Cascade testing in mitochondrial diseases: a cross-sectional retrospective study.

Background: Cascade testing can offer improved surveillance and timely introduction of clinical management for the at-risk biological relatives. Data on cascade testing and costs in mitochondrial diseases are lacking. To address this gap, we performed a cross-sectional retrospective study to provide a framework for cascade testing in mitochondrial diseases, to estimate the eligibility versus real-time uptake of cascade testing and to evaluate the cost of the genetic diagnosis of index cases and the cost of predictive cascade testing.

Methods: Data was collected through retrospective chart review. The variant inheritance pattern guided the identification of eligible first-degree relatives: (i) Males with mitochondrial DNA (mtDNA) single nucleotide variants (SNVs) - siblings and mothers. (ii) Females with mtDNA SNVs - siblings, mothers and offspring. (iii) Autosomal Dominant (AD) nuclear DNA (nDNA) variants - siblings, offspring and both parents. (iv) Autosomal Recessive (AR) nDNA variants - siblings.

Results: We recruited 99 participants from the Adult Mitochondrial Disease Clinic in Sydney. The uptake of cascade testing was 55.2% in the mtDNA group, 55.8% in the AD nDNA group and 0% in AR nDNA group. Of the relatives in mtDNA group who underwent cascade testing, 65.4% were symptomatic, 20.5% were oligosymptomatic and 14.1% were asymptomatic. The mean cost of cascade testing for eligible first-degree relatives (mtDNA group: $694.7; AD nDNA group: $899.1) was lower than the corresponding index case (mtDNA group: $4578.4; AD nDNA group: $5715.1) (p < 0.001).

Conclusion: The demand for cascade testing in mitochondrial diseases varies according to the genotype and inheritance pattern. The real-time uptake of cascade testing can be influenced by multiple factors. Early diagnosis of at-risk biological relatives of index cases through cascade testing, confirms the diagnosis in those who are symptomatic and facilitates implementation of surveillance strategies and clinical care at an early stage of the disease.