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Meuwissen, M.* ; Verstraeten, A.* ; Ranza, E.* ; Iwaszkiewicz, J.* ; Bastiaansen, M.* ; Mateiu, L.* ; Nemegeer, M.* ; Meester, J.A.N.* ; Afenjar, A.* ; Amaral, M.* ; Ballhausen, D.* ; Barnett, S.* ; Barth, M.* ; Asselbergh, B.* ; Spaas, K.* ; Heeman, B.* ; Bassetti, J.* ; Blackburn, P.* ; Schaer, M.* ; Blanc, X.* ; Zoete, V.* ; Casas, K.* ; Courtin, T.* ; Doummar, D.* ; Guerry, F.* ; Keren, B.* ; Pappas, J.* ; Rabin, R.* ; Begtrup, A.* ; Shinawi, M.* ; Vulto-van Silfhout, A.T.* ; Kleefstra, T.* ; Wagner, M. ; Ziegler, A.* ; Schaefer, E.* ; Gérard, B.* ; De Bie, C.I.* ; Holwerda, S.J.B.* ; Abbot, M.A.* ; Antonarakis, S.E.* ; Loeys, B.*

Heterozygous variants in CTR9, which encodes a major component of the PAF1 complex, are associated with a neurodevelopmental disorder.

Genet. Med. 24, 1583-1591 (2022)
Verlagsversion DOI PMC
Free by publisher
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Purpose: CTR9 is a subunit of the PAF1 complex (PAF1C) that plays a crucial role in transcription regulation by binding CTR9 to RNA polymerase II. It is involved in transcription-coupled histone modification through promoting H3K4 and H3K36 methylation. We describe the clinical and molecular studies in 13 probands, harboring likely pathogenic CTR9 missense variants, collected through GeneMatcher. Methods: Exome sequencing was performed in all individuals. CTR9 variants were assessed through 3-dimensional modeling of the activated human transcription complex Pol II-DSIF-PAF-SPT6 and the PAF1/CTR9 complex. H3K4/H3K36 methylation analysis, mitophagy assessment based on tetramethylrhodamine ethyl ester perchlorate immunofluorescence, and RNA-sequencing in skin fibroblasts from 4 patients was performed. Results: Common clinical findings were variable degrees of intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, and autism spectrum disorder. Mild dysmorphism and cardiac anomalies were less frequent. For 11 CTR9 variants, de novo occurrence was shown. Three-dimensional modeling predicted a likely disruptive effect of the variants on local CTR9 structure and protein interaction. Additional studies in fibroblasts did not unveil the downstream functional consequences of the identified variants. Conclusion: We describe a neurodevelopmental disorder caused by (mainly) de novo variants in CTR9, likely affecting PAF1C function.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Autism Spectrum Disorder ; Ctr9 ; Intellectual Disability ; Neurodevelopmental Disorder ; Paf1c
ISSN (print) / ISBN 1530-0366
e-ISSN 1098-3600
Zeitschrift Genetics in Medicine
Quellenangaben Band: 24, Heft: 7, Seiten: 1583-1591 Artikelnummer: , Supplement: ,
Verlag Lippincott Williams & Wilkins
Verlagsort Baltimore, Md.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
Förderungen Fonds Wetenschappelijk Onderzoek
Hartstichting
European Research Council
European Commission
Marfan Foundation
Dutch Heart Foundation
Belgian Cardiac Surgery Foundation
Universiteit Antwerpen
Universitair Ziekenhuis Antwerpen