Genetic analysis of neurodegenerative diseases in a pathology cohort

Cornelis Blauwendraat¹, Olga Pletnikova², Joshua T Geiger¹, Natalie A Murphy³, Yevgeniya Abramzon⁴, Gay Rudow², Adamantios Mamais³, Marya S Sabir¹, Barbara Crain², Sarah Ahmed³, Liana S Rosenthal⁵, Catherine C Bakker⁵, Faraz Faghri⁶, Ruth Chia³, Jinhui Ding³, Ted M Dawson⁷, Alexander Pantelyat⁵, Marilyn S Albert⁵, Mike A Nalls⁸, Susan M Resnick⁹, Luigi Ferrucci¹⁰, Mark R Cookson³, Argye E Hillis⁵, Juan C Troncoso¹¹, Sonja W Scholz¹²

Affiliations

¹ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
² Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁴ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Department of Molecular Neuroscience, University College London, London, UK.
⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
⁷ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Solomon H. Synder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USA; Department of Pharmacology and Molecular Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Neuroregeneration Program, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Data Tecnica International, Glen Echo, MD, USA.
⁹ Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
¹⁰ Longitudinal Studies Section, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
¹¹ Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: sonja.scholz@nih.gov.

PMID: 30528841
PMCID: PMC6391207
DOI: 10.1016/j.neurobiolaging.2018.11.007

Genetic analysis of neurodegenerative diseases in a pathology cohort

Cornelis Blauwendraat et al. Neurobiol Aging. 2019 Apr.

. 2019 Apr:76:214.e1-214.e9.

doi: 10.1016/j.neurobiolaging.2018.11.007. Epub 2018 Nov 17.

Authors

Affiliations

¹ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
² Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁴ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Department of Molecular Neuroscience, University College London, London, UK.
⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
⁷ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Solomon H. Synder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USA; Department of Pharmacology and Molecular Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Neuroregeneration Program, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Data Tecnica International, Glen Echo, MD, USA.
⁹ Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
¹⁰ Longitudinal Studies Section, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
¹¹ Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: sonja.scholz@nih.gov.

PMID: 30528841
PMCID: PMC6391207
DOI: 10.1016/j.neurobiolaging.2018.11.007

Abstract

Molecular genetic research provides unprecedented opportunities to examine genotype-phenotype correlations underlying complex syndromes. To investigate pathogenic mutations and genotype-phenotype relationships in diverse neurodegenerative conditions, we performed a rare variant analysis of damaging mutations in autopsy-confirmed neurodegenerative cases from the Johns Hopkins Brain Resource Center (n = 1243 patients). We used NeuroChip genotyping and C9orf72 hexanucleotide repeat analysis to rapidly screen our cohort for disease-causing mutations. In total, we identified 42 individuals who carried a pathogenic mutation in LRRK2, GBA, APP, PSEN1, MAPT, GRN, C9orf72, SETX, SPAST, or CSF1R, and we provide a comprehensive description of the diverse clinicopathological features of these well-characterized cases. Our study highlights the utility of high-throughput genetic screening arrays to establish a molecular diagnosis in individuals with complex neurodegenerative syndromes, to broaden disease phenotypes and to provide insights into unexpected disease associations.

Keywords: Brain bank; Genotype-phenotype; NeuroChip; Neurodegeneration.

Published by Elsevier Inc.

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Figures

**Figure 1.**
This multi-layer pie chart illustrates the composition of the Johns Hopkins brain bank cohort by disease category. Abbreviations: AD, Alzheimer’s dementia; ALS, amyotrophic lateral sclerosis; AP, atypical parkinsonism; CBD, corticobasal degeneration; FTD, frontotemporal dementia; HS, hippocampal sclerosis; LBD, Lewy body dementia; MSA, multiple system atrophy; PD, Parkinson’s disease, PSP, progressive supranuclear palsy.

**Figure 2.**
This illustration shows an overview of the analysis workflow that we applied to identify patients with pathogenic mutations, including filtering the data to extract rare, damaging neurological mutations in the Human Genome Mutation Database content, performing C9orf72 repeat expansion screening in pathologically-confirmed ALS/FTD patients, and a copy number variant analysis of selected genes.

**Figure 3.**
This figure shows the histopathological heterogeneity associated with *LRRK2*-related parkinsonism in six patients with a pathogenic p.G2019S *LRRK2* mutation. Three out of six cases had tau-positive neurons, neuropil threads, tufted astrocytes, and coil bodies consistent with a diagnosis of PSP (panels A, B, C: 20x magnification), but no Lewy body pathology. Two patients were found to have nigral neuronal loss with associated Lewy body pathology (panels D, E; Lewy bodies indicated by arrow). One patient had nigral neuronal loss without tau- or asynuclein-positive inclusion (panel F shows a few naturally pigmented nigral neurons; of note this patient was also homozygous for the pathogenic p.N409S GBA mutation). Magnification is 40x for D, 100x for E, and 10x for panel F.

See this image and copyright information in PMC

References

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Genetic analysis of neurodegenerative diseases in a pathology cohort

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Genetic analysis of neurodegenerative diseases in a pathology cohort

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