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 access to 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.
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.
|Dobyns, William B; Aldinger, Kimberly A; Ishak, Gisele E et al. (2018) MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance. Am J Hum Genet 103:1009-1021|
|Kumar, Raman; Gardner, Alison; Homan, Claire C et al. (2018) Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery. Hum Mutat 39:1126-1138|
|Dolman, Lena; Page, Angela; Babb, Lawrence et al. (2018) ClinGen advancing genomic data-sharing standards as a GA4GH driver project. Hum Mutat 39:1686-1689|
|Guissart, Claire; Latypova, Xenia; Rollier, Paul et al. (2018) Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia. Am J Hum Genet 102:744-759|
|Alrohaif, Hadil; Töpf, Ana; Evangelista, Teresinha et al. (2018) Whole-exome sequencing identifies mutations in MYMK in a mild form of Carey-Fineman-Ziter syndrome. Neurol Genet 4:e226|
|Jamshidi, Farzad; Place, Emily M; Mehrotra, Sudeep et al. (2018) Contribution of noncoding pathogenic variants to RPGRIP1-mediated inherited retinal degeneration. Genet Med :|
|van der Ven, Amelie T; Connaughton, Dervla M; Ityel, Hadas et al. (2018) Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract. J Am Soc Nephrol 29:2348-2361|
|Dashnow, Harriet; Lek, Monkol; Phipson, Belinda et al. (2018) STRetch: detecting and discovering pathogenic short tandem repeat expansions. Genome Biol 19:121|
|Arachchi, Harindra; Wojcik, Monica H; Weisburd, Benjamin et al. (2018) matchbox: An open-source tool for patient matching via the Matchmaker Exchange. Hum Mutat 39:1827-1834|
|Sadedin, Simon P; Ellis, Justine A; Masters, Seth L et al. (2018) Ximmer: a system for improving accuracy and consistency of CNV calling from exome data. Gigascience 7:|
Showing the most recent 10 out of 44 publications