This section provides information for investigators on the paperwork required to submit samples to the Broad CMG.

We will initially require the following documents:

  1. Collaborator Agreement: This agreement provides a high-level overview of the CMG and the type of samples we want to sequence, along with benefits to collaborators and policies that are required due to the use of NIH funding. Once you review and sign, it will automatically be sent back to our Center.
  2. Template Informed Consent Form: We require a blank, template copy of the informed consent form(s) used to recruit the participants who provided your samples.

Once we receive this paperwork, we will submit your research consent form(s) to our local IRB for secondary use approval. We will notify you as soon as we have approval.

After your collaboration has been established, we will request Data Use Limitations Letters. These templates must be completed by the ethics committee that approved your protocol and consent form. As a requirement for using NIH funds, data will eventually be deposited into dbGaP. This letter indicates to dbGaP how the data can be shared based on your consent forms. 

The goal of the CMG program is to discover new genes that cause rare disease.  Our case review process is designed to select cases that will give us the best chance for gene discovery. Learn more about the criteria used for case selection here.

We have two different case submission processes: individual case review and cohort review.  To ensure that you use the ideal case submission pipeline for your samples, it is strongly recommended you first send us an email with a description of the cases you would like to submit.  

Individual Case Review

Individual case review is designed for collaborators who have cases with a variety of diverse phenotypes and clinical histories. To submit cases for individual case review, we ask you first submit a pedigree file with a list of all cases, and their family members, who you would like us to consider for our project.  After your list of cases have been added to our system, we will then ask you to enter all relevant clinical, testing and family history into seqr. This video tutorial will guide you through the process. Once all required information has been entered, our case review team will review your cases and notify you of which cases have been accepted for the CMG.

Cohort Review

Our cohort review process is for collaborators who have groups (>20) of cases with a similar phenotype and prior testing for most known causes of diseases associated with this phenotype. Cohorts have added power for gene discovery, so we encourage these submissions. The first step is to fill out the cohort review form that describes your cohort and provide existing information about the genetic architecture.  Our case review team will review this form and notify you if the cohort is a good fit for CMG and how many cases we would be able to accept. You would then submit a pedigree file and enter all relevant clinical, testing and family history into seqr. Genomic data analysis requires good phenotype information.

Minimum criteria:

  1. Consent is appropriate for exome, genome and RNA sequencing, as well as individual­ level data sharing via controlled­ access databases (Matchmaker Exchange and dbGaP; additional information on dbGaP available below). If you have any questions about language your consent form needs to contain, please review NIH requirements here.
  2. Sample quantity and quality is sufficient for analysis: 3ug DNA for each sample, concentrated around 50­-100ng/ul [via Pico Green method],​to allow for exome sequencing and whole genome sequencing if needed. Sample volume requirement is no less than 20uL or no more than 600uL. Samples volumes outside this range cannot be accepted for automation purposes.
  3. Sufficient clinical phenotype data to permit comprehensive analysis has been entered via PhenoTips interface and reviewed and approved by CMG staff.

Prioritization Criteria:

  1. Likely Mendelian cause: T​he family has a highly penetrant severe and/or early onset phenotype, including those families with phenotypes matching a known but unsolved genetic condition. Families with multiple affected individuals, particularly cases that are consanguineous or large enough to obtain a significant LOD score through linkage, will be prioritized.
  2. Pre­screened for known genetic causes:​ For diseases with known genes, sample has undergone either targeted testing for the major genetic contributors to the phenotype, or exome sequencing.
  3. Likely recessive or d​e novo​ dominant genetic cause:​ Families with multiple affected siblings with unaffected parents, or with a known consanguineous relationship, will be favored over inherited dominant conditions. Probands with a strong suspicion of a de novo cause of disease (embryonic lethal/severe neonatal/pediatric disease) will also be prioritized if parental samples are available for trio analysis.
  4. Multiple cases:​ We will favor submissions for which there are multiple independent cases with the same rare phenotype.
  5. Detailed clinical data and additional samples are available: W​e will favor cases obtained by clinicians in active contact with the patient, for whom detailed medical records are available, and where obtaining additional clinical specimens and data are feasible.
  6. DNA and consent are available from multiple family members: W​e will prioritize cases where DNA samples from additional family members, especially parents and affected relatives, are available for study.
  7. Samples from a disease ­relevant tissue are available for RNA­-seq: W​e will prioritize cases when patient samples from a tissue known to be impacted by the disease phenotype, or a relevant cell line (such as differentiated iPS cells), are available for transcriptome analysis.
  8. Resources are available for detailed follow­up analyses: W​e will favor phenotypes for which there is clinical and biological/laboratory expertise available for the phenotype, and a clear path to targeted testing of candidate genes in other patients with similar phenotypes through local or international collaborations. 

Special note on dominant disease pedigrees: ​It is extremely difficult to discover new genes in dominant pedigrees of modest size. We will thus apply generally more stringent criteria in prioritizing these types of families. As a rule of thumb, we will generally only accept pedigrees that are sufficiently large to use linkage to restrict causal variants to 1% of the genome or less. Families with adult onset, complex phenotypes and evidence of incomplete penetrance will generally have a very low priority for the CMG.