What is the role of a comprehensive genomic panel (CGP) in diagnosing and managing patients with suspected genetic disorders, particularly those with a family history of complex or rare conditions?

Comprehensive Genomic Panel in Genetic Disorder Diagnosis and Management

Comprehensive genomic panels (CGP), including exome sequencing (ES) and genome sequencing (GS), should serve as first- or second-tier testing for patients with unexplained developmental delay, intellectual disability, congenital anomalies, or complex rare conditions when targeted testing is non-diagnostic or when the phenotype suggests genetic heterogeneity. 1

Clinical Indications for Comprehensive Genomic Testing

First-Tier Testing Scenarios

ES/GS should be considered as first-tier testing in the following situations: 1

• Patients with unexplained developmental delay/intellectual disability or congenital anomalies where the phenotype does not point to a specific genetic syndrome 1
• Parental consanguinity is present, which increases likelihood of autosomal recessive conditions 1
• Genetically heterogeneous conditions where multiple genes could explain the presentation 1
• Critically ill infants requiring rapid diagnosis to guide immediate management 2

Second-Tier Testing Scenarios

CGP should follow targeted testing when: 1

• Targeted gene panels or chromosomal microarray analysis are non-diagnostic but clinical suspicion for genetic etiology remains high 1
• The patient's phenotype has evolved or is atypical for the initially suspected condition 1
• Clinical urgency exists for diagnosis that impacts family planning or at-risk relatives 1

Algorithmic Approach to Test Selection

Step 1: Clinical Evaluation Requirements

Before ordering CGP, clinicians must: 1, 3, 4

• Perform three-generation family history with pedigree analysis documenting specific cancers, ages of onset, consanguinity, and ethnic background 1, 3
• Complete genetics-focused physical examination looking for dysmorphic features, growth parameters (>2.5 SD from mean), skin findings (café-au-lait macules, hypopigmentation), and organ system anomalies 1, 4
• Document prior genetic testing results to avoid redundant testing and inform variant interpretation 1

Step 2: Determine Appropriate Test Type

Use targeted gene panels when: 1

• The phenotype is specific to a known genetic condition (e.g., Noonan syndrome, BRCA-related breast cancer) where optimized panels exist with higher sensitivity than ES/GS 1
• The number of candidate genes is limited (typically <10-20 genes) 1

Use chromosomal microarray before ES/GS when: 1

• The phenotype is non-specific and family history does not suggest X-linked or autosomal recessive inheritance 1
• Copy number variant detection is the primary concern until GS platforms achieve equivalent CNV sensitivity 1

Proceed directly to ES/GS when: 1, 2

• Parental consanguinity exists 1
• Rapid diagnosis is needed (trio analysis can provide results in days) 2
• The phenotype suggests multiple possible genetic etiologies 1, 2

Panel Size Considerations and Trade-offs

Small vs. Large Panels

Smaller, focused panels offer: 1

• Higher specificity with fewer variants of uncertain significance (VUS) 1
• Lower likelihood of secondary findings unrelated to clinical presentation 1
• Clearer clinical actionability for identified variants 1

Larger panels and ES/GS provide: 1, 2

• Higher sensitivity for detecting pathogenic variants when family history is incomplete or unavailable 1, 2
• Ability to detect unexpected diagnoses in genes not suggested by phenotype alone 1, 2
• Detection of structural variants, non-coding variants, and repeat expansions (GS only) that ES and panels miss 2, 5

Critical caveat: Larger panels generate more VUS (variants of uncertain significance) and findings of unclear clinical actionability, increasing risk of patient anxiety and inappropriate interventions including unnecessary surgeries. 1

Secondary Findings Management

ACMG Recommendations

The ACMG recommends reporting pathogenic variants in 59 medically actionable genes (updated from original 56) when ES/GS is performed, regardless of patient age or indication. 1

However, significant controversy exists: 1

• Arguments for reporting: Identifies treatable conditions before symptoms develop, particularly for cancer predisposition and cardiac conditions 1
• Arguments against: Lacks evidence for clinical utility in asymptomatic individuals, represents opportunistic screening without established benefit, and may identify findings not actionable in childhood 1

Best practice: Provide pre-test counseling allowing patients/families to opt out of secondary findings, particularly for pediatric testing where predictive information may not benefit the child. 1

Diagnostic Yield Expectations

ES/GS diagnostic rates vary by indication: 1, 2, 6

• Developmental delay/intellectual disability with congenital anomalies: 23-30% diagnostic yield 1, 6
• Autism spectrum disorder: 10-15% when prior testing (CMA, Fragile X) is negative 1
• Critically ill infants: 40-50% with rapid trio sequencing 2
• Prior negative exome testing: minimal additional yield from GS unless structural variants or non-coding variants suspected 6

GS advantages over ES include: 2, 5

• Detection of deep intronic variants affecting splicing 5
• Identification of repeat expansions (e.g., RFC1 gene) 5
• Discovery of retrotransposon insertions and complex structural variants 5
• More uniform coverage across the genome 2

Provider Qualifications

Clinicians ordering CGP must demonstrate: 1, 3, 4

• Ability to perform basic clinical genetics evaluation including family history and genetics-focused examination 1, 3
• Competence in determining whether CGP is appropriate versus other available tests 1, 3
• Capability to provide adequate pre-test counseling including informed consent for primary and secondary findings 1, 3
• Skills to interpret results and provide post-test counseling, or recognition of when to seek genetics professional input 1, 3

When to refer to genetics specialists: 3, 4

• Clinician lacks confidence in any of the above competencies 3
• Complex family history suggesting multiple genetic conditions 4
• VUS or findings of uncertain clinical significance requiring expert interpretation 1

Common Pitfalls to Avoid

Do not order CGP when: 1

• A specific syndrome is clinically diagnosed and targeted testing is more sensitive 1
• The patient lacks clinical features or family history suggesting genetic etiology—CGP is not appropriate for general screening 1
• Prior testing has not been reviewed—redundant testing wastes resources and may generate conflicting results 1

Avoid misinterpretation by: 1

• Recognizing that VUS are not pathogenic variants—they should not guide clinical management 1
• Understanding penetrance limitations—many identified variants have uncertain penetrance in asymptomatic individuals 1
• Consulting genetics professionals when results include moderate-penetrance genes or pleiotropic findings unrelated to presentation 1

Reanalysis and Long-term Management

Periodic reanalysis of negative CGP results improves diagnostic yield by 4-10% as new genes are discovered and variant interpretation improves. 1, 6

Reanalysis should occur: 1, 6

• When phenotype evolves or new clinical features emerge 1
• Every 12-24 months for unsolved cases with high suspicion for genetic etiology 6
• When new disease genes are added to clinical databases 6