Freudenberg-Hua Yun, Freudenberg Jan, Vacic Vladimir, Abhyankar Avinash, Emde Anne-Katrin, Ben-Avraham Danny, Barzilai Nir, Oschwald Dayna, Christen Erika, Koppel Jeremy, Greenwald Blaine, Darnell Robert B, Germer Soren, Atzmon Gil, Davies Peter
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.
Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, North Shore-LIJ Manhasset, New York, 11030.
Mol Genet Genomic Med. 2014 Sep;2(5):438-50. doi: 10.1002/mgg3.86. Epub 2014 Jun 15.
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.
为了识别与超长寿命相符的既往报道的疾病突变，我们对44名阿什肯纳兹犹太裔百岁老人的基因组编码区进行了筛查。利用Illumina HiSeq 2000对个体基因组序列进行30倍覆盖度的测序，并使用基因组分析工具包（GATK）来识别单核苷酸变异。我们鉴定出130个编码变异，根据ClinVar数据库，这些变异被注释为“致病性的”或“可能致病性的”，且在普通人群中较为罕见。这些变异先前被报道可导致多种具有常染色体显性、常染色体隐性和X连锁遗传的退行性疾病、肿瘤性疾病和心脏疾病。根据美国医学遗传学学会的建议，其中一些变异位于含有可采取行动的偶发发现的基因中。此外，我们发现了迟发性神经退行性疾病的风险变异，比如一名未患阿尔茨海默病的百岁老人中甚至存在纯合状态的APOE ε4等位基因。我们的数据表明，在个体基因组中偶然发现某些已报道的疾病变异可能并不排除超长寿命。因此，当在临床测序过程中遇到所观察到的变异时，在做出临床决策时务必谨慎行事。
