My genetic test shows a deletion of exons 8 and 18; what does this indicate and how should I confirm and manage it?

Genetic Test Showing Deletion of Exons 8 and 18

You must immediately confirm this finding through a certified clinical laboratory using orthogonal testing methods, as the clinical significance depends entirely on which gene harbors these deletions—this could represent anything from a benign variant to a life-threatening hereditary condition requiring urgent intervention.

Immediate Confirmation Steps

Validation in a Certified Laboratory

• All positive genetic test results, especially from direct-to-consumer testing, must be validated in a CLIA-approved, ISO 15189 accredited, or equivalent certified molecular diagnostic laboratory 1.
• The confirmation testing should include:
  • Sequencing of the entire open reading frame with intron-exon boundaries 1
  • Copy number analysis of individual exons to detect deletions or duplications 1, 2
  • Orthogonal methods such as multiplex PCR, array comparative genomic hybridization (aCGH), or FISH to confirm the structural variant 2, 3

Critical Gene-Specific Considerations

The clinical implications vary dramatically based on which gene contains these deletions:

If in the GAA Gene (Acid Alpha-Glucosidase)

• Homozygous deletion of exon 18 in GAA causes infantile glycogen storage disease type II (Pompe disease), a life-threatening condition with virtual absence of enzyme activity 4.
• Exon 18 deletion is the most common mutation in this disease with an allele frequency of 0.13 among patients 5.
• The deletion causes degradation of the enzyme precursor in the endoplasmic reticulum or Golgi complex, leading to severe infantile presentation 4.
• Heterozygous carriers may have reduced enzyme activity but are typically asymptomatic 5.

If in the Dystrophin Gene

• Deletions of exons 8 and other exons account for >60% of Duchenne muscular dystrophy (DMD) mutations 6.
• Exon 8 is among the five most commonly deleted exons (8,19,45,47,51) that account for >70% of all DMD deletions 6.
• Males with dystrophin deletions develop progressive muscle weakness; females are typically carriers but may have mild symptoms 6.

If in CDH1 or CTNNA1 Genes

• Large deletions including exons are rare (<5% of pathogenic variants) but confer high risk for hereditary diffuse gastric cancer 1.
• Carriers have cumulative gastric cancer risk of 42-70% by age 80 in males and 33-56% in females 1.

Variant Interpretation Requirements

ACMG/AMP Guidelines Application

• Variant interpretation must follow ACMG/AMP guidelines with careful classification as pathogenic, likely pathogenic, VUS, likely benign, or benign 1.
• "Likely pathogenic" variants have only 90% likelihood of pathogenicity and may be reclassified 1.
• Variant allele frequency (VAF) alone is insufficient to confirm or exclude germline origin—tumor purity and other factors must be considered 1.

Database Consultation

• Review ClinVar and other curated databases at the time of interpretation to ensure sufficient support for pathogenicity 1.
• No single database represents an accurately curated compendium; manual curation is often required 1.

Family and Clinical Evaluation

Cascade Testing

• Offer cascade genetic testing to all first-degree relatives once a pathogenic variant is confirmed 7.
• Relatives who test negative for the family mutation can be discharged from surveillance but should seek reassessment if symptoms develop 7.

Three-Generation Pedigree

• Obtain a minimum three-generation family history to identify other potential cases and guide result interpretation 8.
• Document any family history of relevant cancers, muscle disorders, metabolic diseases, or early deaths 1.

Management Based on Gene Identity

If Cancer Predisposition Gene

• Initiate appropriate cancer surveillance protocols immediately for confirmed pathogenic variants 1, 7.
• Discuss risk-reducing surgery options with multidisciplinary team 1.

If Metabolic or Muscular Dystrophy Gene

• Refer to appropriate subspecialist (genetics, neurology, metabolism) for disease-specific management 4, 5, 6.
• Assess for enzyme replacement therapy eligibility if GAA gene affected 4.

Critical Pitfalls to Avoid

• Never assume a negative result excludes pathogenic variants—approximately 8-10% of germline pathogenic variants are missed on tumor testing 1.
• Do not rely on exome/genome sequencing depth of coverage for incidental findings as equivalent to targeted gene testing—areas of diminished coverage may miss deletions 1.
• Avoid testing family members for variants of unknown significance (VUS)—there is no indication for pre-symptomatic testing with VUS 1.
• Do not use in vitro or in silico functional assays alone to predict pathogenicity of missense variants without clinical validation 1.

Genetic Counseling Requirements

• Provide comprehensive genetic counseling before and after testing, covering implications for the patient and family, test limitations, and recurrence risks 8.
• Discuss autosomal dominant inheritance patterns where applicable and implications for reproductive planning 7, 8.
• Ensure informed consent explicitly covers risks, benefits, limitations, and implications for family members 8.