Introduction

Newborn Metabolic Disease and Neonatal Disorder Testing

Clinical presentations of neonatal disorders can be heterogeneous and variable, rendering results of traditional biochemical-based testing ambiguous and difficult to interpret. Follow-on genetic testing for these suspected cases enables confirmation of the diagnosis.

Establishing an etiologic diagnosis in neonatal care with suspected genetic diseases is remarkably difficult because:

• Disease presentations are usually atypical with incomplete manifestation

• Comorbidity is frequent, including prematurity, birth trauma, and sepsis, etc. obscuring clinical presentations

• Disease progression is rapid in children, causing a race against time to avoid a diagnostic odyssey.

• With the current practice of serial testing, the result rarely allows etiologic diagnosis in time to influence acute management.

The Rainbow Metabolic and Neonatal Disorder Exome/Whole Genome Sequencing Test provides physicians with a comprehensive strategy with timely ascertainment to determine the genetic etiologies of multiple metabolic and neonatal disorders.

Whole Genome or Whole Exome Sequencing

• Physician can choose from various options: Whole-genome or whole-exome sequencing, singleton, duo or trio sequencing approach

• Gene-panel-only, exome-wide or whole-genome clinical interpretation

• Inclusion of incidental findings associated with childhood-onset disorders

• Regular turnaround time is 1.5-2 months.

Emergency Testing

• Rapid trio whole genome sequencing for emergency neonatal cases with 1 to 1.5 week-turnaround available.

Proband vs. Trio sequencing

It has been shown that sequencing both parents in addition to sequencing the child (a trio) increases the yield of a diagnosis, particularly for cases where there were no prior family histories. One reason for the higher diagnostic rate is because of the successful identification of de novo and compound heterozygous mutations via trio sequencing. Rainbow Genomics recommends trio sequencing whenever possible.

Diagnostic Testing

• Based on whole exome sequencing, this is a diagnostic analysis associated with infant's symptoms, parental carrier status and family history

• Panel-specific and Exome-wide Clinical Interpretation Strategy:

  1. Targeted-Gene Analysis - Comprehensive gene-panel analysis determines gene variants associated with:

     1. Treatable metabolic disorder panel (132 disorders, 145 genes)

     2. Metabolic disorder panel (318 disorders, 398 genes)

     3. Neonatal disorder panel (446 disorders, 437 genes)

• Whole-Exome Analysis Included -

  1. To assure recently-discovered gene variants are included in our clinical interpretation, exome-wide review of known pathogenic and likely-pathogenic variants in ClinVar and OMIM associated with newborn metabolic and neonatal disorders will also be performed

• Physicians have the option to easily reflex to whole exome analysis for additional pathogenic variants beyond these gene panels, and with the use of additional symptoms and phenotypes.

• Physicians can order whole genome sequencing which will detect additional pathogenic variants, and with higher sensitivity to determine causative copy-number and structural variations.

Incidental Finding & Health Screening Test

• This test preemptively determines the risks of developing over 600 neonatal and 1000 childhood on-set diseases

• The test approach is modeled after the BabySeq project implemented at the Boston Children's Hospital & Harvard Medical School in the U.S.

• Clinical interpretation using over 1600 genes associated with over 1000 childhood-onset disorders

• Physician can order reports based on the analysis of only metabolic disorders (>300), neonatal disorders (>600), or with a larger set of childhood-onset diseases (>1000)