case_images: PMC10902455_01
case_images: EpiSign  DNA methylation analysis of peripheral blood from a proband. (A) Hierarchical clustering and (B) multidimensional scaling plots indicate that the patient (red) has a DNA methylation signature similar to subjects with a confirmed Dystonia 28 (DYT28) episignature (blue) and distinct from controls (green). Each row of the heatmap represents one CpG probe on the DNA methylation array, and each column represents one individual's sample. The heatmap color scale from blue to red represents the DNA methylation level (beta value) from 0 (no methylation) to 1 (fully methylated). (C) MVP score, a multiclass supervised classification system capable of discerning between multiple episignatures by generating a probability score for each episignature. The elevated patient MVP score for DYT28 compared to other syndromes suggests an episignature concordant with the DYT28 reference signature.
case_images: fgene-15-1346044-g001.jpg
case_images: PMC10902455_01_fgene-15-1346044-g001.jpg
case_images: F1
case_images: The episignature detected for this patient was concordant with the methylation profile observed in patients with Dystonia 28, Childhood-onset syndrome, including Euclidean clustering (Figure 1A) and multidimensional scaling (Figure 1B) consistent with Dystonia 28-specific methylation changes. Additionally, the Methylation Variant Pathogenicity (MVP) score for this patient was positive for Dystonia 28, resulting in a conclusive high-confidence positive result for the Dystonia 28 methylation signature (Figure 1C).
case_images: PMC10902455_02
case_images: Timeline of the patient being followed at the Medical Genetics Clinic in New Brunswick. Patient's initial visit consisted in offering a metabolic workup and a DNA sample was collected for future investigations. Patient was then enrolled in the Episign study. Results came back positive with identification of Dystonia-28. KMT2B single gene sequencing was thus requested and as expected, KMT2B pathogenic variant was confirmed. At the time of the follow-up visit, no dystonia was present in the patient. Recommendations were given to treat possible future manifestations of dystonia onset as well as surveillance, and a follow-up in neurology.
case_images: fgene-15-1346044-g002.jpg
case_images: PMC10902455_02_fgene-15-1346044-g002.jpg
case_images: F2
case_images: During the most recent follow-up appointment, the patient, who was now 5 years old, had experienced three episodes of seizures since the initial evaluation (Figure 2). At this follow-up evaluation, the patient still did not present dystonic features and did not yet present spasticity or myoclonus; however, during the physical exam, an abnormal gait with slight tendency for toe walking and stiffness was noticed on the patient's right lower extremity (Figure 2). The patient was referred to a pediatric neurologist for a complete detailed neurologic examination and for surveillance and follow-ups in the event of later dystonia onset (Figure 2).