Diagnostic Odyssey: Whole Genome Sequencing (WGS)

The goal of this collaborative research is to study human genomes in children with suspected
congenital disease, multiple-congenital anomalies and/or multi-organ disease of unknown
etiology, in order to understand the potential value of WGS in establishing a genetic
diagnosis. The study will examine diagnosis rates, changes in clinical care as a result of a
genetic diagnosis, health economics including potential cost-effectiveness of WGS, and
patient and provider experience with genomic medicine. Other clinical information of the type
collected by treating physicians and stored in electronic medical records will also be
collected to aid in the interpretation of laboratory data. Participants will also be asked to
consent for future access of the medical record, future research on biospecimens and data
generated from genomic sequencing, and for the ability to re-contact.

As part of this effort, Nicklaus Children's Hospital plans to create a large integrated
database that contains the DNA sequences of the participants' whole human genomes and
additional health information regarding characteristics and health of the persons whose
samples have been sequenced. Scientists can then use the database to try to link those
traits, diseases, and other conditions to changes in the sequence of the genome. Nicklaus
Children's Hospital plans to make the database available to its collaborators, such as RCIGM,
pharmaceutical and biotechnology companies, and other academic institutions which will use
the database to find better, innovative ways to prevent, diagnose, and treat cancer and other
diseases. De-identified data from this study will be shared with the community at-large,
including publications and public databases. In addition, participants will be given the
option to allow biospecimens (i.e., residual blood, saliva, CSF, etc.) to be included in
biorepositories at Nicklaus Children's Hospital and Rady Pediatric Genomics & Systems
Medicine Institute (RCIGM).

The study will provide clinical laboratory-confirmed results related to the affected
patient's phenotype, 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 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 WGS. This data will be used to further examine the analytic,
diagnostic, and clinical utility and cost-effectiveness of this testing.

WGS 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. Use WGS to identify new genetic diagnoses in children with multiple congenital
anomalies, developmental delay, autism, seizures, intellectual disabilities,
neurodegenerative disorders, and metabolic illness.

2. Evaluate the diagnosis rate of genetic diseases by WGS in previously undiagnosed
patients.

3. Assess the clinical utility of WGS in the care and management of patients.

4. Examine the health economics and cost-effectiveness of WGS.

5. Evaluate the provider, patient and family experience with genomic medicine

6. Collect biological samples and associated clinical data from pediatric patients who may
have a genetic disease and their family members (the "Phenome").

7. 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 WGS will include single nucleotide variants (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").

8. Analyze and report clinically-confirmed genomic diagnoses and treatment guidance through
use of new research technologies.

9. Identify and study novel gene and disease processes.

Inclusion Criteria:

- Symptomatic male or female children ages 0-21 who have un unknown medical condition
thought to have an underlying genetic cause after parental consent has been obtained.

- Willingness of referring provider or other qualified medical staff member to
participate in this study by facilitating collection of biologic specimens and
clinical information.

- Patient whose medical condition can be reasonably attributed to a possible genetic
etiology.

- Patient have had at least one diagnostic test without a definite diagnosis.

Exclusion Criteria:

- Unwillingness to consent to research.

- Affected adults (>21 years of age), unless they are a biological relative of the
affected child.

- Any patient whose medical condition cannot be reasonably attributed to a possible
genetic etiology or there is a prior diagnosis that explains the child's clinical
presentation.