title: Disease variants in genomes of 44 centenarians.
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.
authors.affiliation: 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.
authors.forename: Yun
authors.initials: Y
authors.lastname: Freudenberg-Hua
authors.affiliation: Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, North Shore-LIJ Manhasset, New York, 11030.
authors.forename: Jan
authors.initials: J
authors.lastname: Freudenberg
authors.affiliation: New York Genome Center 101 Avenue of the Americas, New York, New York, 10013.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vacic
authors.affiliation: New York Genome Center 101 Avenue of the Americas, New York, New York, 10013.
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.affiliation: New York Genome Center 101 Avenue of the Americas, New York, New York, 10013.
authors.forename: Anne-Katrin
authors.initials: AK
authors.lastname: Emde
authors.affiliation: Institute for Aging Research Departments of Medicine and Genetics, Albert Einstein College of Medicine 1300 Morris Park Avenue, Bronx, New York, 10461.
authors.forename: Danny
authors.initials: D
authors.lastname: Ben-Avraham
authors.affiliation: Institute for Aging Research Departments of Medicine and Genetics, Albert Einstein College of Medicine 1300 Morris Park Avenue, Bronx, New York, 10461.
authors.forename: Nir
authors.initials: N
authors.lastname: Barzilai
authors.affiliation: New York Genome Center 101 Avenue of the Americas, New York, New York, 10013.
authors.forename: Dayna
authors.initials: D
authors.lastname: Oschwald
authors.affiliation: 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.
authors.forename: Erika
authors.initials: E
authors.lastname: Christen
authors.affiliation: 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.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Koppel
authors.affiliation: Division of Geriatric Psychiatry, Zucker Hillside Hospital, North Shore-LIJ Glen Oaks, New York, 11040.
authors.forename: Blaine
authors.initials: B
authors.lastname: Greenwald
authors.affiliation: 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.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Darnell
authors.affiliation: New York Genome Center 101 Avenue of the Americas, New York, New York, 10013.
authors.forename: Soren
authors.initials: S
authors.lastname: Germer
authors.affiliation: Institute for Aging Research Departments of Medicine and Genetics, Albert Einstein College of Medicine 1300 Morris Park Avenue, Bronx, New York, 10461.
authors.forename: Gil
authors.initials: G
authors.lastname: Atzmon
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Davies
keywords: Aging; Ashkenazi; centenarian; disease gene; incidental finding; whole genome sequencing