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Войти в исследования The genetic landscape of childhood-onset dystonia in a nationwide Turkish cohort: Clinical spectrum, molecular diagnostics, and therapeutic implications.
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Yilmaz Sanem, Serdaroglu Esra, Simsek Erdem, Kara Bulent, Turkdogan Dilsad, Yis Uluc, Erol Ilknur, Yuksel Deniz, Kanmaz Seda, Eroglu Arzu, Canpolat Mehmet, Komur Mustafa, Cıtak Kurt Nese, Sakarya Gunes Ayfer, Soydemir Didem, Besen Seyda, Bektas Omer, Kirik Serkan, Atalay Celik Hale, Ardicli Didem, Aksoy Ayse, Yarar Coskun, Cerci Kubur Cisil, Olgac Dundar Nihal, Gungor Olcay, Kamasak Tulay, Olculu Cemile Busra, Gumus Hakan, Yildirim Mirac, Isik Esra, Atik Tahir, Cogulu Ozgur, Basak Ayse Nazli, Sunnetci Akkoyunlu Deniz, Özbakır Derya Hazal, Kayhan Gülsüm, Gerik Çelebi Hamide Betul, Karaer Kadri, Dundar Munis, Kaiyrzhanov Rauan, Ceylaner Serdar, Per Huseyin, Hiz Ayse Semra, Cansu Ali, Okuyaz Cetin, Anlar Banu, Tekgul Hasan
Аннотация
OBJECTIVE: To delineate the molecular genetic etiology, phenotypic characteristics, and treatment strategies in a multicenter cohort with gene-related CODs.
METHODS: The study cohort comprised 81 patients with gene-related COD from 19 tertiary pediatric neurology centers in Turkiye. Clinical phenomenology, biochemical, electrophysiological, neuroimaging findings, diagnostic genetic tests, causative genes and variants, inheritance patterns, gene-related phenotypes, treatment modalities, and their efficacy were gathered.
RESULTS: A diverse genetic landscape was identified in the cohort of 81 patients, revealing 62 distinct (pathogenic/likely pathogenic) variants across 26 genes. The genetic diagnoses were established through whole-exome sequencing (49.4%), single-gene testing (25.9%), and targeted gene panels (23.5%). Of the 81 patients, 59 had single-nucleotide variants (SNVs), 21 had deletions or duplications, and one patient carried a pathogenic trinucleotide repeat expansion. The common etiologies of gene-related COD were KMT2B (16%), GCH1 (11.1%), SLC2A1 (11.1%), GNAO1 (8.6%), TOR1A (8.6%), GNAL (6.2%). Rare etiologies were SLC18A2 and TH (each 4.9%), ATP1A3, NKX2-1, PRKN, SCN4A, THAP1 (each 2.5%), and ultra-rare etiologies (single patients) were: ACY5, ADPRS, ANO3, COL6A3, DNM1L, GNB1, HTT, PRKRA, PRRT2, RHOBTB2, SETX, SLC6A3, TUBB4A (1.2%). Based on Gene Ontology classification, the most represented functional categories were neurotransmission (n = 18, 22.2%), gene expression (n = 17, 20.9%), and signaling (n = 14, 17.3%). Genetic diagnosis influenced treatment modalities with pharmacotherapy modification or implementation of deep brain stimulation in 60.5% of the cohort, with targeted therapies being more effective than symptomatic treatments (p = 0.0118).
CONCLUSION: This nationwide study highlights the phenotypic and genetic diversity of gene-related COD with certain therapeutic implications based on the molecular etiology-specific diagnosis.