Genetic Testing in Pediatrics

Genetic testing in pediatrics encompasses a broad range of laboratory-based analyses used to identify inherited conditions, chromosomal abnormalities, and gene variants in infants, children, and adolescents. These tests inform diagnosis, guide treatment selection, and shape long-term care planning across dozens of pediatric subspecialties. The scope of genetic testing extends from universal newborn screening programs mandated by state public health agencies to targeted sequencing ordered for a child with unexplained developmental delay or a rare disease presentation. Understanding how these tests are classified, when they are indicated, and what boundaries govern their use is essential for families and clinicians navigating a rapidly evolving field.

Definition and Scope

Genetic testing in the pediatric context refers to the analysis of DNA, RNA, chromosomes, or gene products to detect heritable changes associated with disease, disease risk, or carrier status. The field is governed at the federal level by the Clinical Laboratory Improvement Amendments (CLIA), administered by the Centers for Medicare & Medicaid Services (CMS, CLIA Program), which set minimum standards for laboratory quality and personnel. The American College of Medical Genetics and Genomics (ACMG) publishes guidelines that classify genetic tests into categories including diagnostic, predictive, carrier, prenatal, and pharmacogenomic testing (ACMG Standards and Guidelines).

In pediatrics, genetic testing is broader in scope than in adult medicine because children cannot defer testing decisions and because many genetic conditions manifest exclusively or most severely in early childhood. The regulatory context for pediatrics includes federal statutes such as the Genetic Information Nondiscrimination Act (GINA) of 2008, which prohibits discrimination in health insurance and employment based on genetic information, though GINA's protections do not extend to life, disability, or long-term care insurance.

The breadth of conditions detectable by genetic testing in children spans more than 7,000 recognized rare diseases, the majority of which have a genetic basis according to the National Institutes of Health's National Center for Advancing Translational Sciences (NIH NCATS Rare Diseases).

How It Works

Genetic testing follows a structured process that differs by test type and clinical indication.

  1. Clinical assessment and indication identification — A pediatrician, geneticist, or specialist identifies features such as dysmorphic findings, developmental delay, or a positive family history that raise suspicion for a heritable condition.
  2. Test selection — The ordering clinician chooses the appropriate assay. Test types include chromosomal microarray analysis (CMA), single-gene sequencing, gene panels, whole-exome sequencing (WES), whole-genome sequencing (WGS), and fluorescence in situ hybridization (FISH).
  3. Sample collection — Blood, saliva, or tissue is collected. For newborn screening, a heel-prick blood spot is collected within 24–48 hours of birth per state protocol.
  4. Laboratory analysis — CLIA-certified laboratories perform the analysis. Turnaround times range from 3–5 days for rapid WGS in neonatal intensive care settings to 4–6 weeks for comprehensive panels.
  5. Variant interpretation — Variants are classified using the ACMG/AMP 5-tier system: Pathogenic, Likely Pathogenic, Variant of Uncertain Significance (VUS), Likely Benign, or Benign (ACMG/AMP 2015 Variant Classification Standards).
  6. Genetic counseling and result disclosure — Results are disclosed in the context of genetic counseling. The ACMG recommends pre- and post-test counseling for all predictive and diagnostic testing in pediatric patients.
  7. Care integration — Results are integrated into the child's medical record and inform subspecialty referrals, medication selection, or surveillance protocols.

Chromosomal microarray analysis detects copy number variants (CNVs) at a resolution far exceeding standard karyotype; it identifies a clinically significant finding in approximately 10–20% of children with unexplained intellectual disability, according to a landmark study published in the New England Journal of Medicine (Miller et al., 2010, NEJM 363:2161–2171).

Common Scenarios

Genetic testing arises across a predictable set of pediatric clinical situations:

Newborn Screening — All 50 states and the District of Columbia mandate newborn screening for a core set of conditions. The federal Health Resources and Services Administration (HRSA) maintains the Recommended Uniform Screening Panel (RUSP), which as of its most recent update includes 37 core conditions and 26 secondary conditions (HRSA RUSP). Positive screening results require confirmatory diagnostic testing before a diagnosis is established.

Unexplained Developmental Delay or Intellectual Disability — ACMG guidelines recommend chromosomal microarray as the first-tier genetic test for children with global developmental delay or intellectual disability of unknown cause. Whole-exome sequencing is recommended as a second-tier test when CMA is non-diagnostic.

Suspected Rare or Undiagnosed Disease — Children evaluated through programs such as the NIH Undiagnosed Diseases Program may undergo WGS. Rapid WGS has demonstrated a diagnostic yield of approximately 36–57% in critically ill neonates across published clinical studies.

Hereditary Cancer Predisposition — Children with a strong family history or specific tumor types may be tested for variants in genes such as TP53, APC, or BRCA1/2. The ACMG has established specific guidelines governing when pediatric hereditary cancer testing is appropriate, emphasizing that testing for adult-onset conditions is generally deferred until adulthood unless early intervention changes management.

Pharmacogenomics — Gene variants affecting drug metabolism (e.g., CYP2D6, TPMT) influence medication dosing for pediatric patients on chemotherapy, antidepressants, or other agents. The FDA maintains a Table of Pharmacogenomic Biomarkers in Drug Labeling (FDA Pharmacogenomics) that applies to pediatric indications.

Newborn screening results differ structurally from diagnostic test results; a positive screen indicates elevated risk, not confirmed disease. This distinction shapes the urgency and pathway of follow-up, as covered under the main pediatrics reference index.

Decision Boundaries

Not all genetic testing is clinically equivalent, and the decision to test involves clearly defined ethical and clinical thresholds.

Diagnostic vs. Predictive Testing — Diagnostic testing is ordered when a child presents with active symptoms consistent with a genetic condition. Predictive testing—identifying risk for a condition not yet clinically apparent—in children is subject to stricter scrutiny. The American Academy of Pediatrics (AAP) and ACMG jointly recommend that predictive genetic testing for adult-onset conditions be deferred until the individual can provide autonomous informed consent, except when early detection enables childhood interventions that reduce morbidity (AAP Policy on Ethical Issues in Genetic Testing).

Variants of Uncertain Significance — A VUS result does not confirm disease and should not drive clinical management decisions. Families require careful counseling to avoid inappropriate medical interventions based on VUS findings.

Carrier Testing — Testing a child to determine carrier status for a recessive condition (e.g., cystic fibrosis, sickle cell disease) when the child themselves has no health risk from carrier status is generally discouraged until the child reaches an age at which carrier status has personal reproductive relevance—typically young adulthood.

Incidental Findings — When exome or genome sequencing is performed, laboratories may detect pathogenic variants unrelated to the initial clinical question. The ACMG maintains a list of 81 genes (the ACMG SF v3.1 list) for which reporting of secondary findings is recommended (ACMG Secondary Findings v3.1). Families must be counseled about this possibility before testing begins.

Turnaround and Urgency — In critically ill neonates where a rapid genetic diagnosis can redirect care within 48–72 hours, rapid WGS may be prioritized over standard panels. Outside of urgent settings, standard diagnostic timelines apply, and results should not be acted upon until formal variant interpretation is complete and communicated by a qualified clinician.

References

The law belongs to the people. Georgia v. Public.Resource.Org, 590 U.S. (2020)