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Next-Generation Phenotyping Using the Parkin Example Time to Catch Up With Genetics

Anne Grünewald, PhD1; Meike Kasten, MD1,2; Andreas Ziegler, PhD3; Christine Klein, MD1
[+] Author Affiliations
1Insitute of Neurogenetics, University of Lübeck, Lübeck, Germany
2Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany
3Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany
JAMA Neurol. 2013;70(9):1186-1191. doi:10.1001/jamaneurol.2013.488.
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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.

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Type and Quality of Parkin Publications

A, Flowchart summarizing information contained in articles resulting from the MEDLINE literature search. AAO indicates age at onset; PD, Parkinson disease. B, Criteria for the quality score devised to evaluate study methodology. These could be United Parkinson Disease Rating Scale motor part (UPDRS III), Hoehn and Yahr rating, or any other well-accepted motor symptom rating. MLPA indicates Multiplex Ligation-Dependent Probe Amplification; NMS, nonmotor symptoms; and qPCR, quantitative polymerase chain reaction. C, Overview on average study quality between the years 1998 and 2012. In addition, the average annual impact factor (IF) of the included studies is given. Data were smoothed by exponential smoothing, a technique applied to time series data.

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