The Broad Center for Mendelian Genomics (CMG) is a collaborative venture between the Broad Institute of MIT and Harvard, Boston Children's Hospital, Rockefeller University and many other participating institutions. The central goals of the Center are: to discover new genes underlying Mendelian diseases; to develop collaborative networks of investigators to facilitate gene discovery, validation and follow­up; and to generate new methods for gene discovery applicable across a wide spectrum of rare disorders.

Our Center expects to perform exome or genome sequencing on thousands of unsolved Mendelian cases and unaffected family members over the next three years. To improve gene discovery, the Center will focus heavily on cases previously screened for known disease genes, as well as those from multiplex recessive pedigrees. It will emphasize recruitment of cases from six major disease areas: retinal disease, kidney diseases, primary muscle disease, neurodevelopmental disorders, kidney disease, and cardiac disease – but 20% of cases will be accepted from any disease area.


Inherited retinal degenerations (IRDs) are characterized by progressive dysfunction and death of rod and cone photoreceptor cells, leading to vision loss, and are one of the most genetically diverse groups of inherited disorders. Identifying the genetic cause of patients’ IRD has become especially important with the success of gene therapy trials. The specific genetic cause remains elusive in half of IRD patients, indicating many gene discoveries remain.


Inherited neuromuscular diseases represent diverse clinical phenotypes with the unifying feature of weakness; primary muscle disease alone has a combined population prevalence of over one in 3,000. Currently over 50% of neuromuscular disease patients cannot be provided with a genetic diagnosis even after extensive targeted screening of known genes, indicating that many causal genes remain undiscovered.


Neurodevelopmental disorders (NDDs) affect ~4-6% of the population and account for >5-10% of total healthcare costs, Mendelian NDDs remain a diagnostic dilemma because they are frequently difficult to distinguish from NDDs with more complex inheritance, like autism or epilepsy. Collectively NDDs comprise the biggest set of discoveries of Mendelian centers to date, but more than 50% of patients are still left undiagnosed, indicating that NDDs remain a fertile area for novel gene discovery. To enrich for new genes we will focus primarily on cases with specific features (e.g. metabolic, degenerative, ataxia, microcephaly, syndromic) for which Mendelian causes far outweigh non-Mendelian ones.


A rare, or “orphan” disease is defined as a disease or disorder that affects less than 200,000 people in the United States at any given time. However, there are approximately 30 million people in the U.S. that are affected by a rare disease. We will recruit samples from patients with rare, undiagnosed diseases with a suspected Mendelian basis.


Inherited forms of cardiomyopathy, including hypertrophic (HCM) and dilated (DCM), are among the most common Mendelian diseases and are associated with risk for sudden cardiac death. HCM alone is the leading cause of sudden nontraumatic death in young adults. Although a number of genes have been identified for these disorders, the cause of over half of cases remain unknown even after comprehensive testing. In addition, congenital heart malformations are the most common birth defect and the most common cause of infant death, yet only 20% are diagnosable with known genetic causes.


Chronic kidney disease (CKD) is characterized by irreversible deterioration of renal function that gradually progresses to end-stage renal disease. The majority of CKD that presents before the age of 25 is caused by congenital anomalies of the kidneys and urinary tract (CAKUT), steroid-resistant nephrotic syndrome (SRNS), chronic glomerulonephritis and renal cystic ciliopathies. Variants in over 200 different monogenic genes have been associated with 70% of the most common causes of early-onset CKD.

The Center will provide exome and/or whole­ genome sequencing at no cost to the collaborator for affected cases and relatives. This centralized service will offer high­ quality sequencing and analysis at the Broad Institute, incorporating discovery of all classes of variation (including copy number variants) and interpretation of both coding and non­coding variation, compared against a database of >100,000 reference exomes and genomes. We will provide a report for each family outlining the analyses performed and highlighting variants we consider to be likely causal.

All raw data generated by the Center will be available to the collaborators who provided the corresponding samples. In addition, we will provide an intuitive online portal giving collaborators the ability to analyze their own data, alongside the Broad's reference database, thus facilitating collaborative gene discovery. Our analysts will work closely with collaborators in exploring the data and providing candidate and likely causal variants, and will work in tandem with your team to discuss challenging cases.

The Center will provide centralized services for DNA extraction (if required) and storage, sequencing, alignment and variant calling, interpretation and raw data storage. We will also support the generation of manuscripts reporting novel genes by providing publication-­quality text and figures, by connecting collaborators with sources of additional cases with mutations in the same gene, and by creating a network of investigators capable of functional validation of newly discovered genes.

Collaborators are expected to provide high­ quality, appropriately consented DNA samples from patients and family members. The consent form signed by subjects must include language regarding secondary use, data sharing, and deposition into a controlled access database such as dbGaP. Before sequencing can be conducted we will require phenotype and pedigree information from samples to be entered into a custom PhenoTips interface. Prioritization of samples for CMG sequencing will take place after phenotype data has been made available.

While the Center will provide lists of candidate causal variants and genes, we are not funded for targeted functional validation, experimental assays, or clinical follow­up of candidate genes. As such, collaborators will be responsible for detailed clinical and experimental follow­up of candidate variants and genes.

The Center's results will be generated in a research environment, not a clinical diagnostic laboratory. As such, collaborators will generally be responsible for their own clinical validation of results in an appropriately regulated setting (e.g. a CLIA laboratory) before using them in clinical practice. We request that collaborators update the CMG on the validation status and clinical outcomes of variants discovered by the Center.

dgmacarthur_bw2Daniel MacArthur, PhD 
is the co-director for the Center for Mendelian Genomics at the Broad Institute. He is also a group leader within the Analytic and Translational Genetics Unit (ATGU) at Massachusetts General Hospital, Assistant Professor at Harvard Medical School and the Associate Director of Medical and Population Genetics at the Broad Institute of Harvard and MIT.
heidi-web-2007.jpgHeidi Rehm, PhD, FACMG 
is the co-director for the Center for Mendelian Genomics at the Broad Institute.  She is also the Director of the Laboratory for Molecular Medicine at Partners Healthcare Personalized Medicine, Medical Director of the Broad's Clinical Research Sequencing Platform and Associate Professor of Pathology at Brigham & Women's Hospital and Harvard Medical School.
Samantha Baxter - Genetic Counselor/Clinical Project Manager
Samantha is the clinical project manager at the Broad's Center for Mendelian Genomics. She is a genetic counselor who has worked in the area of cardiovascular and laboratory genetics throughout her career. Her work now focuses on the management and sharing of both clinical and genetic data.

profilepic.png.jpgHarindra Arachchi - Senior Software Engineer
Harindra works on building tools to help study rare genetic diseases. Prior to that, he has been with the Center of Bioinformatics, Biostatistics and Integrative Biology at the Pasteur Institute in Paris France, and the Broad Institute of MIT. He works on developing infrastructure, software tools, and methods that help study rare genetic diseases. He has a Bachelors degree in Computer science with minors in Biology and Mathematics along with a MBA with a concentration in Strategy and Business analysis.

Laura GauthierLaura Gauthier - Computational Biologist
Laura is a computational biologist jointly based in the MacArthur lab and the Broad Institute Data Sciences and Data Engineering (DSDE) platform. She works on the development of variant-calling pipelines for rare disease samples.
monkollek_bwMonkol Lek - Computational biologist
Monkol is a computational biologist focusing on the large-scale analysis of exome sequencing data, and its application to improving understanding of human biology and disease risk. He leads the analysis team in the Exome Aggregation Consortium as well as many of our rare disease projects.
Anne O'DonnellAnne O'Donnell Luria - Clinical and Biochemical Geneticist / Senior Clinical Analyst
Anne is the Associate Director for the Broad Center for Mendelian Genomics, clinical genetics and metabolic specialist and a board-certified pediatrician. Her current research focuses on the use of exome and genome sequence data to identify genetic variation in health and disease to improve rare disease diagnosis and better understand incomplete penetrance. Her prior research in the MD/PhD training program at Columbia University focused on the role of epigenetic variation in complex disease.
Beryl Cummings - Graduate Student and RNA-seq Analyst
Beryl is a graduate student from the Biomedical and Biological Sciences Program at Harvard who works on using RNA sequencing data to interpret the functional impact of human genetic variation.
Jamie MarshallJamie Marshall - Research Scientist
Jamie is a research scientist leading the group's efforts to create in vivoand in vitro models of muscle disease. She studied mechanisms of and therapeutic approaches for the treatment of muscular dystrophy during her PhD at UCLA and her postdoctoral research at Boston Children's Hospital.
benweisburdBen Weisburd - Software Engineer
Ben is a software engineer working on developing methods for interpreting DNA sequencing data in the context of severe Mendelian diseases. He is the lead developer for our xBrowse rare disease analysis platform.
Monica WojcikMonica Wojcik - Senior Clinical Analyst
Monica is Senior Clinical Analyst and a board-certified pediatrician who is now completing her combined fellowship training through the Harvard Medical School Genetics Training Program and the Harvard Program in Neonatal-Perinatal Medicine. Her research focuses on gene discovery and the diagnosis of rare disease in the neonatal population.
Miriam UdlerMiriam Udler - Clinical Analyst
Miriam is Clinical Analyst in the Rare Genomes Project. Board Certified in Internal Medicine and Endocrinology, Diabetes, and Metabolism, she sees patients at Massachusetts General Hospital (MGH) with a special focus on Endocrine Clinical Genetics. She holds a PhD in Genetic Epidemiology and is a research analyst at the Broad Institute and MGH.
Jaime ChangJaime Chang - Project Coordinator
Jaime is a Project Coordinator for the Rare Genomes Project and Broad Institute's Center for Mendelian Genomics. She was previously a research associate in the Broad Institute’s Genetic Perturbation Platform and also has prior marketing experience in healthcare and biotech.
Kristen LaricchiaKristen Laricchia - Associate Computational Biologist
Kristen is an Associate Computational Biologist who works on the preliminary analyses and management of datasets for the Exome Aggregation Consortium and novel gene discovery for Mendelian diseases.
Mike WilsonMike Wilson - Associate Computational Biologist
Mike is an associate computational biologist working on the preliminary analyses of exomes and genomes to identify causal candidate genes and variants. He also manages datasets from Mendelian disease collaborators.


Steering Committee

Joe Gleeson.jpgJoseph G. Gleeson, M.D. 
is the head of the Laboratory for Pediatric Brain Diseases and Professor at Rockefeller University and Director of Mendelian Genetics at the New York Genome Center.  He is also an investigator with the Howard Hughes Medical Institute.  His research focuses on understanding the genetic basis of neurodevelopmental disorders and the discovery of new treatments.  He has uncovered over 50 novel causes of disease.
Eric Pierce.jpgEric A. Pierce, M.D., Ph.D. 
is the Director of the ocular Genomics Institute at Massachusetts Eye and Ear Infirmary and Associate Professor of Ophthalmology at Harvard Medical School.  He has over 20 years of research and clinical experience with inherited retinal degenerations and has identified four new disease genes to date.
Alan Biggs.jpgAlan H. Beggs, Ph.D. 
is a Professor of Pediatrics at Harvard Medical School and the Founding Director of The Manton Center for Orphan Disease Research.  He is also Associate Chief for Research, Division of Genetics, at Boston Children's Hospital.  He brings over 20 years of expertise in genetics of inherited pediatric developmental and neurological disorders.
Mark Daly.jpgMark J. Daly,
is the chair of the Analytic and Translational Genetics Unit at Massachusetts General Hospital, a senior associate member of the Broad Institute, and co-director of the Broad's Program in Medical and Population Genetics.  He has developed many genomic analysis tools and have extensive leadership in large-scale data science and exome sequencing consortia.
Christine Seidman.jpgChristine E. Seidman, M.D. 
is a Professor of Medicine and Genetics at Harvard Medical School, an Investigator with the Howard Hughes Medical Institute, and the Director of the Cardiovascular Genetics Center at Brigham and Women's Hospital.  She researches the molecular basis of hypertrophic and dilated cardiomyopathy, discovering genetic causes of congenital heart disease and elucidating the clinical impact of rate cardiovascular gene variants.
sweetser.jpgDavid Sweetser, M.D. 
is Chief of Medical Genetics at Massachusetts General Hospital and is trained in pediatrics and medical and biochemical genetics. He studies patients with a broad spectrum of hereditary disorders with a focus on pediatric hematology
Vamsi Mootha.jpgVamsi K. Mootha, M.D. 
is an Institute Member of the Broad Institute and Professor of Systems Biology and Medicine at Harvard Medical School.  He is also an Investigator with the Howard Hughes Medical Institute.  He has experimentally defined the mitochondrial proteome and discovered over a dozen genes underlying fatal pediatric disorders.  He brings expertise in strategies to understand the genetic basis of mitochondrial disorders.

Interpreting Genomes for Rare Disease:Variant and Gene Interpretation

Presented by:

Keynotes Speakers Include

Register Here

Course Overview:
Attendees of this course will receive both lecture-based and hands-on learning opportunities. At the end of the course, attendees will understand the processes of next generation sequencing data generation, comprehend the guidelines and best practices for variant and gene curation, recognize the role for clinical information in genomic analysis, appreciate the role of data sharing in genomic interpretation, and hear a patients perspective on diagnosis and next steps.

May 15th – 16th, 2019
Broad Institute
415 Main Street
Cambridge, MA, USA

Cost (meals included):
Early-bird Registration (February - March 31): $225
Regular Registration (April 1 - either full or May 10): $275

Onsite Registration (if not full): $350

*The National Society of Genetic Counselors (NSGC) has authorized the Broad Institute of MIT and Harvard and ClinGen to offer up to 1.25 CEUs or 12.50 Category 1 contact hours for the activity Interpreting Genomes for Rare Disease: Variant and Gene Interpretation. The American Board of Genetic Counseling (ABGC) will accept CEUs earned at this program for the purposes of genetic counselor certification and recertification.

Attendees planning to collect CEUs will be asked to bring a $25 check to registration. Checks should be made out directly to the National Society of Genetic Counselors.



8:30 am – 8:45 am           Registration & Breakfast

8:45 am – 9:00 am           Opening Remarks

9:00 am – 10:00 am         Intro to Next Generation Sequencing - Daniel MacArthur, PhD

10:00am – 11:00 am        Annotation Data and its Uses - Anne O’Donnell-Luria, MD, PhD

11:00 am – 11:30 am       Break

11:30 am – 1:00pm          Workshop: Next Generation Sequencing Data Filtration

1:00 pm – 2:00 pm           Lunch

2:00 pm – 3:30 pm           Gene Curation - Marina DiStefano, PhD

3:30 pm – 4:00 pm           Break

4:00 pm – 5:30 pm           Workshop: Gene Curation

5:30 pm – 7:00 pm           Social and Networking Event

THURSDAY, MAY 16, 2019

9:00 am – 10:30 am         Variant Interpretation - Steven Harrison, PhD

10:30 am – 11:00 am       Break

11:00 am – 12:30 pm       Workshop: Variant Curation

12:30 pm – 1:30 pm         Lunch

1:30 pm – 2:30 pm           Data Sharing - Heidi Rehm, PhD, FACMG

2:30 pm – 3:30 pm           Patient Perspective on Discovery and Next Steps - Sonia Vallabh, PhD

3:30 pm – 4:00 pm           Break

4:00 pm – 5:00 pm           Future Directions Panel & Closing Remarks

For video recordings of the 2018 course, please see below:

Intro to Next Generation Sequencing (Speaker: Daniel MacArthur)

Annotation Data and its Uses (Speaker: Anne O’Donnell-Luria)

Gene Discovery and Interpretation (Speakers: Erin Riggs & Marina Distefano)
Erin Riggs:

Marina Distefano:

Variant Interpretation and the ClinGen Curation Interface (Speaker: Steven Harrison)

The Use of Clinical Information in Data Analysis (Speaker: Samantha Baxter)

Data Sharing (Speaker: Heidi Rehm)

Future Directions Q&A Panel & Closing Remarks

Event sponsored by