Are there other cases where whole exon sequencing significantly alters the treatment plan?

Whole Exome Sequencing Significantly Alters Treatment Plans in Multiple Clinical Scenarios

Yes, whole exome sequencing (WES) significantly alters treatment plans in several critical clinical scenarios beyond the initial diagnostic context, particularly in metabolic disorders, muscular dystrophies, and oncology where genetic subtyping directly determines therapeutic interventions.

Metabolic Disorders Where WES Changes Management

Glycogen Storage Disease Type I (GSD I)

WES is essential when standard sequencing fails to identify the second pathogenic variant, as this genetic confirmation enables definitive subtype classification and guides specific therapeutic interventions including consideration for liver transplantation in severe cases 1.

• Standard G6PC sequence analysis detects mutations in only ~94% of clinically confirmed GSD Ia cases, leaving 6% with incomplete genetic diagnosis 1
• WES detects large multiexon deletions/duplications and novel mutations in unexpected gene regions that standard sequencing misses 1
• The identification of compound heterozygous mutations through WES (such as c.G248A and c.G648T variants) directly enables targeted interventions like growth hormone therapy combined with corn starch treatment 2
• WES can identify alternative diagnoses when initial clinical suspicion is incorrect, completely redirecting management 1

McArdle Disease (Glycogen Storage Disease Type V)

• WES identifies biallelic PYGM variants in adults with atypical presentations, including late-onset disease in former athletes 3
• Detection of novel missense variants (such as p.Asp694Glu) in trans with known pathogenic variants confirms diagnosis and explains variable phenotypes 3
• This genetic confirmation prevents unnecessary muscle biopsies and invasive enzyme testing in some cases 3

Broader Metabolic Disorder Applications

WES using customized gene panels or clinical exome sequencing detects pathogenic mutations not only in suspected GSD genes but also in genes with overlapping phenotypes (ALDOB, LIPA, CPT2), fundamentally changing the treatment approach from glycogen-focused to disorder-specific therapy 4.

• Massive parallel sequencing identified 22 mutations (11 novel) in GSD-associated genes across 23 patients 4
• Five patients initially suspected of having GSD were found to have mutations in non-GSD genes causing hepatic, muscular, or cardiac dysfunction, completely redirecting their treatment plans 4

Muscular Dystrophies Requiring Genetic Subtyping

Sarcoglycanopathy and Calpainopathy

WES simultaneously evaluates all relevant genes in genetically heterogeneous limb-girdle muscular dystrophies, making it more cost-effective than sequential single-gene testing and enabling subtype-specific therapeutic decisions 5.

• These conditions have multiple genetic loci that can explain the syndrome, making WES the optimal first-line approach 5
• WES detects single-nucleotide variants, small insertions/deletions, and copy number variants across all sarcoglycan and calpain genes simultaneously 5
• Genetic subtype identification determines eligibility for emerging gene therapies and clinical trials specific to each mutation 5

Congenital Myasthenia Syndromes

WES is the recommended diagnostic approach for congenital myasthenia when clinical phenotype alone cannot identify the specific genetic defect, as different genetic subtypes require completely different treatment strategies (acetylcholinesterase inhibitors vs. ephedrine vs. albuterol) 6.

• WES is more cost-effective than sequential testing of the multiple genes causing congenital myasthenia 6
• Must be performed in CLIA/CAP-certified laboratories with qualified clinical molecular geneticist review 6

Oncology Applications with Direct Treatment Implications

Non-Small Cell Lung Cancer

Complete sequencing of EGFR exons 18-21 by NGS is strongly recommended over allele-specific methods, as identification of specific mutations (exon 19 deletions, L858R, exon 20 insertions) determines which generation of tyrosine kinase inhibitor to use 7.

• Exon 20 insertions are resistant to first- through third-generation EGFR TKIs but sensitive to emerging agents, requiring precise mutation identification 7
• RNA-based NGS identifies MET exon 14 skipping mutations that DNA sequencing may miss, qualifying patients for MET kinase inhibitors 7
• Detection of ALK, ROS1, NTRK1-3, RET, and NRG1 fusions through RNA-based NGS determines eligibility for multiple approved targeted therapies 7

Myelodysplastic Syndrome

NGS panel testing identifies mutations in genes like SF3B1, TP53, RUNX1, and ASXL1 that directly predict treatment response to specific therapies and determine transplant timing 7.

• SF3B1 mutations (33% of cases) predict longer survival and low leukemic evolution risk, allowing less aggressive management 7
• TP53 mutations (particularly in del(5q) patients at 17%) predict poor outcomes and necessitate early allogeneic transplant consideration 7
• Mutation burden affects erythropoietin response: 74% response with ≤2 mutations versus 46% with >2 mutations 7

Critical Caveats and Implementation Considerations

Technical Limitations

• WES may miss complex structural variants or non-coding regulatory mutations that require whole genome sequencing 5
• Sequencing depth and gene coverage significantly influence diagnostic yield—inadequate depth produces false negatives 5, 6
• Variants of uncertain significance create interpretation challenges and may require functional studies 5

Validation Requirements

All clinically actionable variants identified by WES must be confirmed by Sanger sequencing before making treatment decisions 5.

• Different bioinformatics pipelines can produce discordant results 5
• Multiple variant calling tools with rigorous filtering should be used to minimize false positives 5, 6

Pre-Test Considerations

• If chromosomal abnormalities are suspected clinically, array comparative genomic hybridization should be performed first, as WES routinely misses these 6
• Proper clinical phenotyping and family history are essential for accurate variant interpretation 5
• For germline variant discrimination in oncology, paired tumor-normal sequencing is critical 7