Disease variants in genomes of 44 centenarians

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

Research output: Contribution to journalArticle

38 Scopus citations

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, neo-plastic, 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 Ɛ4 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.

Original languageEnglish (US)
Pages (from-to)438-450
Number of pages13
JournalMolecular Genetics and Genomic Medicine
Volume2
Issue number5
DOIs
StatePublished - Jan 1 2014

Keywords

  • Aging
  • Ashkenazi
  • Centenarian
  • Disease gene
  • Incidental finding
  • Whole genome sequencing

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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  • Cite this

    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 and Genomic Medicine, 2(5), 438-450. https://doi.org/10.1002/mgg3.86