Diagnostic Yield of WES in Infantile HCM with Normal CMA: A Case of PTPN11-associated Noonan Syndrome

1. Clinical Presentation: The Diagnostic Odyssey

A 6-month-old male presented with feeding difficulties and failure to thrive. Echocardiography revealed severe hypertrophic cardiomyopathy (LVH) and mild pulmonary valve stenosis. Despite a strong clinical suspicion of Noonan syndrome, initial Chromosomal Microarray (CMA) was Normal.

While many diagnostic journeys stall here, the team proceeded with Whole Exome Sequencing (WES) based on the persistent syndromic phenotype.

2. The Diagnosis: Definitive Identification via WES

WES analysis identified a heterozygous missense variant, c.922A>G (p.Asn308Asp), in the PTPN11 gene, confirming Noonan Syndrome 1.

Subsequent cascade testing identified the same variant in his 5-year-old brother, who exhibited mild learning disabilities and subtle dysmorphism but no prior cardiac symptoms. This case highlights the Autosomal Dominant (AD) inheritance and phenotypic variability of RASopathies.

3. Clinical Action: Post-Diagnostic Precision Management

Molecular confirmation mandated a shift to a specialized surveillance program:

• Hematologic Surveillance (JMML): Initiated CBC monitoring every 3–6 months until age 5 to screen for Juvenile Myelomonocytic Leukemia (JMML).
• Growth Hormone (GH) Strategy: Established a monitoring protocol for GH therapy to balance growth needs against the risk of exacerbating myocardial hypertrophy.
• Coagulopathy Precautions: Pre-emptive screening for coagulation factors (e.g., Factor VIII) to mitigate surgical bleeding risks.

4. Pitfalls: The Risks of an Incomplete Diagnosis

Failure to pursue WES after a normal CMA would have resulted in:

• Iatrogenic Risks: Potential acceleration of HCM through unmonitored GH therapy.
• Familial Neglect: Leaving the sibling’s underlying risks (e.g., arrhythmia, SCD) unaddressed.
• Unforeseen Emergencies: Vulnerability to unrecognized leukemia or perioperative hemorrhages.

5. Evidence: The Clinical Imperative for WES

• Resolution Limits: CMA fails to detect SNVs/Indels that constitute >95% of Noonan syndrome cases.
• Superior Yield: In syndromic pediatric HCM, WES offers a diagnostic yield of up to 60%. (Circulation, 2021)
• Impact on Management: Molecular diagnosis alters clinical management in 25–50% of confirmed cases. (JAMA Pediatrics, 2020)

6. Essential Checklist for Pediatric Cardiologists

Order WES immediately if the following are present:

1. CMA/Karyotyping Normal: Clear structural cardiac defects with no cytogenetic explanation.
2. Extracardiac Features: Co-occurrence of dysmorphism or developmental delay.
3. Infantile-onset HCM: High probability of a genetic etiology in patients <1 year.
4. Family History: Unexplained early-onset heart disease or Sudden Cardiac Death (SCD).
5. Conduction System Abnormalities: HCM combined with pre-excitation (WPW) or AV blocks.

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[References]

1. Ingles, J., et al. (2021). “Genetic Testing for Inherited Cardiac Disease.” Circulation: Genomic and Precision Medicine. Link
2. Roberts, A. E., et al. (2013). “Noonan syndrome.” The Lancet. Link
3. Vatta, M., et al. (2020). “Evaluation of WES in Pediatric Cardiac Genetics.” JAMA Pediatrics. Link