A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder

Lot Snijders Blok; Jolijn Verseput; Dmitrijs Rots; Hanka Venselaar; A Micheil Innes; Connie Stumpel; Katrin Õunap; Karit Reinson; Eleanor G Seaby; Shane McKee; Barbara Burton; Katherine Kim; Johanna M van Hagen; Quinten Waisfisz; Pascal Joset; Katharina Steindl; Anita Rauch; Dong Li; Elaine H Zackai; Sarah E Sheppard; Beth Keena; Hakon Hakonarson; Andreas Roos; Nicolai Kohlschmidt; Anna Cereda; Maria Iascone; Erika Rebessi; Kristin D Kernohan; Philippe M Campeau; Francisca Millan; Jesse A Taylor; Hanns Lochmüller; Martin R Higgs; Amalia Goula; Birgitta Bernhard; Danita J Velasco; Andrew A Schmanski; Zornitza Stark; Lyndon Gallacher; Lynn Pais; Paul C Marcogliese; Shinya Yamamoto; Nicholas Raun; Taryn E Jakub; Jamie M Kramer; Joery den Hoed; Simon E Fisher; Han G Brunner; Tjitske Kleefstra

doi:10.1016/j.xhgg.2022.100157

A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder

Lot Snijders Blok^*, Jolijn Verseput, Dmitrijs Rots, Hanka Venselaar, A Micheil Innes, Connie Stumpel, Katrin Õunap, Karit Reinson, Eleanor G Seaby, Shane McKee, Barbara Burton, Katherine Kim, Johanna M van Hagen, Quinten Waisfisz, Pascal Joset, Katharina Steindl, Anita Rauch, Dong Li, Elaine H Zackai, Sarah E SheppardBeth Keena, Hakon Hakonarson, Andreas Roos, Nicolai Kohlschmidt, Anna Cereda, Maria Iascone, Erika Rebessi, Kristin D Kernohan, Philippe M Campeau, Francisca Millan, Jesse A Taylor, Hanns Lochmüller, Martin R Higgs, Amalia Goula, Birgitta Bernhard, Danita J Velasco, Andrew A Schmanski, Zornitza Stark, Lyndon Gallacher, Lynn Pais, Paul C Marcogliese, Shinya Yamamoto, Nicholas Raun, Taryn E Jakub, Jamie M Kramer, Joery den Hoed, Simon E Fisher, Han G Brunner, Tjitske Kleefstra^*

^*Corresponding author for this work

Cancer and Genomic Sciences

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Abstract

WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (n = 11), intellectual disability (n = 9), epilepsy (n = 7), and autism spectrum disorder (n = 4). Additional phenotypic features included abnormal growth parameters (n = 7), heart anomalies (n = 2), and hearing loss (n = 2). Three-dimensional protein structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS (complex proteins associated with Set1) family complexes. Our experimental approaches in Drosophila melanogaster and human cell lines show normal protein expression, localization, and protein-protein interactions for all tested variants. These results, together with the clustering of variants in a specific region of WDR5 and the absence of truncating variants so far, suggest that dominant-negative or gain-of-function mechanisms might be at play. All in all, we define a neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of features. This finding highlights the important role of genes encoding COMPASS family proteins in neurodevelopmental disorders.

Original language	English
Article number	100157
Number of pages	9
Journal	HGG advances
Volume	4
Issue number	1
Early online date	1 Nov 2022
DOIs	https://doi.org/10.1016/j.xhgg.2022.100157
Publication status	Published - 12 Jan 2023

Bibliographical note

Acknowledgments:
We thank all included individuals and their families for their contribution to this research project. We thank the late Dr. Kenneth L. Scott for providing the human WDR5 cDNA used in this study. Funding was provided by the Netherlands Organisation for Scientific Research (NWO) Gravitation Grant 24.001.006 to the Language in Interaction Consortium (L.S.B., S.E.F., and H.G.B.), the Max Planck Society (J.d.H. and S.E.F.), and the Netherlands Organisation for Health Research and Development (ZonMw grant 91718310 to T.K.). Funding to J.M.K. was provided by a catalyst grant from the Canadian Rare Disease Models and Mechanisms Network. The research of A.C., M.I., and E.R. was supported by PROGETTEO GENE (GENE = Genomic Analysis Evaluation Network) founded by PROGETTI DI INNOVAZIONE IN AMBITO SANITARIO E SOCIO SANITARIO (BANDO EX DECRETO N. 2713 DEL 28/02/2018). A.Roos and N.K. acknowledge funding from the European Regional Development Fund (ERDF). K.Õ. and K.R. were supported by the Estonian Research Council grants PUT355 and PRG471. The Broad Center for Mendelian Genomics (UM1 HG008900) is funded by the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute. This work was generated within ITHACA: European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability. Individuals 3 and 4 were part of the DDD study cohort, individual 6 was ascertained through the Care4Rare consortium, and individual 9 was part of the UDP-Vic program. Further information on these cohort studies is included in the supplemental information.

Copyright:
© 2022 The Authors.

Keywords

Animals
Humans
Autism Spectrum Disorder/genetics
Drosophila melanogaster/genetics
Neurodevelopmental Disorders/genetics
Language Development Disorders
Cluster Analysis
Chromatin
Intracellular Signaling Peptides and Proteins/genetics
Histone-Lysine N-Methyltransferase/genetics
Drosophila Proteins/genetics

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Snijders Blok, L., Verseput, J., Rots, D., Venselaar, H., Innes, A. M., Stumpel, C., Õunap, K., Reinson, K., Seaby, E. G., McKee, S., Burton, B., Kim, K., van Hagen, J. M., Waisfisz, Q., Joset, P., Steindl, K., Rauch, A., Li, D., Zackai, E. H., ... Kleefstra, T. (2023). A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder. HGG advances, 4(1), Article 100157. https://doi.org/10.1016/j.xhgg.2022.100157

@article{402686375ae54e5aa6253cf08a877e23,

title = "A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder",

abstract = "WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (n = 11), intellectual disability (n = 9), epilepsy (n = 7), and autism spectrum disorder (n = 4). Additional phenotypic features included abnormal growth parameters (n = 7), heart anomalies (n = 2), and hearing loss (n = 2). Three-dimensional protein structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS (complex proteins associated with Set1) family complexes. Our experimental approaches in Drosophila melanogaster and human cell lines show normal protein expression, localization, and protein-protein interactions for all tested variants. These results, together with the clustering of variants in a specific region of WDR5 and the absence of truncating variants so far, suggest that dominant-negative or gain-of-function mechanisms might be at play. All in all, we define a neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of features. This finding highlights the important role of genes encoding COMPASS family proteins in neurodevelopmental disorders.",

keywords = "Animals, Humans, Autism Spectrum Disorder/genetics, Drosophila melanogaster/genetics, Neurodevelopmental Disorders/genetics, Language Development Disorders, Cluster Analysis, Chromatin, Intracellular Signaling Peptides and Proteins/genetics, Histone-Lysine N-Methyltransferase/genetics, Drosophila Proteins/genetics",

author = "{Snijders Blok}, Lot and Jolijn Verseput and Dmitrijs Rots and Hanka Venselaar and Innes, {A Micheil} and Connie Stumpel and Katrin {\~O}unap and Karit Reinson and Seaby, {Eleanor G} and Shane McKee and Barbara Burton and Katherine Kim and {van Hagen}, {Johanna M} and Quinten Waisfisz and Pascal Joset and Katharina Steindl and Anita Rauch and Dong Li and Zackai, {Elaine H} and Sheppard, {Sarah E} and Beth Keena and Hakon Hakonarson and Andreas Roos and Nicolai Kohlschmidt and Anna Cereda and Maria Iascone and Erika Rebessi and Kernohan, {Kristin D} and Campeau, {Philippe M} and Francisca Millan and Taylor, {Jesse A} and Hanns Lochm{\"u}ller and Higgs, {Martin R} and Amalia Goula and Birgitta Bernhard and Velasco, {Danita J} and Schmanski, {Andrew A} and Zornitza Stark and Lyndon Gallacher and Lynn Pais and Marcogliese, {Paul C} and Shinya Yamamoto and Nicholas Raun and Jakub, {Taryn E} and Kramer, {Jamie M} and {den Hoed}, Joery and Fisher, {Simon E} and Brunner, {Han G} and Tjitske Kleefstra",

note = "Acknowledgments: We thank all included individuals and their families for their contribution to this research project. We thank the late Dr. Kenneth L. Scott for providing the human WDR5 cDNA used in this study. Funding was provided by the Netherlands Organisation for Scientific Research (NWO) Gravitation Grant 24.001.006 to the Language in Interaction Consortium (L.S.B., S.E.F., and H.G.B.), the Max Planck Society (J.d.H. and S.E.F.), and the Netherlands Organisation for Health Research and Development (ZonMw grant 91718310 to T.K.). Funding to J.M.K. was provided by a catalyst grant from the Canadian Rare Disease Models and Mechanisms Network. The research of A.C., M.I., and E.R. was supported by PROGETTEO GENE (GENE = Genomic Analysis Evaluation Network) founded by PROGETTI DI INNOVAZIONE IN AMBITO SANITARIO E SOCIO SANITARIO (BANDO EX DECRETO N. 2713 DEL 28/02/2018). A.Roos and N.K. acknowledge funding from the European Regional Development Fund (ERDF). K.{\~O}. and K.R. were supported by the Estonian Research Council grants PUT355 and PRG471. The Broad Center for Mendelian Genomics (UM1 HG008900) is funded by the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute. This work was generated within ITHACA: European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability. Individuals 3 and 4 were part of the DDD study cohort, individual 6 was ascertained through the Care4Rare consortium, and individual 9 was part of the UDP-Vic program. Further information on these cohort studies is included in the supplemental information. Copyright: {\textcopyright} 2022 The Authors.",

year = "2023",

month = jan,

day = "12",

doi = "10.1016/j.xhgg.2022.100157",

language = "English",

volume = "4",

journal = "HGG advances",

issn = "2666-2477",

number = "1",

}

Snijders Blok, L, Verseput, J, Rots, D, Venselaar, H, Innes, AM, Stumpel, C, Õunap, K, Reinson, K, Seaby, EG, McKee, S, Burton, B, Kim, K, van Hagen, JM, Waisfisz, Q, Joset, P, Steindl, K, Rauch, A, Li, D, Zackai, EH, Sheppard, SE, Keena, B, Hakonarson, H, Roos, A, Kohlschmidt, N, Cereda, A, Iascone, M, Rebessi, E, Kernohan, KD, Campeau, PM, Millan, F, Taylor, JA, Lochmüller, H, Higgs, MR, Goula, A, Bernhard, B, Velasco, DJ, Schmanski, AA, Stark, Z, Gallacher, L, Pais, L, Marcogliese, PC, Yamamoto, S, Raun, N, Jakub, TE, Kramer, JM, den Hoed, J, Fisher, SE, Brunner, HG & Kleefstra, T 2023, 'A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder', HGG advances, vol. 4, no. 1, 100157. https://doi.org/10.1016/j.xhgg.2022.100157

TY - JOUR

T1 - A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder

AU - Snijders Blok, Lot

AU - Verseput, Jolijn

AU - Rots, Dmitrijs

AU - Venselaar, Hanka

AU - Innes, A Micheil

AU - Stumpel, Connie

AU - Õunap, Katrin

AU - Reinson, Karit

AU - Seaby, Eleanor G

AU - McKee, Shane

AU - Burton, Barbara

AU - Kim, Katherine

AU - van Hagen, Johanna M

AU - Waisfisz, Quinten

AU - Joset, Pascal

AU - Steindl, Katharina

AU - Rauch, Anita

AU - Li, Dong

AU - Zackai, Elaine H

AU - Sheppard, Sarah E

AU - Keena, Beth

AU - Hakonarson, Hakon

AU - Roos, Andreas

AU - Kohlschmidt, Nicolai

AU - Cereda, Anna

AU - Iascone, Maria

AU - Rebessi, Erika

AU - Kernohan, Kristin D

AU - Campeau, Philippe M

AU - Millan, Francisca

AU - Taylor, Jesse A

AU - Lochmüller, Hanns

AU - Higgs, Martin R

AU - Goula, Amalia

AU - Bernhard, Birgitta

AU - Velasco, Danita J

AU - Schmanski, Andrew A

AU - Stark, Zornitza

AU - Gallacher, Lyndon

AU - Pais, Lynn

AU - Marcogliese, Paul C

AU - Yamamoto, Shinya

AU - Raun, Nicholas

AU - Jakub, Taryn E

AU - Kramer, Jamie M

AU - den Hoed, Joery

AU - Fisher, Simon E

AU - Brunner, Han G

AU - Kleefstra, Tjitske

N1 - Acknowledgments: We thank all included individuals and their families for their contribution to this research project. We thank the late Dr. Kenneth L. Scott for providing the human WDR5 cDNA used in this study. Funding was provided by the Netherlands Organisation for Scientific Research (NWO) Gravitation Grant 24.001.006 to the Language in Interaction Consortium (L.S.B., S.E.F., and H.G.B.), the Max Planck Society (J.d.H. and S.E.F.), and the Netherlands Organisation for Health Research and Development (ZonMw grant 91718310 to T.K.). Funding to J.M.K. was provided by a catalyst grant from the Canadian Rare Disease Models and Mechanisms Network. The research of A.C., M.I., and E.R. was supported by PROGETTEO GENE (GENE = Genomic Analysis Evaluation Network) founded by PROGETTI DI INNOVAZIONE IN AMBITO SANITARIO E SOCIO SANITARIO (BANDO EX DECRETO N. 2713 DEL 28/02/2018). A.Roos and N.K. acknowledge funding from the European Regional Development Fund (ERDF). K.Õ. and K.R. were supported by the Estonian Research Council grants PUT355 and PRG471. The Broad Center for Mendelian Genomics (UM1 HG008900) is funded by the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute. This work was generated within ITHACA: European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability. Individuals 3 and 4 were part of the DDD study cohort, individual 6 was ascertained through the Care4Rare consortium, and individual 9 was part of the UDP-Vic program. Further information on these cohort studies is included in the supplemental information. Copyright: © 2022 The Authors.

PY - 2023/1/12

Y1 - 2023/1/12

N2 - WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (n = 11), intellectual disability (n = 9), epilepsy (n = 7), and autism spectrum disorder (n = 4). Additional phenotypic features included abnormal growth parameters (n = 7), heart anomalies (n = 2), and hearing loss (n = 2). Three-dimensional protein structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS (complex proteins associated with Set1) family complexes. Our experimental approaches in Drosophila melanogaster and human cell lines show normal protein expression, localization, and protein-protein interactions for all tested variants. These results, together with the clustering of variants in a specific region of WDR5 and the absence of truncating variants so far, suggest that dominant-negative or gain-of-function mechanisms might be at play. All in all, we define a neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of features. This finding highlights the important role of genes encoding COMPASS family proteins in neurodevelopmental disorders.

AB - WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (n = 11), intellectual disability (n = 9), epilepsy (n = 7), and autism spectrum disorder (n = 4). Additional phenotypic features included abnormal growth parameters (n = 7), heart anomalies (n = 2), and hearing loss (n = 2). Three-dimensional protein structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS (complex proteins associated with Set1) family complexes. Our experimental approaches in Drosophila melanogaster and human cell lines show normal protein expression, localization, and protein-protein interactions for all tested variants. These results, together with the clustering of variants in a specific region of WDR5 and the absence of truncating variants so far, suggest that dominant-negative or gain-of-function mechanisms might be at play. All in all, we define a neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of features. This finding highlights the important role of genes encoding COMPASS family proteins in neurodevelopmental disorders.

KW - Animals

KW - Humans

KW - Autism Spectrum Disorder/genetics

KW - Drosophila melanogaster/genetics

KW - Neurodevelopmental Disorders/genetics

KW - Language Development Disorders

KW - Cluster Analysis

KW - Chromatin

KW - Intracellular Signaling Peptides and Proteins/genetics

KW - Histone-Lysine N-Methyltransferase/genetics

KW - Drosophila Proteins/genetics

U2 - 10.1016/j.xhgg.2022.100157

DO - 10.1016/j.xhgg.2022.100157

M3 - Article

C2 - 36408368

SN - 2666-2477

VL - 4

JO - HGG advances

JF - HGG advances

IS - 1

M1 - 100157

ER -

A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder

Abstract

Bibliographical note

Keywords

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