ancestry [39], then in a German family [40], in a family of unknown ancestry [41], and in a Brazilian family [42]. In the family 3, the Thr272fs mutation was identified in GRN gene. It was first reported in an Italian family [43] and in other 34 Italian and one French families [44‐49]. In the family 5, the IVS10+3G>A genetic mutation was identified in the MAPT gene. It was described in three families of European ancestry [50‐52], one American family [53] and one Japanese family [54]. In the family 6, the Arg377Trp mutation was identified in PSEN1 gene. It was first reported in a French family [55] and then in an Italian one [56]. In these two families, as well as in the one described in the present study, family history was unremarkable. Overall, no distinctive clinical phenotypes were evident in our index cases relative to the literature. Only slight differences in age at onset were noted in the index cases of families 4 and 5 relative to the previously reported age ranges (64 vs 44 to 58 years, and 33 vs 38 to 59 years, respectively).

In healthy at-risk relatives, the uptake rate of predictive testing (i.e. the number of predictive tests performed as a proportion of the 50% at-risk members of families with an identified pathogenic mutation) was 8% (3 out of 38). Our result was consistent with the uptake of 8% reported by the experience of the University of Washington in persons at-risk for AD and FTD [13] and slightly higher to that (3%) reported in the experience of genetic counselling for FTD in the Netherlands [14]. A direct comparison with the literature data in HD was limited by methodological differences in the approaches used to calculate the uptake rate [57]. The figures varied between 5 and 45%, even if an uptake ratio lower than 20% were more consistently reported [57, 58]. The pre-familial amyotrophic lateral sclerosis (FALS) study, a prospective, observational study of individuals at risk of FALS, reported a very high uptake rate (70%). However, the design of the study can explain this discrepancy [59]. Furthermore, our figure of 8% may be underestimated because about 40% of the 50% at-risk members were unable to access predictive testing being less than 18 years old or were not aware of the presence of a pathogenic mutation in the family. To preserve confidentiality, after withdrawal we refrained from exploring whether and how the genetic information was shared within the family.

As regards the sociodemographics of at-risk relatives included in the protocol, the gender ratio (73% women) was consistent with a previous study of predictive genetic counselling for AD, in which 60% of at-risk participants were women [13] and with the literature of predictive testing for HD, reporting a female predominance among those tested [57, 58]. Also the mean age close to 40 years in our series was in line with the literature of predictive testing for AD [13], inherited dementias [60] and HD [58, 61]. The prevalence of highly educated subjects (82% with high school o graduation) in our series was higher than previously reported in both dementia and HD [13, 58, 60, 62]. Notably, in our study, the 3 at-risk relatives with university degree were the only ones who completed the protocol, suggesting that high education may be one of the variables associated to greater ability to deal with the process of genetic counselling. This finding would encourage our community to take into account the unequal access to the advanced health technologies, such as molecular genetic analyses, and proactively act to reduce it. Gender can also be a variable related to higher attitude of women to cope with an unfavourable result [63] or to seek medical attention [64]. For 4 out of 11 at-risk relatives (36%), the expected time to disease onset was less than 15 years. Interestingly, 3 out of them were those who completed the entire protocol, suggesting that proximity to the expected time to disease onset may be a factor related to the willingness to know own genetic status.

The most common reasons for requesting genetic testing, expressed by more than 60% of at-risk relatives, were the opportunity to participate in future clinical trials of experimental drugs, to support research and to plan the future. Considering the literature on reasons for predictive testing in HD, the most common reported (> 70%) were different, i.e. to reduce uncertainty about the risk of illness, reproductive decision-making and future planning [57, 58]. The hope for future treatment, when cited, was the reason in less than 10% of cases [57]. In an observational study of 24 subjects at risk for FTD or AD, the main reasons (> 75%) for requesting genetic testing were financial and family planning, and relief from worry and anxiety [13]. Possible eligibility for future treatment trial was the less common cited reason [13]. The recent availability of clinical trials of experimental drugs for inherited AD [65] can explain this change of demand for genetic testing. High prevalence of motivation related to support research can be also explained by awareness that our Institution was a research centre and that the IT-DIAfN protocol was developed in the context of a research project. This view was supported by a study on a research protocol developed to evaluate the impact of genetic susceptibility testing among asymptomatic relatives of people with AD [66]. The most common reasons (> 85%) for seeking testing were comparable with our findings, i.e. to contribute to AD research, to hope that effective treatments will be developed and to arrange personal affairs [66].

The rate of withdrawals from the protocol of our at-risk relatives was 72%. The figure was higher than that reported in studies of predictive testing for HD, showing a withdrawal rate between 12 and 51% [58]. In the experience with genetic counselling for dementia in Spain, 30 out of 54 (56%) at-risk subjects who entered genetic counselling protocol decided to not receive the genetic test result [11]. In the experience with genetic counselling for FTD in the Netherlands, the rate of withdrawal was very similar (7/13, 54%) [14], while in the Washington University series 1 out of 15 at-risk subjects (7%) did not proceed with the genetic testing [13]. Some peculiar characteristics of participants, such as emotional vulnerability due to young age—in the present series two participants were 19 and 24 years old, can partially explain the different rate of withdrawals. However, the limited number of enrolled individuals and the heterogeneous setting across studies do not allow to infer definite explanations from observed frequencies.

The most common reason for leaving the protocol in the present study was the same reported in the literature for HD, that is worry of being unable to cope with an unfavourable result [58, 67]. The analyses of data from multiple cohorts of families with HD and other neurodegenerative diseases demonstrated that self-selection occurs. In most cases, the reason to choose not to proceed with the test is driven by the concern about the possible unfavourable result—worry, anxiety, presumed inability to cope with an unfavourable result are all possible reasons to choose to not to know. Conversely, individuals who solicit testing have stronger coping abilities and are more able to handle stressful situations [68]. In the context of an extended counselling protocol, a high rate of self-withdrawal could be considered as a favourable outcome. The time lapse between the pre-test consultations and the final decision to undergo the test had a major role in providing a proper decision-making process and, for the counselling team, to evaluate the counselee’s emotional stability.

In a minority of cases, the participants left the protocol because of the absence of a conscious motivation to undergo the genetic test, or without providing a reason. We observed that emotional stability and specific motivation had great relevance in determining the decision of knowing own genetic status. A study in HD [69] found that the motivation to testing had a strong predictive value in foreseeing personal reactions to the disclosure of the genetic status, independently from ego-strength and test result. In general, the literature in HD showed that those who opt for genetic testing were the best equipped emotionally to deal with the test results [70].

The current unavailability of clinical trials of experimental drugs was the reason of withdrawals in one of our at-risk relatives after genetic testing. As underlined above, the research setting in which genetic counselling had been provided possibly induced the expectation of access to experimental drugs. To this regard, genetic counselling was critical to deeply investigate if the counselee understood all the possible implications associated to the disclosure of his/her genetic status. The access to clinical trials was discussed with the counselees and the families during counselling sessions as a possible option, which could be offered to selected individuals in the future.

At present, no catastrophic reactions, defined as major depressive disorder, psychiatric hospitalization or suicide attempt occurred. For the three at-risk siblings who completed the protocol, the familial relationship strengthened the mutual support in the decision-making process and helped the individuals to perceive their ability to deal with an unfavourable outcome. This finding is consistent with previous studies [11‐14, 60]. Long-term follow-up studies are warranted to investigate the personal impact of the test result, as well as the social consequences of an unfavourable outcome such as discrimination or stigma, and the impact of sharing the genetic information within the family.

All families informally expressed satisfaction of having pursued the genetic counselling and testing, in line with previous literature in HD [58]. However, a formal assessment of satisfaction had not been implemented. We believe that a structured examination of families’ satisfaction should be included as an additional tool to evaluate the outcomes of the counselling and testing procedure.

The workflow of molecular analyses originally developed has been adapted to our centre as far as concerns the decision tree for mutation analysis, according to the innovations that could be easily foreseen at that time [15]. The massive sequencing approach based on NGS platforms has become the first tier for molecular diagnosis of heterogeneous genetic disorders such as AD and FTD, integrated with PCR analyses of the C9orf72 hexanucleotide repeat expansion and the PRNP octapeptide repeat region. In a research setting, massive sequencing may be an added value. In a recent study, we demonstrated that the polygenic risk score may contribute to interpret the role for the genetic load in families without single-gene mutations associated to autosomal dominant forms of dementia [29].

Based on this evaluation, future changes may improve the IT-DIAfN protocol. A psychometric assessment of the state of mind of caregivers should be implemented [10], as well as a formal measurement of participants’ satisfaction. In view of translation in routine clinical practice, we acknowledge that the entire procedure is demanding, especially in terms of human resources. A few steps of the protocol that are currently held in-person may be replaced by remote consultations, provided that a dedicated platform is securely implemented. It is apparent that the availability in the future of innovative drugs, or preventive strategies able to change the course of dementia, will lead the neurogenetics community to develop novel genetic counselling and testing procedures for familial cases.

This study showed that the structured procedures of genetic counselling and testing, with planned pre- and post-test counselling sessions, can be implemented in both affected individuals and at-risk relatives in a research setting. The development of an optimized protocol is an essential prerequisite for a safe and effective integration of genetic counselling and testing for dementia in the health care system.