Professor Di Fonzo and his group were awarded with the Movement Disorder Journal Paper of the Year. The paper was titled, Harmonizing Genetic Testing for Parkinson's Disease, Results of the ParkNet Multicentric Study. Thank you, professor, for being here with us.
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[00:00:42] Prof. Alessio Di Fonzo: So, thank you for the invitation to the podcast.
[00:00:46] Dr. Sarah Camargos: Yes, it's a pleasure for us.
Could you please tell us a little bit about the paper of the year?
[00:00:52] Prof. Alessio Di Fonzo: Yes, of course. So, it's a paper from the Italian network of the [00:01:00] Institute of Research and Science. in this let's say, study, the six major institutes following patient with Parkinson's disease shared the results off genetic testing, and then we aim to analyze this results in order to try a way to standardize the methods. For the analysis in the in the diagnostic settings and also to to harmonize the make me interpretation off the variance and also how to report the results to patient in a harmonized way. And this is very hot topic, so this was the aim off the study. And in this study, we showed that harmonizing the approach for the diagnostic setting, [00:02:00] some of the interpretation, some of the, yeah, results of the first phase before their motivation were different than what we had after the harmonization. So I think that this is very important for patients, for clinicians, that they may have a network behind these results that that is working as a team and is giving the same type of results with the same methods to patients.
[00:02:28] Dr. Sarah Camargos: Of course, and then revise this diagnosis because as we are having different classification on the variants, it's important to revise this new classification.
Sometimes one variant was of uncertain significance and then it becomes likely benign or likely pathogenic. Right?
[00:02:52] Prof. Alessio Di Fonzo: Yes, this is a very important point. And we did already with some patients. When [00:03:00] we follow the patients, we update them on the let's say information that we have about variants. And with some other, maybe we, we to inform and to write in the report that the variants is variant of an unknown significance. but in time, we will update. the information and also the patient about the new possible classification of the variant.
[00:03:28] Dr. Sarah Camargos: Interesting. And this happened with some patients, right? So, it's important to revise this, especially this variant of a unknown significance periodically. and what about the age of your patients?
[00:03:44] Prof. Alessio Di Fonzo: patients? Yes. In this specific study, we decide to analyze the gene test of patients with the, let's say, more, earlier onset. We put a cutoff at [00:04:00] 55, which let's say is not the ones that is usually used for to classify as early onset, but still, with this approach, we had more results of the gene test to analyze for harmonization And yeah, the reason was also that most of the patients with the earlier onset undergo genetic testing for sure. More than the late onset patients. So this also was one of the reason why we selected patient with earlier onset PD.
PD.
[00:04:33] Dr. Sarah Camargos: And interesting because when you compared the very early onset, you said in your paper, less than 40, you have different index for, the frequency of the mutations, right?
[00:04:46] Prof. Alessio Di Fonzo: Yes, we observed that before, the patient that had onset before 40, where I reached in PRKN mutation, in part two. of course, this was [00:05:00] expected, but we confirmed. And while patient with early onset, but before, let's say, 55, the most common variant that we found was GBA1, which is a risk factor for Parkinson's disease. It's not a Mendelian, let's say, form. it's not fully penetrant, but still it's a risk factor with some phenotypic characteristic that may be more common. And also, we think Now, it's very important to know that patients are carrying such as variants because they may be enrolled in clinical, therapeutic trials, and so for young and juvenile and early onset patient, this is very important.
[00:05:45] Dr. Sarah Camargos: Yes,
and you highlighted also that in PARK2 most of the variants were CNVs. And did you do some pipeline for [00:06:00] analyzing it or what did you do?
[00:06:02] Prof. Alessio Di Fonzo: Yeah, so single institute was doing, and for duplication multiplication and deletions of PRKN. the approach was the MLPA, the multiple allegations that was using diagnostic, is set for diagnostic, is certified. And so was used in the diagnostic setting. So we combined the MLPA to analyze The duplication and deletion in PRKN and the NGS approach for the, for the point mutation. And we found that 50 or more than else were indeed
CNVs. Yeah, CNVs.
[00:06:41] Dr. Sarah Camargos: And does the NGS could reach out the same results of the CNVs?
[00:06:50] Prof. Alessio Di Fonzo: Actually, not in our case, of course, because applying the panel with the pipelines that we had heterozygous deletion or heterozygous duplication [00:07:00] were not detected. So it's very important to have another technique. to confirm especially for diagnostic to confirm now, of course, we are going to more advanced pipelines of analysis, also in genome sequencing that may be able also to identify the heterozygous duplication and deletions, but it's still a good, especially in diagnostic setting, it would be good to confirm with an independent. technique.
[00:07:30] Dr. Sarah Camargos: Yeah, so the clinicians have to be aware that some mutations only can be assessed with MLPA or other instrument to see deletions, larger deletions, or duplications, right?
[00:07:47] Prof. Alessio Di Fonzo: Right. That is very important. And if it's not on the report, they have to ask the the analysis.
[00:07:56] Dr. Sarah Camargos: Yes. And how many institutes did you [00:08:00] enroll in your study?
[00:08:01] Prof. Alessio Di Fonzo: So we start with institutes because they were the institute that collected already the diagnostic, already done. But now, this is expanding and the Italian network, the name is net Project and it's Italian Network that was funded by the ministry of health to
let's say to, collaboration between Institutes in Italy that now are sharing all the information of patients and also the data and this, of course, is increasing the robustness of what we are observing. And the future is, of course, in this direction, not only. In our experience in italy, but worldwide as is happening with all the consortia like
the GP2 and all the studies like the PD gene that are really showing that the network of institutes are providing very important data, especially in the field of genetics, it's important to [00:09:00] have collaborative works.
[00:09:01] Dr. Sarah Camargos: Of course, but you in your country could award, the Ministry of Health and everybody's working together with the goal to benefit patients
but do you think the most important lesson of your study, if you have to pick one very important thing from your paper. What would it be?
[00:09:25] Prof. Alessio Di Fonzo: I think that, last point is the most important creating network between institutes, supporting the network, sharing the results, the genetic data
Trying to harmonize the interpretation, the whatever is coming as new for especially in diagnostic setting to be able to give the same type of results, robust results, to patients in the harmonized way. I think this is the most important.
[00:09:58] Dr. Sarah Camargos: Definitely. And then [00:10:00] harmonized data as well, just environment or clinical data, and perhaps we find a lot of good interesting things,
[00:10:10] Prof. Alessio Di Fonzo: Yes. right. And also for this the same project is Parknet is collecting, in a harmonized way also the data of patient clinical data, family history, all the exposure, and also longitudinally. So Is not the future. It's the present. It's the present.
[00:10:28] Dr. Sarah Camargos: The longitudinal data is. extremely interesting and important.
[00:10:34] Prof. Alessio Di Fonzo: Yes, have to say that in this, project the, all the support, that the ministry of health, all the institutes, all the collaborators from the genetic part, especially Enza Maria Valente and and me that work on this. together in this project Pietro Cortelli that was coordinating the ParkNet project and all the other neurologists from the institutes in, in Italy did really an amazing job.[00:11:00]
[00:11:00] Dr. Sarah Camargos: Wow, it was a real pleasure to meet you and talk to you. I really appreciate your time being with us and thank you so much.
[00:11:09] Prof. Alessio Di Fonzo: Thank you.