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Genet Med. 2019 Apr;21(4):798-812. doi: 10.1038/s41436-018-0408-7. Epub 2019 Jan 18.

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

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. jennifer.posey@bcm.edu.
2
Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
3
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
4
Boston Children's Hospital, Boston, MA, USA.
5
Department of Pediatrics, University of Washington, Seattle, WA, USA.
6
Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
7
The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
8
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
9
Department of Genetics, Rutgers University, Piscataway, NJ, USA.
10
Department of Statistics, Rutgers University, Piscataway, NJ, USA.
11
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
12
Baylor Genetics Laboratory, Houston, TX, USA.
13
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
14
Computational Biology and Bioinformatics Program, Yale University Medical School, New Haven, CT, USA.
15
Center for Inherited Disease Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
16
Human Genetics Center, University of Texas Health Science Center, Houston, TX, USA.
17
Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
18
Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
19
Department of Genome Sciences, University of Washington, Seattle, WA, USA.
20
Yale Center for Genome Analysis, Yale School of Medicine, Yale University, New Haven, CT, USA.
21
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
22
Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
23
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. jlupski@bcm.edu.
24
The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. jlupski@bcm.edu.
25
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. jlupski@bcm.edu.
26
Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. jlupski@bcm.edu.

Abstract

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.

KEYWORDS:

Centers for Mendelian Genomics (CMG); Mendelian conditions; disease traits; genetic models for disease; rare variant phenotypes

PMID:
30655598
DOI:
10.1038/s41436-018-0408-7

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