Therapeutic implications of etiology-specific diagnosis of early-onset developmental and epileptic encephalopathies (EO-DEEs): A nationwide Turkish cohort study

•Gene-related EO-DEEs are 48.3 % in the nationwide-Turkish cohort.•Common non-structural genetic variants are SCN1A, CDKL5, STXBP, KCNQ2, and PCDH19.•Ultra-rare variants of gene-related EO-DEEs are 52 % in the next-generation sequencing era.•Therapeutic yield of genetic testing was 33.1 % in the NGS...

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Published in:	Seizure (London, England) Vol. 123; pp. 17 - 25
Main Authors:	Kanmaz, Seda, Tekgul, Hasan, Kayilioglu, Hulya, Atas, Yavuz, Kart, Pinar Ozkan, Yildiz, Nihal, Gumus, Hakan, Aydin, Kursad, Olculu, Cemile Busra, Dogan, Dilara Ece Toprak, Per, Huseyin, Canpolat, Mehmet, Gulec, Ayten, Yildirim, Nalan, Turk, Emre, Celik, Neslihan, Ozturk, Selcan, Kumandas, Sefer, Kilic, Betul, Topcu, Yasemin, Ozpinar, Esra, Coskun, Aysenur, Arslan, Mutluay, Akkoyunlu, Deniz Sunnetci, Cine, Naci, Uzan, Gamze Sarikaya, Gunay, Cagatay, Akyol, Duygu, Ersoy, Ozlem, Direk, Meltem Cobanogullari, Komur, Mustafa, Kirkgoz, Hilal, Karaoğlu, Pakize, Ibis, Ipek Burcu Parlak, Cerci, Cisil, Orak, Ali, Oktay, Secil, Ayanoglu, Muge, Yildirim, Mirac, Bektas, Omer, Serdaroglu, Esra, Yilmaz, Sema Bozkaya, Cankurt, Ilknur, Hirfanoglu, Tugba, Arhan, Ebru, Gencpinar, Pinar, Dundar, Nihal Olgac, Teber, Serap, Serin, Hepsen Mine, Yilmaz, Sanem, Tosun, Ayse, Polat, Muzaffer, Yilmaz, Unsal, Unalp, Aycan, Kara, Bulent, Okuyaz, Cetin, Yis, Uluc, Hiz, Semra, Aktan, Gul, Gokben, Sarenur, Unay, Bulent, Serdaroglu, Ayse, Cansu, Ali
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-12-2024
Subjects:	Early-onset developmental epileptic encephalopathies Genetic testing Precision medicine Stepwise diagnostic model Genetic testing Precision medicine Stepwise diagnostic model Early-onset developmental epileptic encephalopathies
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Summary:	•Gene-related EO-DEEs are 48.3 % in the nationwide-Turkish cohort.•Common non-structural genetic variants are SCN1A, CDKL5, STXBP, KCNQ2, and PCDH19.•Ultra-rare variants of gene-related EO-DEEs are 52 % in the next-generation sequencing era.•Therapeutic yield of genetic testing was 33.1 % in the NGS era in EO-DEEs.•A step-wise diagnostic model indicated early implementation of WES in EO-DEEs. To evaluate the etiology-specific diagnosis of early-onset developmental epileptic encephalopathies (EO-DEEs) in a nationwide Turkish cohort to determine the implications for therapeutic management. The cohort comprised 1450 patients who underwent EO-DEE. The utility of genetic testing was assessed with respect to the initial phases of next generation sequencing (NGS) (2005–2013) and the current NGS era (2014–2022). A predefined four-stepwise diagnostic model was evaluated using cost-effectiveness analysis. The diagnostic and potential therapeutic yields of the genetic tests were subsequently determined. Gene-related EO-DEEs were identified in 48.3 % (n = 701) of the cohort: non-structural genetic (62.6 %), metabolic genetic (15.1 %), and structural genetic (14.1 %). The most common nonstructural genetic variants were SCN1A (n = 132, 18.8 %), CDKL5 (n = 30, 4.2 %), STXBP1 (n = 21, 2.9 %), KCNQ2 (n = 21, 2.9 %), and PCDH19 (n = 17, 2.4 %). The rate of ultra-rare variants (< 0.5 %) was higher in the NGS era (52 %) than that in the initial phase (36 %). The potential therapeutic yields with precision therapy and antiseizure drug modification were defined in 34.5 % and 56.2 % in genetic-EO-DEEs, respectively. The diagnostic model provided an etiology-specific diagnosis at a rate of 78.7 %: structural (nongenetic) (31.4 %), genetic (38.5 %), metabolic (6.1 %), and immune-infectious (2.8 %). Based on a cost-effectiveness analysis, the presented diagnostic model indicated the early implementation of whole-exome sequencing for EO-DEEs. In the present cohort, the higher rate (48.3 %) of gene-related EO-DEE diagnoses in the NGS era provides a potential therapeutic management plan for more patients. Graphic 1: The landscape of gene-related EO-DEEs in nationwide-Turkish cohort; initial phase of NGS (2005–2013) versus NGS Era (2014–2021) [Display omitted]
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1059-1311 1532-2688 1532-2688
DOI:	10.1016/j.seizure.2024.09.021