Advancing precision medicine in the Cardiac Intensive Care Unit using universal whole-genome sequencing

A retrospective review of Primary Children's Hospital's universal whole-genome sequencing protocol for neonates with congenital heart defects revealed that 19.4% of patients had clinically relevant genetic findings, with 10.6% receiving a causative diagnosis that often occurred before the emergence of extracardiac features, thereby enabling timely medical management and informed family decision-making.

The Gist

Imagine the human body as a complex, high-tech factory. Sometimes, right from the start, a blueprint (our DNA) has a typo or a missing page, causing a major machine in the factory—like the heart—to be built incorrectly. These are called Congenital Heart Defects (CHD).

For a long time, doctors played a game of "detective" with these blueprints. They would only look for errors if the baby had other obvious problems, like a cleft lip or unusual facial features. If the heart was the only thing wrong, they often assumed the blueprint was fine and didn't bother checking it closely.

The Big Change: A Universal Scan
In September 2023, Primary Children's Hospital in Utah decided to change the rules. Instead of waiting for other clues to appear, they introduced a "universal scan" for every newborn baby admitted to the cardiac intensive care unit (CICU) who needed heart surgery before turning one month old.

Think of this like a full factory audit. Instead of just checking the engine because it's making noise, they read the entire instruction manual (the whole genome) for every single baby, regardless of whether they looked sick elsewhere. They used a powerful tool called Whole Genome Sequencing (WGS), which is like a super-magnifying glass that can spot tiny typos (single letters) and missing pages (large chunks of DNA) all at once.

What They Found
The study looked at 217 babies who underwent this new protocol. Here is what the "audit" revealed:

• The "Smoking Gun" (Diagnoses): About 1 in 10 babies (10.6%) had a clear error in their blueprint that explained why their heart was defective.

  • The Surprise: Almost half of these babies (48%) looked like they only had a heart problem. If doctors had stuck to the old rules, they would have missed the genetic cause entirely.
  • The Syndromes: Many of these babies had syndromes (conditions where the heart issue is part of a larger pattern), such as 22q11.2 deletion syndrome or Williams syndrome.
  • The Isolated Cases: A few babies had heart defects caused by a single gene error with no other symptoms.

• The "Side Notes" (Other Findings): Another 8.8% of babies didn't have a cause for their heart defect, but the scan found something else important.

  • Some had a "partial diagnosis" (a genetic issue explaining other health concerns, like blood disorders).
  • Some had "secondary findings" (genetic risks for future conditions, like high cholesterol).
  • Some were found to be "carriers" (they carry a gene for a disease they won't get, but could pass to their own children).

• The Total Impact: In total, nearly 1 in 5 babies (19.4%) got a result that was medically useful, either solving the mystery of their heart defect or revealing other important health information.

How This Changed the Story for Families
Finding these errors wasn't just about labeling the problem; it changed how the families and doctors moved forward:

1. Better Maps for the Journey: Once a diagnosis was made, the medical team knew exactly what other "machines" in the factory might need checking. They sent families to the right specialists (like eye doctors, hearing experts, or brain specialists) before problems even started.
2. Hard Choices Made Clear: For six families, the genetic diagnosis revealed that the baby's condition was so severe that surgery wouldn't help. This gave them the clarity to make the difficult decision to focus on comfort care rather than risky surgeries.
3. Family Planning: For families who received a diagnosis, they could learn if the error was a "one-time accident" (de novo) or if it was inherited. This helped them understand the chances of having another child with the same condition.

The Bottom Line
This study shows that reading the entire genetic instruction manual for every baby with a heart defect is a powerful strategy. It catches problems that the old "wait-and-see" approach missed, especially in babies who looked healthy everywhere else. By finding these answers early, doctors can stop guessing, stop unnecessary tests, and give families a clear plan for their child's future.

Technical Summary

Technical Summary: Universal Whole-Genome Sequencing in the Cardiac Intensive Care Unit

Problem Statement
Congenital heart defects (CHD) are a leading cause of neonatal mortality, with 20–40% of cases attributed to identifiable genetic causes. While 20% of CHD cases present with extracardiac anomalies, 80% appear isolated. Historically, genetic testing in CHD has been reserved for patients with extracardiac features or specific lesions associated with high genetic risk. However, studies indicate that relying solely on extracardiac anomalies misses approximately 13.4% of patients with an identifiable genetic cause. Furthermore, while Whole-Genome Sequencing (WGS) offers superior diagnostic yield over Chromosomal Microarray (CMA) by detecting copy number variants (CNVs) and single-nucleotide variants (SNVs) simultaneously, its utility in a broad, unselected neonatal population undergoing cardiac surgery remains under-evaluated. Existing studies often focus on selected cohorts referred for genetic counseling rather than universal testing strategies.

Methodology
This study is a retrospective chart review conducted at Primary Children's Hospital (University of Utah) from September 2023 to February 2026. The institution implemented a universal genetic testing protocol for all neonates (<30 days of life) admitted to the Cardiac Intensive Care Unit (CICU) for cardiac surgery.

• Cohort: 217 neonates with CHD. Patients with known or highly suspected aneuploidy (e.g., Trisomy 13, 18, 21) based on prenatal screening were excluded.
• Testing Protocol: The default was non-rapid, proband-only WGS. Trio WGS was offered for families with a history of CHD. Rapid duo/trio or proband-only WGS was utilized for acutely ill patients, those with extracardiac anomalies, or when surgical decision-making required immediate results.
• Data Analysis: Clinical data were abstracted from electronic medical records. Variants were classified according to American College of Medical Genetics (ACMG) guidelines. A diagnosis was considered "causative" if a pathogenic or likely pathogenic variant explained the CHD etiology. "Partial diagnoses" explained non-cardiac phenotypes, and "secondary findings" included actionable non-cardiac conditions. Variants of Uncertain Significance (VUS) were reviewed for phenotypic concordance; only those with strong clinical correlation informing management were counted as diagnostic.

Key Results

• Overall Diagnostic Yield: 19.4% of patients (n=42) had clinically relevant variants identified.
  • Causative Diagnoses: 23 patients (10.6%) received a genetic diagnosis causative of their CHD. This included 20 syndromic conditions (e.g., 22q11.2 Deletion, Williams Syndrome, Alagille Syndrome) and 3 non-syndromic conditions (variants in FLT4, NOTCH1, ZFPM2).
  • Non-Diagnostic but Clinically Relevant: 19 patients (8.8%) had results that were clinically relevant but not causative of the CHD. This included partial diagnoses (e.g., HBB, COL4A1), secondary findings (e.g., LDLR, MYH7), and carrier status.
• Phenotype-Based Yield:
  • Among patients with isolated CHD (no extracardiac anomalies at testing, n=170), the diagnostic yield for causative conditions was 6.5% (n=11).
  • Among patients with extracardiac anomalies at the time of testing (n=47), the diagnostic yield was 25.5% (n=12).
  • The difference in yield between isolated and non-isolated groups was statistically significant (p < 0.001).
• Impact on Clinical Management:
  • All 23 patients with a causative diagnosis received additional specialist referrals (e.g., ophthalmology, audiology, endocrinology, neurology) and targeted imaging (renal ultrasounds, MRIs).
  • Care Redirection: 26% of families with a genetic diagnosis (6 families) utilized the results to inform decisions regarding the continuation of care, redirecting to a comfort care pathway. Diagnoses influencing these decisions included Alveolar Capillary Dysplasia, Zellweger Syndrome, and Partial Trisomy 13/Wolff-Hirschhorn Syndrome.
  • Parental Testing: 69.6% of families with a diagnosis underwent parental testing to determine inheritance patterns (de novo vs. inherited).
• Comparison to Prior Protocols: The authors estimate that 35% (8 of 23) of the diagnoses identified by this universal WGS protocol would not have been identified under the institution's previous lesion-based testing approach, which typically reserved testing for specific high-risk lesions.

Significance and Claims
The paper claims that implementing a universal WGS protocol for neonates with CHD in the CICU significantly increases the number of patients receiving a timely genetic diagnosis, including those with ostensibly isolated heart defects. The study demonstrates that:

1. Early Identification: Universal testing identifies genetic conditions before extracardiac features become clinically apparent, allowing for proactive surveillance and management.
2. Clinical Utility: Genetic diagnoses directly inform surgical decision-making, specialist referrals, and, in severe cases, end-of-life care discussions.
3. Equity and Bias Reduction: By testing all eligible patients regardless of phenotype, the protocol eliminates clinician bias regarding who "looks" syndromic, promoting equity in access to genetic diagnostics.
4. Future Utility: The study highlights the long-term value of WGS data, which can be reanalyzed as a patient's phenotype evolves, unlike static testing modalities.

The authors conclude that universal WGS is a valuable first-tier test for neonates with CHD, providing actionable data that improves clinical care, recurrence risk counseling, and family support, even in cases where the heart defect appears isolated.