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. 2022 Oct 26;4(6):fcac276.
doi: 10.1093/braincomms/fcac276. eCollection 2022.

Adult-onset KMT2B-related dystonia

Edoardo Monfrini  1   2 , Andrea Ciolfi  3 , Francesco Cavallieri  4   5 , Marco Ferilli  3 , Paola Soliveri  6   7 , Lucia Pedace  8 , Roberto Erro  9 , Francesca Del Sorbo  6   7 , Franco Valzania  4 , Valentina Fioravanti  4 , Giovanni Cossu  10 , Maria Pellegrini  11 , Leonardo Salviati  12 , Federica Invernizzi  13 , Valentina Oppo  10 , Daniela Murgia  10 , Bruno Giometto  11 , Marina Picillo  9 , Barbara Garavaglia  13 , Francesca Morgante  14   15 , Marco Tartaglia  3 , Miryam Carecchio  16   17 , Alessio Di Fonzo  2
Affiliations

Adult-onset KMT2B-related dystonia

Edoardo Monfrini et al. Brain Commun. .

Abstract

KMT2B-related dystonia (DYT-KMT2B, also known as DYT28) is an autosomal dominant neurological disorder characterized by varying combinations of generalized dystonia, psychomotor developmental delay, mild-to-moderate intellectual disability and short stature. Disease onset occurs typically before 10 years of age. We report the clinical and genetic findings of a series of subjects affected by adult-onset dystonia, hearing loss or intellectual disability carrying rare heterozygous KMT2B variants. Twelve cases from five unrelated families carrying four rare KMT2B missense variants predicted to impact protein function are described. Seven affected subjects presented with adult-onset focal or segmental dystonia, three developed isolated progressive hearing loss, and one displayed intellectual disability and short stature. Genome-wide DNA methylation profiling allowed to discriminate these adult-onset dystonia cases from controls and early-onset DYT-KMT2B patients. These findings document the relevance of KMT2B variants as a potential genetic determinant of adult-onset dystonia and prompt to further characterize KMT2B carriers investigating non-dystonic features.

Keywords: DYT28; KMT2B; dystonia; genetics; hearing loss.

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Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Family pedigrees and KMT2B variants segregation. Families of the probands A.II.4, B.II.3, C.II.1, D.II.2 and E.II.1. Black, dark grey and light grey fillings indicate affected status by dystonia, hearing loss and short stature/intellectual disability, respectively. Asterisks indicate the subjects that underwent DNAm array analysis.
Figure 2
Figure 2
DNAm array analyses. (A) DNAm profiles in patients with KMT2B variants associated with late-onset dystonia differ from those characterizing childhood-onset DYT-KMT2B (DYT28). MDS plot is used to classify the presently identified KMT2B missense variants (orange) with respect to KMT2B variants causing childhood-onset DYT-KMT2B (red) and an in-house DNAm data set including ∼300 healthy individuals and subjects with rare neurodevelopmental disorders (blue). (B) Genome-wide DNAm analysis was able to cluster cases with late-onset dystonia (n = 6), hearing loss (n = 1), and intellectual disability-short stature (n = 1) carrying heterozygous KMT2B missense variants (orange) from childhood-onset DYT-KMT2B (red) and control samples (blue), by MDS analysis. The age-and sex-matched controls selected to identify differentially methylated probes are highlighted in black.
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References

    1. Zech M, Boesch S, Maier EM, et al. . Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia. Am J Hum Genet. 2016;99(6):1377–1387. - PMC - PubMed
    1. Meyer E, Carss KJ, Rankin J, et al. . Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat Genet. 2017;49(2):223–237. - PubMed
    1. Ma J, Wang L, Yang Y, Li S, Wan X. Identification of novel KMT2B variants in Chinese dystonia patients via whole-exome sequencing. Front Neurol. 2019;10:729. - PMC - PubMed
    1. Pandey S, Bhattad S, Panda AK, Mahadevan L. Late-onset KMT2B-related dystonia in an Indian patient with Normal cognition, dystonic opisthotonus and lack of oromandibular and laryngeal involvement. Parkinsonism Relat Disord. 2020;74:33–35. - PubMed
    1. Abela L, Kurian MA. KMT2B-Related Dystonia. GeneReviews® [Internet]. In: Adam MP, Everman DB, Mirzaa GM, et al., eds. GeneReviews is a registered trademark of the University of Washington, Seattle. University of Washington; 1993-2022. https://www.ncbi.nlm.nih.gov/books/NBK493766/.

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