Insights into genetics, human biology and disease gleaned from family based genomic studies.,Genetics in Medicine

当前位置： X-MOL 学术 › Genet. Med. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Insights into genetics, human biology and disease gleaned from family based genomic studies.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2019-Jan-18 , DOI: 10.1038/s41436-018-0408-7
Jennifer E Posey ₁ , Anne H O'Donnell-Luria _{2,

3,

4} , Jessica X Chong ₅ , Tamar Harel ₆ , Shalini N Jhangiani ₇ , Zeynep H Coban Akdemir ₁ , Steven Buyske _{8,

9} , Davut Pehlivan ₁ , Claudia M B Carvalho ₁ , Samantha Baxter ₃ , Nara Sobreira ₁₀ , Pengfei Liu _{1,

11} , Nan Wu _{1,

12} , Jill A Rosenfeld ₁ , Sushant Kumar ₁₃ , Dimitri Avramopoulos ₁₀ , Janson J White _{1,

5} , Kimberly F Doheny _{10,

14} , P Dane Witmer _{10,

14} , Corinne Boehm ₁₀ , V Reid Sutton ₁ , Donna M Muzny ₇ , Eric Boerwinkle _{7,

15} , Murat Günel _{16,

17} , Deborah A Nickerson ₁₈ , Shrikant Mane ₁₉ , Daniel G MacArthur _{2,

3} , Richard A Gibbs _{1,

7} , Ada Hamosh ₁₀ , Richard P Lifton _{16,

20,

21} , Tara C Matise ₈ , Heidi L Rehm _{2,

3} , Mark Gerstein ₁₃ , Michael J Bamshad _{5,

18} , David Valle ₁₀ , James R Lupski _{1,

7,

22,

23} ,

Affiliation

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Boston Children's Hospital, Boston, MA, USA.
Department of Pediatrics, University of Washington, Seattle, WA, USA.
Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
Department of Genetics, Rutgers University, Piscataway, NJ, USA.
Department of Statistics, Rutgers University, Piscataway, NJ, USA.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
Baylor Genetics Laboratory, Houston, TX, USA.
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Computational Biology and Bioinformatics Program, Yale University Medical School, New Haven, CT, USA.
Center for Inherited Disease Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Human Genetics Center, University of Texas Health Science Center, Houston, TX, USA.
Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
Department of Genome Sciences, University of Washington, Seattle, WA, USA.
Yale Center for Genome Analysis, Yale School of Medicine, Yale University, New Haven, CT, USA.
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.

Identifying genes and variants contributing to rare disease phenotypes and Mendelian conditions informs biology and medicine, yet potential phenotypic consequences for variation of >75% of the ~20,000 annotated genes in the human genome are lacking. Technical advances to assess rare variation genome-wide, particularly exome sequencing (ES), enabled establishment in the United States of the National Institutes of Health (NIH)-supported Centers for Mendelian Genomics (CMGs) and have facilitated collaborative studies resulting in novel "disease gene" discoveries. Pedigree-based genomic studies and rare variant analyses in families with suspected Mendelian conditions have led to the elucidation of hundreds of novel disease genes and highlighted the impact of de novo mutational events, somatic variation underlying nononcologic traits, incompletely penetrant alleles, phenotypes with high locus heterogeneity, and multilocus pathogenic variation. Herein, we highlight CMG collaborative discoveries that have contributed to understanding both rare and common diseases and discuss opportunities for future discovery in single-locus Mendelian disorder genomics. Phenotypic annotation of all human genes; development of bioinformatic tools and analytic methods; exploration of non-Mendelian modes of inheritance including reduced penetrance, multilocus variation, and oligogenic inheritance; construction of allelic series at a locus; enhanced data sharing worldwide; and integration with clinical genomics are explored. Realizing the full contribution of rare disease research to functional annotation of the human genome, and further illuminating human biology and health, will lay the foundation for the Precision Medicine Initiative.

中文翻译：

从基于家庭的基因组研究中收集到对遗传学、人类生物学和疾病的见解。

识别导致罕见疾病表型和孟德尔病症的基因和变异为生物学和医学提供了信息，但人类基因组中约 20,000 个注释基因中超过 75% 的变异的潜在表型后果尚不清楚。评估全基因组罕见变异的技术进步，特别是外显子组测序（ES），使得美国国立卫生研究院（NIH）支持的孟德尔基因组中心（CMG）得以在美国建立，并促进了合作研究，从而产生了新颖的“疾病基因”的发现。基于谱系的基因组研究和对疑似孟德尔疾病家族的罕见变异分析已经阐明了数百个新的疾病基因，并强调了从头突变事件、非肿瘤性状背后的体细胞变异、不完全渗透等位基因、高位点表型的影响异质性和多位点致病变异。在此，我们重点介绍了 CMG 的合作发现，这些发现有助于了解罕见和常见疾病，并讨论了单基因座孟德尔疾病基因组学的未来发现机会。所有人类基因的表型注释；生物信息学工具和分析方法的开发；探索非孟德尔遗传模式，包括外显率降低、多位点变异和寡基因遗传；在一个基因座构建等位基因序列；加强全球数据共享；并探索了与临床基因组学的整合。实现罕见病研究对人类基因组功能注释的全面贡献，进一步阐明人类生物学和健康，将为精准医学计划奠定基础。

更新日期：2019-01-26

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11