Objective: To investigate the genetic cause in patients with rare movement disorders by utilizing optical genome mapping (OGM).

Background: OGM is a genetic imaging technique, allowing detection of structural variants such as repeat expansions and copy number variants, also in hard-to-sequence regions, with a lower detection limit of about 500 base pairs (bp). This technique may help to unravel the genetic cause in patients with a movement disorder and a previously unremarkable genetic workup.

Method: Sixteen patients with an assumed genetic disorder and unremarkable exome sequencing were included in the study. Medical and family history were collected, and a neurological examination was performed. Ultra-high molecular weight DNA was extracted from blood or fibroblasts. OGM was performed on the Saphyr system (Bionano). A two-step approach was utilized for variant filtering and interpretation. First, all structural variant calls were screened for alterations in 20 known ataxia genes in which the pathogenic repeat expansion might be long enough to be detected. Second, all variant calls with a frequency of <1% in 300 Bionano controls were evaluated for their reported disease link using OMIM or PubMed in comparison to the patients´ phenotype. If there was at least an overlap in phenotype, the variant was validated using long-range PCR or short-read genome sequencing.

Results: Patients with ataxia comprised the largest group, accounting for 50% (8/16) of the cohort. Other patients were diagnosed with dystonia, parkinsonism, or a combination of different movement disorders. We identified notable results in four patients (25%), including a 753-bp insertion (n=251 repeats) in the FGF14 gene (SCA27B), a biallelic 5025-bp and 6625-bp insertion in RFC1 (CANVAS) (n=1,005 and 1,325 repeats), a 660-bp insertion (corresponding to 132 repeats) in DAB1 (SCA37), and a 27,557-bp deletion including the 5´- untranslated region of ZFHX3, the gene in which a repeat expansion leads to SCA4. The repeat expansion in DAB1 was also detected in the affected father, the ZFHX3 deletion was also present in the unaffected mother. All three repeat expansions are considered disease-causing, the deletion in ZFHX3 is of uncertain significance.

Conclusion: Our data demonstrate that OGM increases  diagnostic yield in rare movement disorders and is a powerful tool for screening for repeat expansions and other structural variants.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/detecting-repeat-expansions-added-diagnostic-yield-in-movement-disorders-by-optical-genome-mapping/