Next-generation phenotyping using the parkin example: time to catch up with genetics

Abstract

Importance: Two decades of intense research have led to important insights into the pathophysiology of neurodegenerative diseases, with limited direct clinical impact. While next-generation sequencing has emerged as a powerful research tool, we hypothesized that systematic exploitation of phenotypic data are lagging behind genetic advances.

Objectives: To use the 15-year experience with parkin-associated Parkinson disease (PD) to evaluate type, quality, and quantity of genetic and phenotypic data and to elucidate clinical or genetic features impacting genetic testing and counseling.

Evidence review: We searched MEDLINE: (1998-2012) using the term parkin AND mutation for English publications about proved parkin-associated PD and at least minimal, individual clinical information excluding digenic cases, and redundant articles. This approach identified 877 articles, of which 196 described patients with PD with confirmed parkin mutations and 127 articles fulfilled our inclusion criteria. Information was extracted using predefined criteria and a consensus approach for questionable details. To evaluate study method differences, we devised a quality score representing the completeness of clinical, demographic, and genetic information.

Findings: In the data about 1184 patients, the quality score increased steadily and was driven exclusively by improvements in genetic analyses. By contrast, demographic and clinical content stagnated. The mean age at onset was 9 years lower in index patients with 2 mutant parkin alleles than in heterozygotes. Genotype-phenotype correlation was observed for the number of mutated alleles and dystonia. By contrast, dementia was rare in all parkin-mutation carriers (<3%), despite long disease duration.

Conclusions and relevance: Notwithstanding large gaps in phenotypic information content, we identified dystonia and the absence of dementia as "red flags" to be incorporated in counseling guidelines. We propose mandatory minimal criteria for genotype-phenotype studies to facilitate the next breakthrough-following genetics-toward more personalized medicine for genetic conditions, extending well beyond the parkin example.