Objective: To describe a family with a new variant in X chromosome as possible aetiology for inherited generalised dystonia.

Background: Chromosomopathies are rare but well-known causes of movement disorders, including parkinsonism, tremor, and dystonia. The co-occurrence of clinical features typically associated to chromosomal aberrations, such as dysmorphisms, multisystemic involvement and cognitive impairment should elicit further chromosomal studies.

Method: A multigene panel, followed by clinical exome, chromosomal microarray (CMA), segregation studies and X chromosome inactivation analysis were performed.

Results: A 43-year-old woman presented a left lower limb dystonia at the age of 12, which slowly progressed to generalized dystonia, with significant craniocervical and speech involvement. Later, puerility, an irritative pyramidal syndrome, and myoclonus appeared.

Brain MRI, EEG, EMG, metabolic studies (copper, lysosomal enzymes, presence of acanthocytes, lactate/pyruvate, amino acids, oligosaccharides, and organic acids), and a multigene panel for dystonias based on whole-exome sequencing (WES) were performed, all normal or negative.

The patient has two male children, currently aged 17 and 10, both with dystonia and learning difficulties. The first child presented with left limbs dystonia at the age of 3, also slowly progressive, and later accompanied by a myoclonic epilepsy.

Genetic studies were expanded to clinical exome, which identified a duplication on the X chromosome (X:76709547_79286710dup), involving 16 genes (7 reported in the OMIM Morbid Map), both in the patient and in her first son, which was confirmed by CMA (~4Mb). Family segregation studies demonstrated that this duplication arose as de novo in the index case (absent in her mother, sister, and 4 brothers). Skewed X-chromosome inactivation was identified in the index, leading to a preferred activation of the chromosome carrying the large duplication.

Conclusion: Neither this newly identified duplication (in Xq13.3q21.1) or any of the genes encompassed by the duplication have been previously associated with dystonia. In these cases, CMA is rarely considered as a first-line diagnostic approach. We emphasize the importance of analysing copy number variations (CNVs) together with intragenic variants.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/hereditary-generalised-dystonia-associated-with-a-new-large-duplication-on-the-x-chromosome/