Abstract
Original language | English |
---|---|
Pages (from-to) | 215-227 |
Number of pages | 13 |
Journal | American journal of human genetics |
Volume | 110 |
Issue number | 2 |
DOIs | |
Publication status | Published - 2 Feb 2023 |
Keywords
- X-linked intellectual disability
- ZMYM3
- chromatin modifiers
- neurodevelopmental disorder
- transcriptional coregulators
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In: American journal of human genetics, Vol. 110, No. 2, 02.02.2023, p. 215-227.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype
AU - Hiatt, Susan M.
AU - Trajkova, Slavica
AU - Sebastiano, Matteo Rossi
AU - Partridge, E. Christopher
AU - Abidi, Fatima E.
AU - Anderson, Ashlyn
AU - Ansar, Muhammad
AU - Antonarakis, Stylianos E.
AU - Azadi, Azadeh
AU - Bachmann-Gagescu, Ruxandra
AU - Bartuli, Andrea
AU - Benech, Caroline
AU - Berkowitz, Jennifer L.
AU - Betti, Michael J.
AU - Brusco, Alfredo
AU - Cannon, Ashley
AU - Caron, Giulia
AU - Chen, Yanmin
AU - Cochran, Meagan E.
AU - Coleman, Tanner F.
AU - Crenshaw, Molly M.
AU - Cuisset, Laurence
AU - Curry, Cynthia J.
AU - Darvish, Hossein
AU - Demirdas, Serwet
AU - Descartes, Maria
AU - Douglas, Jessica
AU - Dyment, David A.
AU - Elloumi, Houda Zghal
AU - Ermondi, Giuseppe
AU - Faoucher, Marie
AU - Farrow, Emily G.
AU - Felker, Stephanie A.
AU - Fisher, Heather
AU - Hurst, Anna C. E.
AU - Joset, Pascal
AU - Kelly, Melissa A.
AU - Kmoch, Stanislav
AU - Leadem, Benjamin R.
AU - Lyons, Michael J.
AU - Macchiaiolo, Marina
AU - Magner, Martin
AU - Mandrile, Giorgia
AU - Mattioli, Francesca
AU - McEown, Megan
AU - Meadows, Sarah K.
AU - Medne, Livija
AU - Meeks, Naomi J. L.
AU - Montgomery, Sarah
AU - Napier, Melanie P.
AU - Natowicz, Marvin
AU - Newberry, Kimberly M.
AU - Niceta, Marcello
AU - Noskova, Lenka
AU - Nowak, Catherine B.
AU - Noyes, Amanda G.
AU - Osmond, Matthew
AU - Prijoles, Eloise J.
AU - Pugh, Jada
AU - Pullano, Verdiana
AU - Quélin, Chloé
AU - Rahimi-Aliabadi, Simin
AU - Rauch, Anita
AU - Redon, Sylvia
AU - Reymond, Alexandre
AU - Schwager, Caitlin R.
AU - Sellars, Elizabeth A.
AU - Scheuerle, Angela E.
AU - Shukarova-Angelovska, Elena
AU - Skraban, Cara
AU - Stolerman, Elliot
AU - Sullivan, Bonnie R.
AU - Tartaglia, Marco
AU - Thiffault, Isabelle
AU - Uguen, Kevin
AU - Umaña, Luis A.
AU - van Bever, Yolande
AU - van der Crabben, Saskia N.
AU - van Slegtenhorst, Marjon A.
AU - Waisfisz, Quinten
AU - Washington, Camerun
AU - Rodan, Lance H.
AU - Myers, Richard M.
AU - Cooper, Gregory M.
N1 - Funding Information: We thank all the families who participated in this study. This work was supported by many funding sources, including the following: Alabama Genomic Health Initiative , an Alabama-State earmarked project ( F170303004 ) through the University of Alabama in Birmingham (S.M.H., A.C., A.C.E.H., M.D., and G.M.C.); National Human Genome Research Institute ( NHGRI ) UM1HG007301 (S.M.H., G.M.C.); National Institute of Mental Health ( NIMH ) F31MH126628 (S.A.F.); National Institute of Nursing Research (Program EXCELES, ID Project No. LX22NPO5107 ), funded by the European Union , Next Generation EU (L.N.); UNCE/MED/007 of Charles University in Prague (L.N.); Ministry of Health of the Czech Republic , NV19-07-00136 (S.K.); Italian Ministry of Health (Ricerca 5x1000, RCR-2020-23670068_001 , and RCR-2021-23671215 ) (M.T.); Italian Ministry of Research ( FOE 2019 ) (M.T.), and PRIN2020 (code 20203P8C3X ) (A. Brusco); Swiss National Science Foundation ( 31003A_182632 ) (A. Reymond); Blackswan Foundation (A. Reymond); ChildCare Foundation (S.E.A.); CRT Foundation (Program "Erogazioni Ordinarie" 2019) (G.C. and G.E.); Italian Ministry of University and Research (Assegni, Tornata 2022, Bando: BMSS.2022.06/XXIV) (M.R.S.); RVO VFN 64165, Czech Ministry of Health (M. Magner); Swiss National Science Foundation grant 320030_179547 (A. Rauch); and The Genesis Foundation for Children (C.B.N., J.D.). L.N. and S.K. thank the National Center for Medical Genomics ( LM2018132 ) for exome-sequencing analyses. Sequencing and analysis of one individual in this study was made possible by the generous gifts to Children’s Mercy Research Institute and Genomic Answers for Kids program at Children’s Mercy Kansas City. Reanalysis of exome sequencing for individual 14 was performed on a research basis by the Care4Rare Canada Consortium. Funding Information: We thank all the families who participated in this study. This work was supported by many funding sources, including the following: Alabama Genomic Health Initiative, an Alabama-State earmarked project (F170303004) through the University of Alabama in Birmingham (S.M.H. A.C. A.C.E.H. M.D. and G.M.C.); National Human Genome Research Institute (NHGRI) UM1HG007301 (S.M.H. G.M.C.); National Institute of Mental Health (NIMH) F31MH126628 (S.A.F.); National Institute of Nursing Research (Program EXCELES, ID Project No. LX22NPO5107), funded by the European Union, Next Generation EU (L.N.); UNCE/MED/007 of Charles University in Prague (L.N.); Ministry of Health of the Czech Republic, NV19-07-00136 (S.K.); Italian Ministry of Health (Ricerca 5x1000, RCR-2020-23670068_001, and RCR-2021-23671215) (M.T.); Italian Ministry of Research (FOE 2019) (M.T.), and PRIN2020 (code 20203P8C3X) (A. Brusco); Swiss National Science Foundation (31003A_182632) (A. Reymond); Blackswan Foundation (A. Reymond); ChildCare Foundation (S.E.A.); CRT Foundation (Program “Erogazioni Ordinarie” 2019) (G.C. and G.E.); Italian Ministry of University and Research (Assegni, Tornata 2022, Bando: BMSS.2022.06/XXIV) (M.R.S.); RVO VFN 64165, Czech Ministry of Health (M. Magner); Swiss National Science Foundation grant 320030_179547 (A. Rauch); and The Genesis Foundation for Children (C.B.N. J.D.). L.N. and S.K. thank the National Center for Medical Genomics (LM2018132) for exome-sequencing analyses. Sequencing and analysis of one individual in this study was made possible by the generous gifts to Children's Mercy Research Institute and Genomic Answers for Kids program at Children's Mercy Kansas City. Reanalysis of exome sequencing for individual 14 was performed on a research basis by the Care4Rare Canada Consortium. J.L.B. Y.C. B.R.L. M.P.N. A.G.N. and H.Z.E. are employees of GeneDx, LLC. S.E.A. is a cofounder and CEO of MediGenome, the Swiss Institute of Genomic Medicine. All other authors declare no competing interests. Publisher Copyright: © 2022 American Society of Human Genetics
PY - 2023/2/2
Y1 - 2023/2/2
N2 - Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene.
AB - Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene.
KW - X-linked intellectual disability
KW - ZMYM3
KW - chromatin modifiers
KW - neurodevelopmental disorder
KW - transcriptional coregulators
UR - http://www.scopus.com/inward/record.url?scp=85147457278&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ajhg.2022.12.007
DO - https://doi.org/10.1016/j.ajhg.2022.12.007
M3 - Article
C2 - 36586412
SN - 0002-9297
VL - 110
SP - 215
EP - 227
JO - American journal of human genetics
JF - American journal of human genetics
IS - 2
ER -