Clinical Utility of Pediatric Whole Exome Sequencing

Next-generation sequencing (NGS) is changing the paradigm of clinical genetic testing. Unlike
highly focused single-gene tests, NGS allows one to examine gene panels, the exome, and the
whole genome. With the broad array of molecular tests now available, ordering physicians face
the conundrum of selecting the best diagnostic tool for patients with suspected genetic
conditions. Single-gene testing is often most appropriate for conditions with distinctive
clinical features and minimal locus heterogeneity. NGS-based gene panel testing, which can be
complemented with chromosomal microarray analysis (CMA) and other ancillary methods, provides
a comprehensive and feasible approach for well documented but genetically heterogeneous
disorders. Whole exome sequencing (WES) and whole genome sequencing (WGS) have the advantage
of enabling parallel interrogation of most of the genes in the human genome. To some, WES is
preferable to previously used methods due to higher diagnostic yield, shorter time to
diagnosis, and improved cost-efficiency.

The ability to survey the exome opens up both new opportunities and new challenges. For
example, all coding regions of known genes must be analyzed when applying WES to undiagnosed
cases with unclear inheritance patterns. Current limitations on variant interpretation
capabilities and clinical validity raise questions about the clinical utility of WES as
either a stand-alone or a first-choice diagnostic test. Additional challenges include pre-
and post-test counseling with appropriate and robust informed consent, bioinformatics
analysis setup and validation, variant interpretation and classification, the need for
policies and protocols concerning the discovery and reporting of secondary findings unrelated
to the presenting indication, a requirement for validation of WES results, assurance of
conformation to quality control standards, data storage and accessibility, and reimbursement
issues.

Introducing WES into pediatric clinical care of underrepresented populations raises
additional issues and considerations of payment coverage, access, and standards of care.
Beyond the sheer complexity of the test and its results, clinicians and health systems must
address numerous considerations, including: private and public insurance coverage; language
and culture differences and their implications for genetic counseling and clinician-patient
relationships; ability to access follow-up testing and clinical care; and ability to access
appropriate treatment and services. These issues and others will affect not only patients'
decision-making regarding WES, but also their post-test needs for patient follow up. The
importance of systematically assessing the clinical utility of NGS is critical for
determining in which clinical and health care contexts WES will be useful and for commencing
research on these considerations.

Inclusion Criteria:

1. Presenting clinical features suggestive of a genetic etiology, including intellectual
disability, seizures, multiple congenital anomalies, metabolic conditions, and
neurodegenerative conditions or idiopathic cerebral palsy.

2. A minimum of one biological parent is available and willing to provide a specimen for
WES, with a preference for two available parents. At least one parent consenting to
WES of the child.

4. Pediatric patients must have had at least one prior genetics appointment or evaluation
5. Pediatric patients must have had a single nucleotide polymorphism (SNP) array or
oligonucleotide array that did not provide a diagnosis.

Exclusion Criteria:

1. Prior WES performed for a clinical or research indication

2. Lack of phenotypic indication of a likely underlying genetic etiology

3. Both biological parents are unavailable.