Objective: This study aimed at identifying the missing genetic causes in dystonia without diagnosis following movement disorders gene panel sequencing.

Background: Dystonia aetiologies are highly diverse and regroup both acquired and genetic causes. Many genes have been associated with this condition, so achieving a molecular diagnosis remains often challenging. By assessing a 127 movement disorders genes panel including 69 genes responsible for dystonia on a cohort of patients with early-onset or family movement disorders, we previously showed that diagnostic rate of success was significantly lower in patients showing dystonia as prominent symptom [1]. Since Whole Exome Sequencing (WES) has shown to improve the diagnostic rate afteer gene panel analysis in several mendelian disorders, we aimed to apply this strategy on dystonic patients.

Method: We included patients experiencing early-onset or family dystonia witout clinical or paraclinical findings suggestive of an acquired cause of dystonia and without genetic diagnosis following a 127 movement disorders genes panel analysis. Availability of DNA samples from the patient and the two parents in sporadic and family cases consistent with de novo event or autosomal recessive inheritance, or from at least two related patients coming from two different generations in familial cases consistent with autosomal dominant inheritance was required. Dystonia was characterized by a movement disorder specialist according to age of onset, body distribution, temporal pattern and associated symptoms.

Results: WES was performed on 32 patients from 24 families with early onset and/or family dystonia of unknown aetiology despite gene panel analysis. We identified causative variants for 13 patients from 10 different families in CTNNB1, SUCLG1, NUS1, CNTNAP1, KCNB1, RELN, GNAO1, HIBCH, ADCK3 genes, yielding a diagnostic rate of 40.6%. Diagnostic yield was significantly higher in patients showing complex phenotypes characterized by the association of dystonia with other neurological signs (62.5% vs 18.5%; p=0.029) including intellectual disability (87.50% vs 25%; p<0.01). We also identified two heterozygous missense mutations in GNA01 in two families showing autosomal dominant inherited dystonia, while only de novo mutations have been reported until now.

Conclusion: Exome sequencing provides high diagnostic yield in complex dystonia patients and means to improve movement disorders gene panel efficiency.

References: [1] Montaut S, Tranchant C, Drouot N, Rudolf G, Guissart C, Tarabeux J, et al. Assessment of a Targeted Gene Panel for Identification of Genes Associated With Movement Disorders. JAMA Neurol. 2018 Jun 18;

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MDS Abstracts - https://www.mdsabstracts.org/abstract/high-rate-of-mutations-in-complex-dystonia-revealed-by-exome-sequencing/