What is an example of a metabolic disorder where whole exon sequencing changed the treatment plan?

Glycogen Storage Disease Type I: A Paradigm Case of Whole Exome Sequencing Changing Treatment

Glycogen Storage Disease Type I (GSD I) represents an exemplary metabolic disorder where whole exome sequencing fundamentally altered diagnostic and treatment approaches, particularly when standard targeted mutation analysis fails to identify both pathogenic variants in mixed populations.

Clinical Context and Diagnostic Challenge

GSD I is an autosomal recessive metabolic disorder caused by mutations in either the G6PC gene (GSD Ia) or SLC37A4 gene (GSD Ib), presenting with:

• Hypoglycemia, lactic acidosis, hypercholesterolemia, hypertriglyceridemia, and hyperuricemia 1
• Neutropenia (particularly suggestive of GSD Ib, though can occur in GSD Ia) 1
• Variable presentation that may not always include all classic biochemical features 1

How WES Changed the Treatment Plan

The Diagnostic Gap

In mixed populations like the United States, standard sequence analysis of G6PC detects mutations in only ~94% of clinically and enzymatically confirmed GSD Ia cases, leaving approximately 6% of patients with only one identified mutation despite clear disease 1. This diagnostic gap occurs because:

• Large deletion mutations of one or more exons, introns, or the whole gene are unlikely to be detected by standard sequencing methods 1
• Promoter region mutations are missed by standard sequence analysis 1
• Similar detection limitations exist for SLC37A4 in GSD Ib 1

WES as the Solution

When targeted gene sequencing identifies only one mutation in a patient with clinically confirmed GSD I, whole exome sequencing can detect:

• Large multiexon deletions/duplications that standard sequencing misses 1
• Novel mutations in unexpected regions of the causative genes 1
• Mutations in other metabolic disorder genes if the initial clinical diagnosis was incorrect 1

Treatment Impact

The identification of the second pathogenic variant through WES:

• Confirms the definitive genetic diagnosis, allowing appropriate genetic counseling for family planning 1
• Enables precise subtype classification (GSD Ia vs Ib), which is critical because GSD Ib requires additional monitoring and treatment for neutropenia and inflammatory bowel disease complications 1
• Guides specific therapeutic interventions, including consideration for liver transplantation in severe cases 1
• Allows for targeted family screening once both mutations are identified 1

Practical Algorithm for Using WES in GSD I

Step 1: Initial Biochemical Screening

• Document hypoglycemia, lactic acidosis, hypercholesterolemia, hypertriglyceridemia, hyperuricemia 1
• Check neutrophil counts (neutropenia suggests GSD Ib) 1

Step 2: First-Line Genetic Testing

• Perform complete G6PC sequencing first (unless neutropenia is present, then start with SLC37A4) 1
• In homogeneous ethnic populations, targeted mutation analysis may identify up to 100% of cases 1

Step 3: WES Indication

• If only one mutation is identified in a patient with clinical and biochemical features consistent with GSD I 1
• If enzymatic confirmation is available (deficient G6Pase activity in liver biopsy) but genetic testing is incomplete 1

Step 4: Post-WES Validation

• Confirm identified variants with Sanger sequencing 1
• Perform deletion/duplication analysis using quantitative PCR, multiplex ligation-dependent probe amplification, or targeted array if large structural variants are suspected 1

Common Pitfalls and How to Avoid Them

Pitfall 1: Assuming negative results mean no genetic cause

• In mixed populations, standard sequencing may miss 6% of pathogenic variants 1
• Always consider WES when clinical phenotype strongly suggests GSD I but genetic testing is incomplete 1

Pitfall 2: Not distinguishing GSD Ia from Ib

• Neutropenia may be absent in GSD Ib during the first years of life 1
• Complete genetic characterization through WES prevents misclassification and ensures appropriate monitoring for inflammatory complications 1

Pitfall 3: Overlooking other metabolic disorders

• Approximately 30% of patients with a PFIC (progressive familial intrahepatic cholestasis) phenotype have no mutations in known genes 1
• WES can identify novel genes or alternative diagnoses when the initial clinical suspicion is incorrect 1

Broader Context: WES in Metabolic Disorders

WES is particularly valuable in metabolic disorders when:

• Multiple genetic loci could explain the syndrome, making it more cost-effective than sequential single-gene testing 2, 3
• Clinical phenotype alone cannot identify the specific genetic defect 3
• Standard targeted testing fails to identify all pathogenic variants in a clinically confirmed case 1

The technology detects single-nucleotide variants, small insertions/deletions, and copy number variants 2, and should be performed in CLIA/CAP-certified laboratories with review by qualified clinical molecular geneticists 2, 3.