Considering mitochondrial genomes in whole exome testing

Rare disease is individually uncommon but collectively affects millions worldwide and can present with neurodevelopmental concerns or complex multisystem findings that don’t fit a clear diagnostic pattern. Historically, multiple sequential genetic tests could not yield clear diagnostic answers for these complex conditions. However, with advances in technology over the last 2 decades, whole exome sequencing (WES) has become a standard diagnostic test for these patients.

Clinical practice guidelines from the American College of Medical Genetics and Genomics (ACMG), American Academy of Pediatrics (AAP), and National Society of Genetic Counselors (NSGC) support early exome sequencing in children with unexplained developmental delay, epilepsy, or multisystem disease.^1,2 Exome sequencing is warranted in both the pediatric population and adult population, given that clinical presentations change or progress over time and may present differently at different ages.

One limitation in sequencing the whole exome of the nuclear genome is that it will miss some mitochondrial disorders, a subset of rare diseases that also present as complex, often multisystem phenotypes. In this regard, simultaneous analysis of nuclear and mitochondrial genomes improves diagnostic yield and can guide patient care.³

Mitochondrial disorders are a complex group of genetic conditions caused by impaired mitochondrial energy production. Mitochondria are organelles that have their own circular DNA.  Because mitochondria are present in nearly all tissues, mitochondrial dysfunction can affect multiple organ systems, particularly those with high energy demands such as the brain, heart, muscle, and liver. 

From a genetic perspective, mitochondrial disorders are unique. They can be caused by both nuclear DNA and mitochondrial DNA with some key differences: 

Clinical features in mitochondrial disorders are highly variable and may include developmental delay or regression, hypotonia, failure to thrive or poor feeding, seizures or episodic encephalopathy, cardiomyopathy, liver dysfunction, and sensorineural hearing loss or vision impairment. Since many of these symptoms overlap with more common pediatric conditions or with adult neurological conditions, diagnosis is frequently delayed or missed.^3,4

Identifying a molecular diagnosis can have a meaningful impact on families. Comprehensive genetic testing can

• Guide clinical management and surveillance 
• Clarify prognosis 
• Support family planning and recurrence risk counseling 
• Reduce unnecessary testing and invasive procedures (such as muscle biopsies)

Given the overlap in symptoms seen across multiple rare disease conditions, selecting the appropriate genetic test is critical. Unlike targeted gene panels that focus on a subset of genes, exome sequencing with mitochondrial analysis evaluates both nuclear and mitochondrial genomes simultaneously. The benefits of this complete approach can be life-changing to families. WES + mtDNA analysis has been documented to increase diagnostic yield compared to using WES alone. ³

Practical cues to consider exome sequencing with mtDNA analysis include 

• Developmental delay or regression with neurologic features 
• Multisystem involvement (neurologic, cardiac, muscular, hepatic, or metabolic) 
• Unexplained epilepsy or episodic decompensation that cannot be explained by routine medical diagnostics, such as brain MRIs or standard EEG tests.

With the constant advancements in genetic diagnostics, it is important to reflect on what drives this pursuit for an answer­—the rare disease patient. A comprehensive genetic test can reduce uncertainty, end a diagnostic odyssey, streamline clinical care, and more.  

To learn more about mitochondrial disorders, please visit support groups such as 

• https://umdf.org/
• https://www.curemito.org
• https://www.mitoaction.org/

1. Manickam K, McClain MR, Demmer LA, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. Nov 2021;23(11):2029-2037. doi:10.1038/s41436-021-01242-6 
2. Rodan LH, Stoler J, Chen E, Geleske T. Genetic Evaluation of the Child With Intellectual Disability or Global Developmental Delay: Clinical Report. Pediatrics. Jul 1 2025;156(1)doi:10.1542/peds.2025-072219 
3. Poole OV, Pizzamiglio C, Murphy D, et al. Mitochondrial DNA Analysis from Exome Sequencing Data Improves Diagnostic Yield in Neurological Diseases. Ann Neurol. Jun 2021;89(6):1240-1247. doi:10.1002/ana.26063 
4. Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. Sep 2015;17(9):689-701. doi:10.1038/gim.2014.177