rs76763715

This paper presents a CRISPR-Cas9 gene editing strategy in patient-derived induced pluripotent stem cells (iPSCs) for correcting or inserting point mutations (particularly the N370S mutation in GBA, rs76763715), with quality control measures to prevent off-target editing of the GBA pseudogene (GBAP1). The approach is validated as a tool to investigate genetic mechanisms in GBA-related Parkinson's disease and Gaucher's disease.

Whole genome sequencing of 44 Ashkenazi Jewish centenarians identified 216 coding variants annotated as pathogenic or likely pathogenic in ClinVar. The study found 130 rare variants (MAF <5%) reported to cause degenerative, neoplastic, and cardiac diseases with various inheritance patterns. Notably, several carriers had no clinical manifestations despite carrying variants linked to serious diseases (e.g., an APOE ε4 homozygote without Alzheimer's disease, a UBQLN2 P525S carrier without ALS). These findings suggest incomplete penetrance and reduced clinical significance for many reported disease mutations.

A genome-wide survival meta-analysis of 3,923 Parkinson's disease patients identified three genome-wide significant loci associated with progression to Parkinson's disease dementia: APOE rs429358 (HR=2.41, P=2.32×10−15), LRP1B rs80306347 (HR=3.23, P=7.07×10−9), and BBS9 rs78294974 (HR=3.90, P=3.59×10−8). The study reveals APOE ε4 and LRP1B as major risk factors and suggests the amyloid pathway's involvement in dementia development.

PhD thesis describing a gene hunting study of Parkinson's disease in Queensland families with inherited parkinsonism. Identified multiple pathogenic mutations including KCNJ15 p.R28C segregating in a 9-member kindred, SIPA1L1 p.R236Q in one multi-incident family, and de novo FAM134B p.D381V mutation. Also screened known PD genes (VPS35 p.D620N, LRRK2 p.G2019S, SNCA duplications, PARK2) and examined segregation of putative PD genes in multi-incident families.

This PhD thesis from the Queensland Parkinson's Project screened 3,660 participants (1,861 PD patients and 1,799 controls) for genetic causes of Parkinson's disease. The study identified known pathogenic mutations in PD genes (VPS35 p.D620N, LRRK2 p.G2019S, SNCA duplications, PARK2) and conducted gene hunting in multi-incident families using whole exome sequencing. Novel candidate mutations were identified including KCNJ15 p.R28C (segregating in a 9-member affected family, also found in 2 additional patients), SIPA1L1 p.R236Q (identified in 1 multi-incident family and 1 familial case), and FAM134B p.D381V (found in an early-onset de novo case), though additional evidence is required to establish causality.