North Carolina Newborn Exome Sequencing for Universal Screening

Study Overview
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Brief Summary
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The NC NEXUS research study is exploring the utility of next generation sequencing in newborn screening and parental decision making. The National Institutes of Health (NICHD and NHGRI) are co-funding this study under a single U-19.

Detailed Description
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The investigators will enroll and perform whole exome sequencing on two cohorts of patients. One cohort will consist of two hundred newborns with no known conditions whose parents will be recruited during the mother's pregnancy. The second cohort will include two hundred infants and children up to the age of five years with diagnosed conditions including conditions detected through standard newborn screening such as phenylketonuria and other inborn errors of metabolism, hearing loss and other rare conditions that may fit criteria for newborn screening in the future. Parents will be introduced to the study by their clinician or a study recruiter. Those who agree to enroll in Phase I will review an online decision guide and be offered a study visit conducted by a genetic counselor to obtain informed consent for genomic sequencing of their child. Parents consenting to have their child's genome sequenced will be seen after the child's birth or at a convenient pre-arranged time and duplicate saliva samples will be collected from the children and one sample will be sent to the BioSpecimen Processing (BSP) Facility and to Dr. Jonathan Berg's laboratory for sequencing and the other sent to the Molecular Genetics Laboratory (MGL) for DNA extraction and storage until needed for clinical confirmation. Results will be returned for diagnostic (in the Diagnosed cohort) and medically actionable disorders of childhood (both cohorts). Two-thirds of parents who consent to sequencing will be randomly assigned to be eligible to request additional findings and use a supplement of the online decision aid. All results will be reported to parents by trained genetic professionals (genetic counselors and clinical geneticists)

Official Title
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North Carolina Newborn Exome Sequencing for Universal Screening

Conditions
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Metabolism, Inborn Errors, Hearing Loss, Hereditary Disease

Intervention / Treatment
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* Genetic: Well infant, whole exome sequencing
* Genetic: Diagnosed, whole exome sequencing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Uncomplicated pregnancy and healthy newborn Exclusion Criteria: Abnormalities such as major malformation or chromosomal disorder detected prenatally or significant complications during pregnancy or at the time of delivery.

Ages Eligible for Study
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Minimum Age: 1 Hour
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Well infant, whole exome sequencing<br>Healthy infants and their parents enrolled in the study prenatally will participate. After the infant is born saliva sample will be collected for DNA extraction and whole exome sequencing will be done. | Genetic: Well infant, whole exome sequencing<br>* Whole exome sequencing will be performed in children with diagnosed conditions. Investigators will analyze results that are associated with their condition.<br>|
| Other: Diagnosed, whole exome sequencing<br>Infants and children with diagnosed conditions whose parents enroll in the study and consent to having their child sequenced will have saliva samples obtained and whole exome sequencing will be done on extracted DNA. | Genetic: Diagnosed, whole exome sequencing<br>* In addition to returning results of conditions associated with a child's phenotype, investigators will also analyze genes that are associated with conditions that have childhood onset and are medically actionable.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parental Choices Following Decision Aid | Analysis of parents' decisions after they complete an on-line decision aid to see if they wish to participate in the study. Options will be yes, no, or undecided. | average of 3-6 months | 
| Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | Investigators analyzed next generation sequencing (NGS) results in the diagnosed cohort to determine the ability of whole exome sequencing to detect pathogenic variants in genes related to phenotype determined by standard newborn screening (NBS). The category of genes analyzed is termed the Next Generation Sequencing/Newborn Screening (NGS/NBS) category. Healthy newborns with no known genetic conditions also had the NGS/NBS category of genes analyzed. | approximately 3-6 months after DNA sample obtained | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parental Reaction Scores | Test-related distress is assessed with an adapted version of the Multidimensional Impact of Cancer Risk Assessment (MICRA). It asks participants to report how often in the past week they have experienced worries and distress related to their child's genomic sequencing procedure and test results, and the social and familial consequences of sequencing and the test results. Possible responses are provided on the following scale: 0=Never, 1=Rarely, 3=Sometimes, and 5=Often. Because it refers to respondents' experience of their child's sequencing and the test results they received, it is administered only in assessments that occurred after sequencing at Time 3 (2 weeks after results visit and Time 4 (3 months after results visit). Comparisons are made between couples who could chose to receive additional information about their child's genome and a control group who were not eligible to receive additional information. | Time 3 - 2 weeks after results visit and Time 4 - 3 months after results visit |