TY - JOUR
T1 - Heterozygous variants in CTR9, which encodes a major component of the PAF1 complex, are associated with a neurodevelopmental disorder
AU - Meuwissen, Marije
AU - Verstraeten, Aline
AU - Ranza, Emmanuelle
AU - Iwaszkiewicz, Justyna
AU - Bastiaansen, Maaike
AU - Mateiu, Ligia
AU - Nemegeer, Merlijn
AU - Meester, Josephina A N
AU - Afenjar, Alexandra
AU - Amaral, Michelle
AU - Ballhausen, Diana
AU - Barnett, Sarah
AU - Barth, Magalie
AU - Asselbergh, Bob
AU - Spaas, Katrien
AU - Heeman, Bavo
AU - Bassetti, Jennifer
AU - Blackburn, Patrick
AU - Schaer, Marie
AU - Blanc, Xavier
AU - Zoete, Vincent
AU - Casas, Kari
AU - Courtin, Thomas
AU - Doummar, Diane
AU - Guerry, Frédéric
AU - Keren, Boris
AU - Pappas, John
AU - Rabin, Rachel
AU - Begtrup, Amber
AU - Shinawi, Marwan
AU - Vulto-van Silfhout, Anneke T
AU - Kleefstra, Tjitske
AU - Wagner, Matias
AU - Ziegler, Alban
AU - Schaefer, Elise
AU - Gerard, Benedicte
AU - De Bie, Charlotte I
AU - Holwerda, Sjoerd J B
AU - Abbot, Mary Alice
AU - Antonarakis, Stylianos E
AU - Loeys, Bart
N1 - Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
PY - 2022/7
Y1 - 2022/7
N2 - 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.
AB - 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.
KW - Autism Spectrum Disorder
KW - Gene Expression Regulation
KW - Heterozygote
KW - Humans
KW - Intellectual Disability/genetics
KW - Neurodevelopmental Disorders/genetics
KW - Phosphoproteins/genetics
KW - Transcription Factors/genetics
U2 - 10.1016/j.gim.2022.04.003
DO - 10.1016/j.gim.2022.04.003
M3 - Article
C2 - 35499524
SN - 1098-3600
VL - 24
SP - 1583
EP - 1591
JO - Genetics in medicine : official journal of the American College of Medical Genetics
JF - Genetics in medicine : official journal of the American College of Medical Genetics
IS - 7
ER -