Case Studies

At four weeks of age, our patient was diagnosed with tonic-clonic seizures. At two years old, he had developmental delays in multiple areas. He also had difficulty swallowing, difficulty processing visual information (cortical visual impairment), low muscle tone (hypotonia), and a small head size relative to his body (relative microcephaly).

He had many previous genetic tests from other laboratories that were non-diagnostic. His tests included a chromosomal microarray analysis (CMA), a 250-gene epilepsy panel, whole exome sequencing, and mitochondrial genome testing.

His provider then ordered the comprehensive Genomic Unity^® Whole Genome Analysis.

Our analysis found a deletion in the CDKL5 gene that was not inherited (de novo). This deletion was about 2,100 base pairs and spanned one of the gene’s coding regions (exon 7). Importantly, the deletion was mosaic, found in about 40% of the data, meaning only about 40% of his cells had this deletion. This finding was too small for a CMA to find. Due to its location extending beyond exon 7 and into the gene’s non-coding regions (the introns), it was too difficult for a panel or exome sequencing to detect. 

The deletion causes CDKL5-related disorder, also called X-linked dominant developmental and epileptic encephalopathy, type 2. This provides diagnostic clarity for the patient and family, ending a years-long journey.

Though our patient had many previous genetic tests, this deletion in CDKL5 was not identified. This is likely because the deletion begins and ends outside of the coding portion of the gene (in the introns) and because it is mosaic – included in only a portion of his cells. These two characteristics make detection by other genetic tests extremely difficult or impossible. Whole genome data, using both coding and non-coding genetic information, showed this diagnostic finding.

At age seven, our patient noticed his leg muscles seemed to be getting weaker. By age 16, his symptoms had slowly worsened with significant muscle weakness and a loss of muscle mass. He also experienced other muscle-related symptoms, such as foot drop, curving of the spine (scoliosis), mild enlargement of his heart (left ventricular cardiac hypertrophy), and sensations of pain, tingling, or numbness in his hands or feet (neuropathy). A nerve conduction velocity test showed he likely had a form of demyelinating neuropathy.

Due to his symptoms, his providers started with tests from other laboratories including a targeted, 42-gene neuropathy panel and a 112-gene neuropathy and hereditary spastic paraplegia panel. Both were non-diagnostic.

His provider then ordered the comprehensive Genomic Unity^® Whole Genome Analysis.

Two different types of genetic findings were reported in the FXN gene. One was a tandem repeat of DNA (from his father) and the other was a pathogenic sequence variant (from his mother). This provided a diagnosis of Friedreich’s ataxia, as well as family-planning information for the parents.

Our whole genome analysis method allows us to analyze multiple genes and variants that cause a disorder, all at once. The typical work-up for Friedreich’s ataxia likely would have required two different tests, two samples, and multiple office visits. Our testing simplified and sped up his time to find this diagnosis, shortening the time to start strategies to manage his condition.