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Freudenberg-Hua Y, Freudenberg J, Vacic V, et al. Disease variants in genomes of 44 centenarians. Mol Genet Genomic Med. 2014;2(5):438-50doi: 10.1002/mgg3.86.
Freudenberg-Hua, Y., Freudenberg, J., Vacic, V., Abhyankar, A., Emde, A. K., Ben-Avraham, D., Barzilai, N., Oschwald, D., Christen, E., Koppel, J., Greenwald, B., Darnell, R. B., Germer, S., Atzmon, G., & Davies, P. (2014). Disease variants in genomes of 44 centenarians. Molecular genetics & genomic medicine, 2(5), 438-50. https://doi.org/10.1002/mgg3.86
Freudenberg-Hua, Yun, et al. "Disease variants in genomes of 44 centenarians." Molecular genetics & genomic medicine vol. 2,5 (2014): 438-50. doi: https://doi.org/10.1002/mgg3.86
Freudenberg-Hua Y, Freudenberg J, Vacic V, Abhyankar A, Emde AK, Ben-Avraham D, Barzilai N, Oschwald D, Christen E, Koppel J, Greenwald B, Darnell RB, Germer S, Atzmon G, Davies P. Disease variants in genomes of 44 centenarians. Mol Genet Genomic Med. 2014 Sep;2(5):438-50. doi: 10.1002/mgg3.86. Epub 2014 Jun 15. PMID: 25333069; PMCID: PMC4190879.
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Mol Genet Genomic Med. 2014 Sep;2(5):438-50. doi: 10.1002/mgg3.86. Epub 2014 Jun 15.

Disease variants in genomes of 44 centenarians.

Molecular genetics & genomic medicine

Yun Freudenberg-Hua, Jan Freudenberg, Vladimir Vacic, Avinash Abhyankar, Anne-Katrin Emde, Danny Ben-Avraham, Nir Barzilai, Dayna Oschwald, Erika Christen, Jeremy Koppel, Blaine Greenwald, Robert B Darnell, Soren Germer, Gil Atzmon, Peter Davies

Affiliations

  1. The Litwin-Zucker Research Center for the Study of Alzheimer's Disease and Memory Disorders, The Feinstein Institute for Medical Research, North Shore-LIJ Manhasset, New York, 11030 ; Division of Geriatric Psychiatry, Zucker Hillside Hospital, North Shore-LIJ Glen Oaks, New York, 11040.
  2. Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, North Shore-LIJ Manhasset, New York, 11030.
  3. New York Genome Center 101 Avenue of the Americas, New York, New York, 10013.
  4. Institute for Aging Research Departments of Medicine and Genetics, Albert Einstein College of Medicine 1300 Morris Park Avenue, Bronx, New York, 10461.
  5. The Litwin-Zucker Research Center for the Study of Alzheimer's Disease and Memory Disorders, The Feinstein Institute for Medical Research, North Shore-LIJ Manhasset, New York, 11030.
  6. Division of Geriatric Psychiatry, Zucker Hillside Hospital, North Shore-LIJ Glen Oaks, New York, 11040.
  7. New York Genome Center 101 Avenue of the Americas, New York, New York, 10013 ; Department of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University 1230 York Avenue, New York, New York, 10065.

PMID: 25333069 PMCID: PMC4190879 DOI: 10.1002/mgg3.86

Abstract

To identify previously reported disease mutations that are compatible with extraordinary longevity, we screened the coding regions of the genomes of 44 Ashkenazi Jewish centenarians. Individual genome sequences were generated with 30× coverage on the Illumina HiSeq 2000 and single-nucleotide variants were called with the genome analysis toolkit (GATK). We identified 130 coding variants that were annotated as "pathogenic" or "likely pathogenic" based on the ClinVar database and that are infrequent in the general population. These variants were previously reported to cause a wide range of degenerative, neoplastic, and cardiac diseases with autosomal dominant, autosomal recessive, and X-linked inheritance. Several of these variants are located in genes that harbor actionable incidental findings, according to the recommendations of the American College of Medical Genetics. In addition, we found risk variants for late-onset neurodegenerative diseases, such as the APOE ε4 allele that was even present in a homozygous state in one centenarian who did not develop Alzheimer's disease. Our data demonstrate that the incidental finding of certain reported disease variants in an individual genome may not preclude an extraordinarily long life. When the observed variants are encountered in the context of clinical sequencing, it is thus important to exercise caution in justifying clinical decisions.

Keywords: Aging; Ashkenazi; centenarian; disease gene; incidental finding; whole genome sequencing

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