The targeted assay detects X-linked dystonia-parkinsonism cases that standard sequencing methods have missed.
Scientists at Brigham and Women’s Hospital and Harvard Medical School have developed a targeted genetic test to improve diagnosis for X-linked dystonia-parkinsonism (XDP), a rare movement disorder that primarily affects men of Filipino ancestry.
The research was presented at the Association for Molecular Pathology 2025 Annual Meeting & Expo.
XDP causes symptoms similar to Parkinson’s disease, including muscle spasms, tremors, and abnormal postures and movements. The condition usually presents initially in the face, jaw, or neck, progressing to affect speech, walking, and independent living. Early recognition helps patients access support, plan care, and receive appropriate genetic counseling.
Detecting Subtle DNA Changes
Several neurological disorders share similar symptoms, making accurate XDP diagnosis difficult and slow. An abnormal region in the TAF1 gene causes the disease, containing subtle DNA changes known as disease-specific single nucleotide changes (DSCs) that are not routinely analyzed by commercial gene panels or whole-exome sequencing.
Eirini Christodoulou, PhD, clinical fellow in pathology at Harvard University and laboratory genetics and genomic fellow at Brigham and Women’s Hospital, led the study. Her team designed the test to sequence three key DSCs associated with XDP.
The researchers validated the test in eight patients already known to carry the mutation, seven people without the mutation, and three others suspected of having it. The test correctly identified all positive cases and led to proper diagnosis of the three suspected cases, two of whom had received negative results from standard genetic testing.
“Our test picked up cases that routine sequencing methods such as exome sequencing and panel testing have missed,” says Christodoulou in a release. “We need to identify these cases that would otherwise remain hidden and end diagnostic odysseys, particularly in patients whose symptoms overlap with other movement disorders.”
X-Linked Inheritance Pattern
X-linked diseases are caused by changes on the X chromosome and affect males disproportionately because they have only one X chromosome. Women have two X chromosomes, so if they inherit the mutation on one copy, the other copy can compensate. Most women are carriers and do not develop the full syndrome, although some may show mild symptoms.
No cure exists for XDP, but medications can help with movement and muscle symptoms. Some patients undergo deep-brain stimulation. Physical, speech, and occupational therapy are key components of patient care plans.
The XDP mutation, also known as Lubag disease, is believed to have arisen generations ago and is strongly linked to families from the Philippines island of Panay. Limited awareness among clinicians outside of Filipino communities contributes to underdiagnosis.
Custom Testing Required
In their study abstract, the authors wrote: “Including this testing as part of the diagnostic differential may increase the diagnosis rate in this population and reduce the costs associated with a diagnostic odyssey for these patients. Ordering providers need to be aware that currently only custom XDP-specific assays assess and report this disease haplotype. Therefore, this test should be ordered alongside other tests in individuals who are at high suspicion for this condition.”
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