Rapid Whole Genome Sequencing Study

Rapid Whole Genome Sequencing (rWGS) is a new technology that is able to deliver
symptom-driven diagnoses of childhood-onset genetic diseases in as little as 26 hours.
Investigators at RCIGM have shown that rWGS has higher diagnostic rates than traditional
molecular testing in acutely ill infants suspected of a genetic diagnosis, with diagnostic
rates up to 57%. Similarly, in the infant population, RCIGM researchers have shown that these
diagnoses are useful in directing clinical care, with up to 70% of infants who receive a
diagnosis having a subsequent change in management. In some cases, a timely diagnosis results
in treatments that are lifesaving. RCIGM investigators have shown that up to 25% of infants
who receive a diagnosis have a subsequent change in management that prevents morbidity. More
data is needed to determine whether these results are found at other institutions, among
other ethnic and racial groups, and in larger numbers of patients. More data is needed to
examine the acute and long-term clinical utility of such testing, both in newborns and older
children, as well as to determine the cost-effectiveness of this testing for other
institutions. As such, this study will be a collaboration of multiple sites to share data and
experiences of rWGS with the scientific community as well as hospital administrations,
insurance companies and other key stakeholders who may be interested in promoting rWGS as a
first-line clinical test in the future.

The study will provide clinical laboratory-confirmed results related to the affected
patient's symptoms, including optional incidental findings unless subjects opt-out for these
additional results, to allow for these research findings to be used in clinical care.
Furthermore, this study will aggregate data regarding standard clinical genetic testing from
multiple sites as well as cost measures to not only identify differences in diagnostic rates,
diagnostic accuracy, and times to diagnoses, but to determine the cost-effectiveness of this
testing and subsequent changes in care management. Clinical utility will be defined as
changes in care that follow directly from results of genetic testing (both positive and
negative), including standard clinical tests and rWGS. This data will be used to further
examine the analytic, diagnostic, and clinical utility and cost-effectiveness of this
testing.

rWGS methods continue to improve, and pediatric genomic medicine is a very new field of
medical practice. This study will also inform investigators regarding best practices, both in
terms of traditional medical outcomes and patient-centered outcomes. Consequently, this study
will also act as a biorepository for samples and data as the ability to share genomic and
phenotypic data amongst researchers is critical to progressing our understanding of the
nascent field of pediatric genomic medicine.

Specific Aims:

1. To collect biological samples and associated clinical data from acutely ill pediatric
patients who may have a genetic disease and their family members (Phenome).

2. To create, analyze and store genomic data from the biological samples. Genomic data will
include genomic (gDNA) sequences, RNA sequences, and/or other related 'omic data
(including, but not limited to, pharmacogenomics, transcriptomics, and epigenomics).
Genomic data from rWGS will include single nucleotide calls (SNVs), structural variants
such as copy number testing, genomic rearrangements, gene expression , the "whole
transcriptome" or more limited DNA sequencing panels of specific genes or of all exons
of genes (the "Exome").

3. To evaluate the diagnosis rate of genetic diseases by rWGS in an acutely ill population
enrolling from multiple sites with comparisons to standard clinical genetic testing.

4. To assess the clinical utility of rapid genetic diagnoses in the care and management of
patients.

5. To examine the health economics and cost-effectiveness of this rapid testing across many
sites.

6. To investigate and improve genomics technologies and software to enhance understanding
and testing abilities related to childhood diseases and potential treatment responses.

7. To make specimens and data available for qualified researchers and collaborators to
further the understanding of rare childhood diseases and treatment responses.

8. To collect and correlate genomic data from a wide variety of populations and clinical
presentations.

9. To provide sample and data collections with uniform consent, methods of acquisition,
storage for genome-based research studies with subsequent IRB approvals.

10. To analyze and report clinically-confirmed genomic diagnoses and treatment guidance
through use of new research technologies.

11. To identify and study novel gene and disease processes.

Inclusion Criteria:

- The Repository will be comprised of samples from symptomatic patients, individuals
reported to be their (symptomatic or asymptomatic) biologic family members, and
control individuals. In this context a "symptomatic patient" is characterized as a
patient whose treating physician has identified phenotypic features and/or signs of
illness potentially attributable to a genetic disorder (also referred to as "Affected"
or "Proband"). There will be no age, gender, race, or health restrictions for this
Biorepository Study. However, since this study will be performed at children's
hospitals and since genetic disorders are more likely to be present in children less
than 4 months of age these cases will likely be preferentially enrolled. Preference
will also be given to those who are acutely ill, suspected of a genetic condition, and
for whom a diagnosis may result in change of clinical management.

Exclusion Criteria:

- Participants will be excluded if they are unwilling to consent to research.

A patient may be determined ineligible if there is a prior diagnosis that explains their
clinical presentation, if other traditional clinical genetic testing is more appropriate at
the time of referral, if the clinical presentation is insufficient at the time of referral
to suggest a genetic etiology, if the parents are unable or unwilling to provide permission
for participation, if child protective services is involved in the case unless the child's
life is in immediate danger and research holds out a prospect of direct benefit that is
important to the health or well-being of the child and is available only in the context of
the research in which case permission will be obtained from the party legally responsible
for medical decisions.