Rare variants of LRRK2 for Parkinson’s disease in Chinese population

Abstract Background Mitochondrial dysfunction is involved in the pathogenicity of Parkinson’s disease (PD). However, the genetic roles of mitochondrial function-associated genes responsible for PD need to be replicated in different cohorts. Methods Whole-exome and Sanger sequencing were used to identify the genetic etiology of 400 autosomal dominant-inherited PD (ADPD) patients. Variants in six dominant inherited mitochondrial function-associated genes, including HTRA2, CHCHD2, CHCHD10, TRAP1, HSPA9 and RHOT1, were analyzed. Results A total of 12 rare variants identified in the five genes accounted for 3% of ADPD cases, including 0.5% in HTRA2, 0.8% in CHCHD2, 1% in TRAP1, 0.3% in RHOT1 and 0.5% in HSPA9. Among them, five novel variants, p.E4A, p.R13Cfs*107 and p.R449X in TRAP1, p.S95N in RHOT1 and p.N180I in HSPA9, were identified in ADPD patients. Evidence of a founder event that occurred exclusively in Asia was identified in two probands with p.P53Afs*37 in CHCHD2, which was further observed in one patient from 300 sporadic cases. Based on burden analysis, CHCHD2 tended to be slightly enriched in ADPD. Clinically, all patients carrying mutations in the genes presented typical motor symptoms and a good response to L-DOPA. Most of them had slower disease progression (8/12) and mild cognitive impairment (9/12), but the age of onset varied. No rare variant was detected in CHCHD10. Conclusion Our study expands the mutation spectra and enhances the understanding of the clinical phenotype of PD patients with mitochondrial function-related gene variants. Additionally, the CHCHD2 gene should be given more attention in PD originating in the Chinese population.

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Analysis of rare variants of autosomal‐dominant genes in a Chinese population with sporadic Parkinson’s disease

Molecular Genetics & Genomic Medicine ◽

10.1002/mgg3.1449 ◽

2020 ◽

Vol 8 (10) ◽

Cited By ~ 1

Author(s):

Ran Zheng ◽

Chong‐Yao Jin ◽

Ying Chen ◽

Yang Ruan ◽

Ting Gao ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Chinese Population ◽

Autosomal Dominant ◽

Rare Variants ◽

Sporadic Parkinson’S Disease ◽

Dominant Genes

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Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era

Genes ◽

10.3390/genes12030430 ◽

2021 ◽

Vol 12 (3) ◽

pp. 430

Author(s):

Steven R. Bentley ◽

Ilaria Guella ◽

Holly E. Sherman ◽

Hannah M. Neuendorf ◽

Alex M. Sykes ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Family History ◽

Rare Variants ◽

Strong Family History ◽

Disease Mutations ◽

Whole Exome ◽

History Of ◽

Functional Consequences ◽

Multiplex Families

Parkinson’s disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The LRRK2 p.G2019S mutation causes PD in 42.5–68% of carriers by the age of 80 years. We hypothesise similarly intermediately penetrant mutations may present in multi-incident families with a generally strong family history of disease. We have analysed six multiplex families for missense variants using whole exome sequencing to find 32 rare heterozygous mutations shared amongst affected members. Included in these mutations was the KCNJ15 p.R28C variant, identified in five affected members of the same family, two elderly unaffected members of the same family, and two unrelated PD cases. Additionally, the SIPA1L1 p.R236Q variant was identified in three related affected members and an unrelated familial case. While the evidence presented here is not sufficient to assign causality to these rare variants, it does provide novel candidates for hypothesis testing in other modestly sized families with a strong family history. Future analysis will include characterisation of functional consequences and assessment of carriers in other familial cases.

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Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease

npj Genomic Medicine ◽

10.1038/s41525-020-00163-8 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Muhammad Aslam ◽

Nirosiya Kandasamy ◽

Anwar Ullah ◽

Nagarajan Paramasivam ◽

Mehmet Ali Öztürk ◽

...

Keyword(s):

Risk Factors ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Genetic Variants ◽

Rare Variants ◽

Alpha Synuclein ◽

Younger Age ◽

Targeted Treatments ◽

Genes Encoding ◽

Rare Genetic Variants

AbstractRare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.

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Common and rare variants in HFE are not associated with Parkinson's disease in Europeans

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2021.05.019 ◽

2021 ◽

Author(s):

Prabhjyot Saini ◽

Sara Bandres-Ciga ◽

Jose Luis Alcantud ◽

Clara Ruz ◽

Ronald B. Postuma ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Rare Variants

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Identification of sixteen novel candidate genes for late onset Parkinson’s disease

Molecular Neurodegeneration ◽

10.1186/s13024-021-00455-2 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Alessandro Gialluisi ◽

Mafalda Giovanna Reccia ◽

Nicola Modugno ◽

Teresa Nutile ◽

Alessia Lombardi ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Candidate Genes ◽

Rare Variants ◽

Late Onset ◽

High Specificity ◽

Diagnostic Tools ◽

Multi Stage ◽

Whole Exome ◽

Family Based

Abstract Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment.

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