Despite recent advances in genomic technology, more than half of the genes underlying severe Mendelian disease remain undiscovered. Identifying the genes responsible for rare diseases can yield critical new insights into human biology, empowering the development of therapies for these diseases as well as more common conditions. However, current approaches are inadequate to detect or correctly interpret many of the variants likely to cause rare diseases. Assembling a complete catalogue of genes that underlie rare diseases will require fundamentally new approaches to gene discovery and variant interpretation. The Joint Center for Mendelian Genomics, led by the Broad Institute, Boston Children's Hospital, and Rockefeller University, has assembled a large, international network of collaborators with a world-class track record of both genomic methods development and Mendelian gene discovery. Our Center's global team of clinical investigators has both strong domain expertise and access to wider collaborative networks, providing over 35,000 existing well-phenotyped samples from over 16,000 Mendelian families for genomic analysis as well as strong sources of ongoing and diverse recruitment. We will apply deep, high-quality exome sequencing, analyzing over 10,000 exomes, to systematically discover causal variants in or near protein-coding regions. Secondly, we will use PCR-free whole-genome sequencing and novel variant- calling methods for comprehensive discovery in 7,000 samples from exome-unsolved families. Finally, we will apply transcriptome sequencing of disease-relevant tissues and cell lines from Mendelian patients to focus the search for variants altering gene expression or transcript splicing. We will implement a robust analytical framework for variant assessment and disease gene discovery, taking advantage of our investigators' world-leading roles in statistical genetics, functional annotation, and clinical variant interpretation, as well as accessto exome and genome data from over 250,000 reference samples, to build a systematic pipeline for Mendelian gene discovery applied across all patients sequenced by the Center, and also made freely available to external investigators. For many rare diseases, confident discovery of causal genes will require aggregation of cases across centers around the world. To enable this, we will set a new standard for data sharing in clinical genomics by rapidly releasing genetic and phenotype data to an international network of databases, accelerating collaboration and facilitating robust disease gene discovery.

Public Health Relevance

Clinical sequencing has become a frontline strategy for diagnosing rare, severe disease, particularly in pediatrics: 10% of pediatric admissions and up to 20% of infant deaths derive from Mendelian disease. However, the capability for generating sequence data far outstrips the capability to accurately interpret these data, and over half of patients with suspected genetic disorders do not currently receive a genetic diagnosis. Our Center will contribute substantially to the establishment of a comprehensive catalog of the genetic causes of Mendelian diseases, thus improving disease diagnosis rates as well as building the biological understanding needed to develop more effective therapeutics.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
Application #
Study Section
Special Emphasis Panel (ZHG1)
Program Officer
Wang, Lu
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Broad Institute, Inc.
United States
Zip Code
Edvardson, Simon; Nicolae, Claudia M; Agrawal, Pankaj B et al. (2017) Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood. Am J Hum Genet 101:267-273
Reddy, Hemakumar M; Cho, Kyung-Ah; Lek, Monkol et al. (2017) The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States. J Hum Genet 62:243-252
Marin-Valencia, Isaac; Gerondopoulos, Andreas; Zaki, Maha S et al. (2017) Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of Pontocerebellar Hypoplasia. Am J Hum Genet 101:441-450
Cummings, Beryl B; Marshall, Jamie L; Tukiainen, Taru et al. (2017) Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Sci Transl Med 9:
Friedman, Jennifer; Feigenbaum, Annette; Chuang, Nathaniel et al. (2017) Pyruvate dehydrogenase complex-E2 deficiency causes paroxysmal exercise-induced dyskinesia. Neurology 89:2297-2298
Shaw, Natalie D; Brand, Harrison; Kupchinsky, Zachary A et al. (2017) SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. Nat Genet 49:238-248
Boycott, Kym M; Rath, Ana; Chong, Jessica X et al. (2017) International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases. Am J Hum Genet 100:695-705
Harris, Elizabeth; Burki, Umar; Marini-Bettolo, Chiara et al. (2017) Complex phenotypes associated with STIM1 mutations in both coiled coil and EF-hand domains. Neuromuscul Disord 27:861-872
Lardelli, Rea M; Schaffer, Ashleigh E; Eggens, Veerle R C et al. (2017) Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing. Nat Genet 49:457-464
van der Ven, Amelie T; Shril, Shirlee; Ityel, Hadas et al. (2017) Whole-Exome Sequencing Reveals FAT4 Mutations in a Clinically Unrecognizable Patient with Syndromic CAKUT: A Case Report. Mol Syndromol 8:272-277

Showing the most recent 10 out of 15 publications