What is the interpretation and recommended management plan for a whole exome sequencing (WES) report?

Interpretation and Management of Whole Exome Sequencing Reports

Whole exome sequencing (WES) reports require systematic interpretation by the ordering clinician who must contextualize findings in light of the patient's personal and family history, physical examination, and clinical phenotype, with consultation from a clinical geneticist when appropriate. 1

Understanding WES Report Components

Primary Findings

• Primary findings address the specific clinical indication for which WES was ordered (e.g., undiagnosed rare disease, developmental disorder, specific phenotype) 1
• The diagnostic yield of WES is approximately 28.8% overall, with higher yields (31%) when trio analysis (proband plus two parents) is performed versus proband-only testing (23.6%) 2
• Diagnostic rates vary significantly by clinical indication: hearing disorders (55%), vision disorders (47%), skeletal muscle disorders (40%), skeletal system disorders (39%), multiple congenital anomalies (36%), and central nervous system disorders (31%) 2

Secondary/Incidental Findings

• Laboratories must actively search for and report pathogenic variants in ACMG-recommended genes regardless of the primary indication for sequencing 1
• These findings occur in approximately 6.2% of cases and involve medically actionable conditions where preventive measures or treatments are available 2
• Secondary findings should be reported for all ages and for any constitutional (germline) tissue sequencing, including the normal sample in tumor-normal analyses 1

Critical Interpretation Framework

Variant Classification

Only report variants classified as "pathogenic" or "likely pathogenic" based on established ACMG criteria 1:

• Known pathogenic (KP): Previously reported variants that are recognized causes of the disorder
• Expected pathogenic (EP): Previously unreported variants of a type expected to cause the disorder
• Variants of uncertain significance should generally not be reported as incidental findings given the low prior probability of disease 1

Technical Limitations to Communicate

A negative WES report does not guarantee absence of pathogenic variants due to several technical limitations 1:

• Coverage gaps may exist in genes examined for secondary findings that would be filled by Sanger sequencing if tested as a primary indication
• WES has limited reliability for detecting structural variants, copy number variations, repeat expansions, and translocations 1
• Depth of coverage for incidental findings may not equal that of primary molecular testing 1

Recommended Management Algorithm

Step 1: Pre-Test Responsibilities

• Discuss the possibility of incidental findings with patients before ordering WES 1
• Explain that secondary findings will be reported and cannot be opted out of for the minimum ACMG gene list 1
• Ensure patients understand basic attributes and limitations of clinical sequencing 1

Step 2: Report Review and Validation

• Verify that reported variants have sufficient literature and database support for pathogenicity 1
• Recognize that significant manual curation is required as no single curated database of pathogenic variants exists 1
• Confirm variant classification meets ACMG pathogenicity criteria 1

Step 3: Clinical Contextualization

Re-evaluate the patient's personal and family history in light of any positive findings 1:

• Assess whether findings explain current symptoms or predict future disease risk
• Consider phenotypic overlap, as 7% of diagnoses involve dual Mendelian conditions creating blended phenotypes 3
• Note that 61.4% of autosomal dominant diagnoses result from de novo mutations, making family history less predictive 3

Step 4: Genetic Counseling Consultation

Consult a clinical geneticist for 1:

• Ordering decisions in complex cases
• Interpreting genomic results
• Communicating findings to patients and families
• Determining surveillance or intervention strategies for at-risk individuals

Step 5: Family Implications

• Evaluate implications for family members when pathogenic variants are identified 1
• Consider cascade testing for at-risk relatives when medically actionable findings are discovered
• Provide appropriate genetic counseling regarding recurrence risks 3

Key Clinical Pitfalls to Avoid

Misinterpretation of Negative Results

• Never interpret a negative WES report as definitive exclusion of genetic disease 1
• Technical limitations mean pathogenic variants may be missed, particularly structural variants and repeat expansions 1

Overlooking Candidate Genes

• In 24.2% of cases, candidate genes are reported that may later be reclassified as definitive diagnoses 2
• Maintain follow-up for periodic re-analysis as new evidence emerges 1

Age-Related Considerations

• Diagnostic yield is higher in younger adults (23.9% for ages 18-30) compared to those over 30 years (10.4%) 3
• Secondary findings should be reported regardless of patient age, including children 1

Family History Dependence

• Do not rely solely on family history to predict diagnostic yield, as de novo mutations are common 3
• Absence of family history does not reduce the likelihood of finding pathogenic variants 3

Ongoing Management

• Annual updates of the ACMG secondary findings gene list should be monitored and applied to previous cases when appropriate 1
• Periodic re-analysis of negative cases may be warranted as new disease genes and variant interpretations emerge 2
• Document all findings, interpretations, and management decisions thoroughly in the medical record 1