Objective: This study aims to classify GBA variants detected in the Genetic Movement Disorders Laboratory (GMDL) of the Neurological Institute “Carlo Besta” in Milan over the last 16 years. This classification is mandatory for the development of therapies and for the recruitment of patients for any clinical trials.

Background: GBA variants are the most frequent genetic risk factors for Parkinson’s Disease (PD), because 5% to 20% of patients worldwide carry variants in this gene [1;2]. In the first comprehensive analysis of whole GBA gene in Italian population Petrucci and colleagues [3] reported a GBA variants frequency of 14.3%. Since 2006, in the GMDL we analysed GBA gene in a cohort of 1027 PD patients (658 Male/369 Female) with various methodologies and we classified, according to GBA1-PD browser criteria [4], all variants we have found.

Method: From 2006 to 2013 we analysed the first group of 320 PD patients through Restriction Fragment Length Polymorphism (RFLP) for the detection of the most common L444P and N370S GBA variants.  Since 2013 the second group of 707 PD patients was analysed through a specific PCR that excludes the presence of a highly homologous pseudogene (GBAP1) and amplifies the portion between exon 8 and exon 11, where about 82% of GBA deleterious variants are located [5] (L444P, N370S, E326K and T369M) and then with NGS.

Results: In the first group we detected 35 positive samples out of 320 (10.9%: 19M/16F) (15 N370S and 20 L444P). In the second group we detected 93 positive samples out of 707 (13.15%: 53M/40F), of which 5.5% derives from 18 L444P, 21 N370S, 3.3% from 10 E326K and 12 T369M and 4.5% from the other ones. We can classify all detected variants in these categories: 49 severe variants (32M/17F), 36 mild variants (18M/18F), 22 risk variants (10M/12F), 12 complex alleles (7M/5F), 5 unknown variants (2M/3F). In addition, we found 5 novel variants never described before (p.Tyr352*, p.Glu427*, p.Gln265Serfs*4 and p.Asn409Ser + p.Arg159Trp).

Conclusion: We report a large monocentric study on GBA variants PD-related confirming the prevalence of L444P and N370S variants in Italian population. We can strongly affirm that the lack of the analysis of the portion 8-11 underestimates by 6% the detection of GBA variants. Our results show a significant sex unbalance towards male subjects except for p.T369M, that we found three times more in females (4 males out of 12)[5].

References: 1. Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Dürr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med. 2009 Oct 22;361(17):1651-61. doi: 10.1056/NEJMoa0901281. PMID: 19846850; PMCID: PMC2856322.
2. Gan-Or Z, Amshalom I, Kilarski LL, Bar-Shira A, Gana-Weisz M, Mirelman A, Marder K, Bressman S, Giladi N, Orr-Urtreger A. Differential effects of severe vs mild GBA mutations on Parkinson disease. Neurology. 2015 Mar 3;84(9):880-7. doi: 10.1212/WNL.0000000000001315. Epub 2015 Feb 4. PMID: 25653295; PMCID: PMC4351661.
3. Petrucci S, Ginevrino M, Trezzi I, Monfrini E, Ricciardi L, Albanese A, Avenali M, Barone P, Bentivoglio AR, Bonifati V, Bove F, Bonanni L, Brusa L, Cereda C, Cossu G, Criscuolo C, Dati G, De Rosa A, Eleopra R, Fabbrini G, Fadda L, Garbellini M, Minafra B, Onofrj M, Pacchetti C, Palmieri I, Pellecchia MT, Petracca M, Picillo M, Pisani A, Vallelunga A, Zangaglia R, Di Fonzo A, Morgante F, Valente EM; ITA-GENE-PD Study Group. GBA-Related Parkinson’s Disease: Dissection of Genotype-Phenotype Correlates in a Large Italian Cohort. Mov Disord. 2020 Nov;35(11):2106-2111. doi: 10.1002/mds.28195. Epub 2020 Jul 13. PMID: 32658388.
4. Parlar SC, Grenn FP, Kim JJ, Baluwendraat C, Gan-Or Z. Classification of GBA1 Variants in Parkinson’s Disease: The GBA1-PD Browser. Mov Disord. 2023 Jan 4. doi: 10.1002/mds.29314. Epub ahead of print. PMID: 36598340.
5. Straniero L, Asselta R, Bonvegna S, Rimoldi V, Melistaccio G, Soldà G, Aureli M, Della Porta M, Lucca U, Di Fonzo A, Zecchinelli A, Pezzoli G, Cilia R, Duga S. The SPID-GBA study: Sex distribution, Penetrance, Incidence, and Dementia in GBA-PD. Neurol Genet. 2020 Oct 20;6(6):e523. doi: 10.1212/NXG.0000000000000523. PMID: 33209983; PMCID: PMC7670574.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/detection-and-classification-of-gba-variants-pd-related-is-there-sex-unbalance/