Objective: To report a Chilean Parkinson’s disease (PD) patient carrying a previously unreported exonic deletion in the CHCHD2 gene identified through the PD GENEration program.

Background: PD is a multifactorial neurodegenerative disorder involving pathways such as mitochondrial dysfunction, oxidative stress, vesicle trafficking and ubiquitination. Variants in CHCHD2 have been associated with autosomal-dominant PD, mainly reported in Asian populations. Although their pathogenic mechanisms remain unclear, evidence suggests both loss- and gain-of-function effects disrupting mitochondrial homeostasis. Pathogenic variants include p.Thr61Ile, p.Arg145Gln, and other rare mutations. To date, CHCHD2-related PD has not been reported in Latin American populations.

Method: A comprehensive neurological evaluation and detailed family history were obtained. Brain CT and laboratory investigations were performed. Genetic testing was conducted through the Parkinson’s Foundation PD GENEration program, a NGS targeted PD gene panel. Informed consent was obtained from the participant.

Results: A 52-year-old male with no family history of PD developed bradykinesia and rigidity affecting the left hemibody at age 46 and was diagnosed with PD at age 50. He reported no relevant environmental exposures and showed a good motor response to levodopa and pramipexole. Brain CT and laboratory studies were unremarkable.

Genetic testing identified a heterozygous deletion of exons 1–2 in CHCHD2 (chr7:g.(56170724_56171899)_(56174189_56182354)del). This variant was classified as likely pathogenic, as it removes the first two exons including the start codon, with no downstream in-frame methionine available for reinitiation, predicting loss of protein function. The variant has not been previously reported in the Human Gene Mutation Database or observed in population databases.

Conclusion: This case expands the spectrum of CHCHD2-associated PD to individuals of Latin American ancestry and describes a previously unreported likely pathogenic variant. Given ongoing debate regarding the pathogenic mechanisms of CHCHD2 mutations, further work will include functional studies, cascade genetic testing in relatives, and ancestry analysis. Identification of the molecular mechanisms underlying CHCHD2-related PD may contribute to future targeted therapeutic strategies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/chchd2-exonic-deletion-in-a-chilean-parkinsons-disease-patient-first-latin-american-report/