Genetic Counselor’s Corner: The Value of an Accurate Genetic Diagnosis

A 5-year-old patient’s mother calls for an appointment to discuss her son’s “multiple genetic diseases.” She is anxious about the prognosis of his unique combination of conditions. No one has explained what this means for her son’s health.

Upon medical records review, you learn he has a diagnosis of Leigh syndrome. He experienced severe neurodevelopmental regression during a viral illness at 3 years old and had a brain MRI showing bilateral basal ganglia lesions. While making slow progress with intensive therapies, he has not yet returned to his pre-metabolic stroke baseline. Gene panel testing performed several years ago was unrevealing of a definitive diagnosis; while he had multiple variants reported in several genes, none were reported to cause his medical concerns.

The mother is very surprised when you tell her he has no clear genetic diagnosis, as she had thought he had every condition linked to genes listed on his genetic testing report. When you explain that newer genomic sequencing tests are now available that could identify the genetic basis of his disease, she agrees to clinical whole exome sequencing. This clinical diagnostic test simultaneously sequences all 20000-plus nuclear genes, including more than 90 genes in which mutations may cause Leigh syndrome, and 350-plus genes in which mutations may cause many different mitochondrial diseases. All 37 mitochondrial DNA (mtDNA) genes will also be sequenced, since mtDNA mutations can also cause mitochondrial disease in children. Following informed consent and insurance approval, blood samples are collected from the child and both parents, and trio-based exome sequencing is initiated.

Three months later, clinical exome sequencing results confirm the child’s genetic diagnosis. He has 2 pathogenic variants in a single gene, 1 inherited from each unaffected, carrier parent. Pathogenic variants in this gene were only recently recognized to cause Leigh syndrome and would not have been detected on his earlier gene panel. This genetic diagnosis will allow for tailored management and treatment, and also allow their son to be eligible for a growing number of emerging Leigh syndrome clinical treatment trials.

Now that they are empowered with clear genetic understanding of their child’s disease, you counsel them about familial recurrence risks and review the family’s reproductive options. Both parents are shocked to hear of the range of preimplantation and prenatal options to definitively determine if a future child would develop Leigh syndrome, and if so, to prevent the condition in that child. They cry when they reveal they had decided they did not want to have more children if there was a chance they would have the same serious condition. They will share this genetic diagnosis with family, so related adults can undergo carrier testing for the exact genetic mutation known to cause Leigh syndrome in their family.

Leigh syndrome is a common pediatric presentation of mitochondrial disease. Remarkably, 10 to 20 novel disease genes that cause mitochondrial disease continue to be discovered each year. Confirming causality of a given gene variant is essential, since all people have extensive genetic variation (>150000 variants per exome) that is confusing to families if they are left without help to interpret complex testing reports. Thus, it is vital the complex genetic testing process is properly explained to families both before and after testing, and used to optimize medical care and empower family members with effective patient management approaches and reproductive options.

References and suggested readings

Muraresku CC, McCormick EM, Falk MJ. Mitochondrial Disease: Advances in clinical diagnosis, management, therapeutic development, and preventative strategies. Curr Genet Med Rep. 2018;6(2):62-72.

McCormick EM, Muraresku CC, Falk MJ. Mitochondrial Genomics: A complex field now coming of age. Curr Genet Med Rep. 2018;6(2):52-61.