Clinical trial NCT03458962: Diagnostic Odyssey: Whole Genome Sequencing (WGS)
Official title: Ending the Diagnostic Odyssey: Whole Genome Sequencing (WGS) to Identify Genetic Determinants of Previously Undiagnosed Disease in Children
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Genetic Disease
Genetic Syndrome
Keywords: Nicklaus Children's
Pediatric
Genomic
Precision Medicine
Biorepository
Rady Children's
Lead sponsor: Nicklaus Children's Hospital f/k/a Miami Children's Hospital
Sponsor class: OTHER
Collaborators: name: Rady Pediatric Genomics & Systems Medicine Institute
First posted: 2018-03-08
Enrollment: 1000
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: FAMILY_BASED
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Children from 0 to 21 years suffering from unknown diagnoses seen at Nicklaus Children's Hospital

Brief summary: 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 by understanding the potential value of Whole Genome Sequencing (WGS) in establishing 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of patients enrolled per year
timeFrame: Yearly throughout study completion up to 50 years
Secondary outcomes:
measure: Diagnosis Rate of genetic diseases
timeFrame: Throughout study completion up to 50 years
measure: Clinical Utility
timeFrame: Throughout study completion up to 50 years
measure: Phenome
timeFrame: Throughout study completion up to 50 years
measure: Clinically-confirmed diagnoses
timeFrame: Throughout study completion up to 50 years
Other outcomes:
Locations:
city: Miami
country: United States
facility: Nickalus Children's Hospital f/k/a Miami Children's Hospital
state: Florida
Study officials:
affiliation: Nicklaus Children's Hospital
name: Parul Jayakar, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: McCandless SE, Brunger JW, Cassidy SB. The burden of genetic disease on inpatient care in a children's hospital. Am J Hum Genet. 2004 Jan;74(1):121-7. doi: 10.1086/381053. Epub 2003 Dec 12.
citation: Sawyer SL, Hartley T, Dyment DA, Beaulieu CL, Schwartzentruber J, Smith A, Bedford HM, Bernard G, Bernier FP, Brais B, Bulman DE, Warman Chardon J, Chitayat D, Deladoey J, Fernandez BA, Frosk P, Geraghty MT, Gerull B, Gibson W, Gow RM, Graham GE, Green JS, Heon E, Horvath G, Innes AM, Jabado N, Kim RH, Koenekoop RK, Khan A, Lehmann OJ, Mendoza-Londono R, Michaud JL, Nikkel SM, Penney LS, Polychronakos C, Richer J, Rouleau GA, Samuels ME, Siu VM, Suchowersky O, Tarnopolsky MA, Yoon G, Zahir FR; FORGE Canada Consortium; Care4Rare Canada Consortium; Majewski J, Boycott KM. Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care. Clin Genet. 2016 Mar;89(3):275-84. doi: 10.1111/cge.12654. Epub 2015 Sep 22.