Neurogenetics Reference Lab · Teaching Example
- Panel
- Mitochondrial Disease Panel (310 nuclear-encoded genes)
- Report ID
- TEACH-0002
- Indication
- Childhood-onset progressive ataxia, seizures, hepatopathy; suspected mtDNA depletion syndrome.
- Specimen
- Peripheral blood, EDTA · Received 2026-03-19
- Reported
- 2026-04-08
- Methodology
- Targeted capture NGS, mean depth 220×. Parental Sanger confirmed for phase. mtDNA sequencing performed separately.
Patient (anonymized teaching example)
Age 4 years · Male · Northern European ancestry
Clinical: Onset at 18 months with developmental regression, ataxia, refractory focal seizures, and transaminitis. Brain MRI shows occipital lobe T2 hyperintensities. CSF lactate elevated.
Reportable Variants
| Gene | Variant | Zygosity | Condition (Mode) | Origin | Classification |
|---|---|---|---|---|---|
in trans with row 2 | |||||
in trans with row 1 |
Interpretation
Two pathogenic variants were detected in POLG: c.1399G>A (p.Ala467Thr), , and c.2243G>C (p.Trp748Ser), . is confirmed by parental segregation. The p.Ala467Thr/p.Trp748Ser genotype is one of the most well-characterized causes of POLG-related disease, with functional studies demonstrating severely reduced polymerase γ activity. This compound heterozygous result is diagnostic for autosomal recessive POLG-related mitochondrial DNA depletion syndrome.
Recommendations
- •Genetic counseling for the family. Each future pregnancy has a 25% recurrence risk; PGT-M is available.
- •AVOID valproate — POLG mutation carriers have a high risk of fatal hepatotoxicity with valproic acid (Alpers-Huttenlocher syndrome).
- •Liver function monitoring; consider hepatology referral.
- •Multidisciplinary mitochondrial-disease care: neurology, ophthalmology (PEO risk in older patients), audiology.
- •At-risk siblings: offer cascade testing.