Newborn Genomic Sequencing Pilot Study

Newborn screening (NBS) by testing dried blood spots (DBS) identifies newborns with a few diseases for which effective treatments are available to enable treatment at or before symptom onset. Because NBS improves outcomes in these diseases, it is performed on almost all US babies. The current Federal recommended NBS list is limited to 35 conditions and identifies \~6,600 affected children per year. In genetic diseases not screened by NBS, however, outcomes remain poor because of delays in diagnosis and treatment. The investigators recently developed a system for NBS for 434 severe, childhood genetic diseases for which effective treatments are available using whole genome sequencing (WGS), called BeginNGS. Retrospective studies showed BeginNGS to have a true negative rate (specificity) of 99.7% and true positive rate (sensitivity) of 88.8%. The investigators now propose to undertake a first prospective study in newborns admitted to the Neonatal Intensive Care Unit (NICU) at Rady Children's Hospital, San Diego (RCHSD) to compare the sensitivity and specificity of BeginNGS with that of standard, diagnostic rapid whole genome sequencing (DWGS) and whole exome sequencing (WES). This study is in preparation for larger, future clinical trials.

• Whole genome sequencing (Genetic): Standard diagnostic whole genome sequencing will be performed.
• BeginNGS test (Genetic): Genomic sequencing that screens for 434 genetic diseases.
• WES (Genetic): Whole exome sequencing will be performed.

Primary outcomes

• Proportion of enrolled infants who are diagnosed with a genetic disease by DWGS. [18 months]: Proportion

Secondary outcomes

• Proportion of enrolled infants who are identified with a genetic disease by BeginNGS. [18 months]: Proportion
• Proportion of enrolled infants who are identified with a genetic disease by WES. [18 months]: Proportion
• Proportion of enrolled infants who have a positive standard NBS test. [18 months]: Proportion
• Proportion of parents approached who agree to participate in the study. [18 months]: Proportion
• Parental reasons for refusal. [18 months]: Questionnaire
• Time from sample arriving in lab to return of DWGS results. [18 months]: Time (days)
• Time from birth to return of DWGS results. [18 months]: Time (days)
• Results of confirmatory testing if BeginNGS or WES identifies a diagnostic finding not reported by DWGS. [18 months]: Proportion of findings confirmed

Sex: All, ages: 1 Day to 10 Days, accepts healthy volunteers

Inclusion Criteria:

* Neonates less than or equal to 10 days old who are admitted to the RCHSD NICU.

Exclusion Criteria:

1. Neonates who have enrolled in another clinical study at Rady Children's Institute for Genomic Medicine or in whom DWGS has been ordered or is being considered.
2. Neonates whose mother is less than 18 years of age.
3. Neonates who are wards of the state.
4. Neonates whose parent/legal guardian is unable to provide consent.

• Stephen Kingsmore, MD DSc, Principal investigator, Rady Children's Institute for Genomic Medicine