Mariam Isayan

Background: Parkinson’s disease (PD), the most common neurodegenerative movement disorder, is commonly thought of as an aging and sporadic disease; however, 5-14% of individuals experience disease onset before the age of 50 years (early-onset PD; EOPD) and about 20% have a positive family history. In the case of both EOPD and people with a family history of PD, evidence suggests higher rates of a disease-causing genetic contribution. Objectives: Our goal was to perform a variant screening of seven PD-related genes and 21 genes associated with related parkinsonian disorders to identify pathogenic/likely pathogenic variants and variants of uncertain significance within EOPD and family-history-positive individuals within the Latin American Research Consortium on the Genetics of PD (LARGE-PD). Methods: We performed short-read whole-genome sequencing on a subset of 263 individuals with EOPD and/or a familial history of PD who had no known pathogenic PD variant in genotyping data. Results: Of the analyzed individuals, a monogenic burden in primary and secondary PD genes due to pathogenic or likely pathogenic variants for PD was observed in 4.7%, an additional 5.5% had pathogenic or likely pathogenic variants for Gaucher’s disease, and 2.7% had known risk variants in GBA1 . Conclusions: By expanding the reported spectrum of disease-associated variants in a Latin American population, we identified previously unreported or underrepresented variants that would likely be missed by array-based or targeted screening approaches and contribute to the characterization of EOPD and familial PD in Latin America.

Several Parkinson’s Disease (PD) linked mutations are known to drive deficits in a pathway that relies on an adequate supply of guanosine nucleotide triphosphate (GTP) to drive cellular neuronal processes. Similarly, there is strong evidence that a deficit in bioenergetic support for neuron function is also a major genetic driver of PD. We show here that the reliance on these two purine-based metabolites intersect at another PD susceptibility gene that encodes nucleoside diphosphate kinase (NDK) which converts ATP into GTP. We show that overexpression of NDK is strongly protective both in-vivo and in-vitro to metabolic lesions and identify mutations in NDK in humans associated both with increased risk and protection from PD. We discovered that NDK lies at the intersection of proper ATP production, de novo synthesis of guanosine diphosphate and the activity of GTP cyclohydrolase I, a consumptive pathway needed to produce the bioactive metabolite tetrahydrobiopterin (BH ₄ ) required for mitochondrial function. Loss of NDK and impairment in guanosine nucleotide synthesis exacerbate synaptic dysfunction, while boosting the GTP consuming pathway promotes bioenergetics. Additionally, analysis of genetic data taken from over 64,000 PD affected individuals and 38,000 controls from diverse ancestries reveal that several genes lying at the intersection of guanosine nucleotide metabolism and bioenergetics pose a significant risk burden for PD.

Background: DNAJC13 was initially linked to autosomal dominant (AD) Parkinson’s disease (PD) in a European Mennonite family carrying the p.N855S variant. However, imperfect segregation and conflicting reports of pathogenicity raised uncertainty of DNAJC13 ’s role in the disease. Objectives: Explore the association between common and rare variants in DNAJC13 and Parkinson’s disease. Methods: We leveraged the largest available PD genetics data from the Accelerating Medicines Partnership - Parkinson Disease (AMP-PD) and the diverse ancestry available through the Global Parkinson’s Genetics Program (GP2), consisting of 2,471 patients and 3,098 controls, and 44,186 patients and 27,066 controls, respectively, to perform burden tests and association tests for rare and common variants, respectively. Results: Burden analysis showed no association between rare variants in DNAJC13 and PD. However, association analysis within common non-synonymous variants nominated 5 variants within DNAJC13 . Nevertheless, these associations require further validation since the analyses are still underpowered. Discussion: Our analysis did not find further evidence supporting DNAJC13 involvement in PD. However, studies of even larger cohorts and AD-PD families may bring definite answers about DNAJC13’s role in PD.

Common and rare variants in LRRK2 influence Parkinson’s disease (PD) risk across diverse populations. We investigated the p.A419V variant across multiple ancestry cohorts comprising over 200,000 individuals. In cases of East Asian ancestry, the variant was significantly associated with increased risk (OR = 2.9; 95% CI: 1.66–5.10; p = 0.0002), It lies on rare EAS haplotypes, and was not in linkage disequilibrium with other LRRK2 coding variants. Although not significant, meta-analysis of age of onset in EAS cases show a suggestive trend (β = –0.89 years; SE = 1.01; p = 0.380). LRRK2 protein modelling prediction indicated that binding sites for RAB8A, RAB10, RAB29 were in close proximity to the p.A419V variant within the ARM domain. Together, these findings confirm the p.A419V as a significant PD risk factor in EAS populations, as well as highlight disease-relevant variants in the ARM domain and the link with LRRK2-RAB signaling pathway.

Background: Hereditary ataxias are genetically diverse, yet up to 75% remain undiagnosed due to technological and financial barriers. A pathogenic ZFHX3 GGC repeat expansion was recently linked to spinocerebellar ataxia type 4 (SCA4), characterized by progressive ataxia and sensory neuropathy, with all reported cases in individuals of Northern European ancestry. Methods: We performed Oxford Nanopore Technologies (ONT) genome long-read sequencing (>115 GB per sample) on a total of 15 individuals from Chile; 14 patients with suspected hereditary movement disorders and one unrelated family member. Variants were identified using PEPPER-Margin-DeepVariant 0.8 (SNVs), Sniffles 2.4 (SVs), and Vamos 2.1.3 (STRs). Ancestry was inferred using GenoTools with reference data from the 1000 Genomes Project, Human Genome Diversity Project, and an Ashkenazi Jewish panel. Haplotype analysis was conducted by phasing SNVs within ZFHX3 , and methylation profiling was performed with modbamtools. Results: We identified ZFHX3 GGC repeat expansions (47–55 repeats) in four individuals with progressive ataxia, polyneuropathy, and vermis atrophy. One case presented parkinsonism–ataxia, expanding the phenotype. Longer expansions correlated with earlier onset and greater severity. Hypermethylation was detected on the expanded allele, and haplotype analysis linked ultra-rare ZFHX3 variants to distant Swedish ancestry. Conclusion: This is the first report of SCA4 outside Northern Europe, confirming a shared founder haplotype and expansion instability. The presence of parkinsonism broadens the clinical spectrum. Comprehensive genetic testing across diverse populations is crucial, and long-read sequencing enhances diagnostic yield by detecting repeat expansions and SNVs in a single assay.

Elucidating the genetic contributions to Parkinson’s disease (PD) etiology across diverse ancestries is a critical priority for the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease-causing, protein-altering and splicing mutations in 710 cases and 11,827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity (ROHs) in prioritized early onset and familial cases. Our study identified rare GBA1 coding variants to be the most frequent mutations among PD patients, with a frequency of 4% in our case cohort. Out of the 18 GBA1 variants identified, ten were previously classified as pathogenic or likely pathogenic, four were novel, and four were reported as of uncertain clinical significance. The most common known disease-associated GBA1 variants in the Ashkenazi Jewish and European populations, p.Asn409Ser, p.Leu483Pro, p.Thr408Met, and p.Glu365Lys, were not identified among the screened PD cases of African and African admixed ancestry. Similarly, the European and Asian LRRK2 disease-causing mutational spectrum, including LRRK2 p.Gly2019Ser and p.Gly2385Arg genetic risk factors, did not appear to play a major role in PD etiology among West African-ancestry populations. However, we found three heterozygous novel missense LRRK2 variants of uncertain significance overrepresented in cases, two of which — p.Glu268Ala and p.Arg1538Cys — had a higher prevalence in the African ancestry population reference datasets. Structural variant analyses revealed the presence of PRKN CNVs with a frequency of 0.7% in African and African admixed cases, with 66% of CNVs detected being compound heterozygous or homozygous in early-onset cases, providing further insights into the genetic underpinnings in early-onset juvenile PD in these populations. Novel genetic variation overrepresented in cases versus controls among screened genes warrants further replication and functional prioritization to unravel their pathogenic potential. Here, we created the most comprehensive genetic catalog of both known and novel coding and splicing variants potentially linked to PD etiology in an underserved population. Our study has the potential to guide the development of targeted therapies in the emerging era of precision medicine. By expanding genetics research to involve underrepresented populations, we hope that future PD treatments are not only effective but also inclusive, addressing the needs of diverse ancestral groups.