rWGS is not considered medically necessary when the infant’s presentation is explained by an isolated, self‑limited condition with a clear precipitating cause. Examples explicitly listed in the policy include: isolated transient neonatal tachypnea; isolated unconjugated hyperbilirubinemia; isolated hypoxic‑ischemic encephalopathy with a clear precipitating event; isolated meconium aspiration; isolated prematurity; and infection/sepsis with a normal response to therapy.

The policy identifies several exclusions to coverage for genome sequencing. Genome sequencing for prenatal diagnosis is considered not supported for routine use. Genome sequencing used to screen asymptomatic or pre‑symptomatic individuals is not covered. Combining whole genome sequencing with optical genome mapping as a single bundled assay is excluded. Reporting CPT 81425 to represent a targeted (non‑whole‑genome) analysis is not appropriate; use the specific panel or unlisted molecular code instead. Repeat CPT 81425 beyond once per lifetime is not covered except when appropriate reanalysis is reported separately under CPT 81427. Tests performed by laboratories that are not a qualified laboratory (including direct‑to‑consumer) are excluded. Finally, genome sequencing is not covered where an adequate targeted test should be performed first.

Comparator genome analysis (CPT 81426) is covered only when the proband meets the medical‑necessity criteria for proband WGS (CPT 81425); comparator sequencing is not separately covered if the proband does not meet Section 6 criteria. Re‑evaluation/reanalysis (CPT 81427) must be requested and billed separately and is not payable as a reflex from a targeted analysis to a full genome.

Rapid WGS (rWGS) is not medically necessary when the infant’s clinical presentation can be explained by an isolated, self‑limited condition with an identifiable precipitating cause. The policy lists illustrative examples such as transient neonatal tachypnea, isolated unconjugated hyperbilirubinemia, isolated hypoxic‑ischemic encephalopathy with a clear precipitant, isolated meconium aspiration, isolated prematurity, and infections/sepsis that respond normally to therapy.

A documented family‑history assessment is required and must be included in the clinical summary letter submitted for prior authorization. The clinical summary must document the genetic evaluation, differential diagnoses, prior tests and results, rationale that genome sequencing is the next appropriate test, and the predicted impact on care. Where applicable (for example in rWGS criteria), a family history strongly suggestive of a genetic etiology—including consanguinity—can satisfy gatekeeping requirements when combined with other clinical findings.

Eligibility for proband whole genome sequencing requires meeting the policy’s gatekeeping conditions: no prior exome or genome sequencing for the same indication; an appropriate clinical genetic evaluation and family‑history assessment documented in the clinical summary letter; consideration and reasonable exclusion of alternative non‑genetic etiologies; and expectation that the result will have a direct impact on health outcomes. For rWGS, additional inpatient and acuity‑specific eligibility elements apply (see rWGS criteria), including the age limit of ≤ 12 months when applicable.

Prior exome or genome sequencing for the same clinical indication is a gatekeeping exclusion — the policy requires that no prior exome or genome sequencing has been performed for the same indication before approving proband WGS or rWGS. If prior exome or chromosomal microarray testing was non‑diagnostic but new evidence suggests intronic, regulatory, or structural variants may explain the phenotype, genome sequencing or targeted follow‑up may be appropriate; reanalysis of a previously obtained genome (CPT 81427) is considered medically necessary only when specified triggers apply and must be billed on a separate date of service. Prior authorization requests must document prior genetic testing and results.

Operational gatekeeping details include documentation and prior‑authorization requirements: the clinical summary must demonstrate appropriate genetic evaluation and family history, list prior tests and results, and explain why WGS is the next step. Evidence of pre‑test genetic counseling and documented informed consent must be provided. The rendering laboratory must be a qualified laboratory (CLIA high‑complexity and Plan‑participating) and the prior authorization request must list the requested CPT/PLA codes and units, including the number of comparator genomes when applicable.

The policy states that whole exome sequencing (CPT 81415/81416/81417), chromosomal microarray (CPT 81228/81229), and condition‑specific panels are governed by other policies and are not covered under this WGS policy. Comparator analysis is not covered if the proband fails to meet criteria, and CPT 81427 reanalysis has its own cross‑referenced criteria.

The policy lists several items explicitly not covered: prenatal WGS, genome sequencing used for screening asymptomatic individuals, WGS combined with optical genome mapping as a single bundled assay, and reporting targeted analyses under CPT 81425. It also excludes repeat CPT 81425 beyond once per lifetime except when appropriate reanalysis is billed as CPT 81427, and testing performed by laboratories that are not qualified (including direct‑to‑consumer).

Genome sequencing analyzes both coding and non‑coding regions of the genome and can detect variant classes (single‑nucleotide variants, small indels, and certain copy‑number and structural variants) that may be missed by targeted approaches. This broader scope makes WGS particularly useful for persons with complex, heterogeneous, or undiagnosed constitutional conditions where a single targeted test is unlikely to identify the cause. The policy recognizes genome sequencing as a first‑ or second‑tier option depending on the clinical context, and emphasizes that targeted testing remains appropriate when a specific diagnosis is strongly suspected.