Dataset Information

Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype.

ABSTRACT: 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.

SUBMITTER: Hiatt SM

PROVIDER: S-EPMC9943726 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype.

Hiatt Susan M SM Trajkova Slavica S Sebastiano Matteo Rossi MR Partridge E Christopher EC Abidi Fatima E FE Anderson Ashlyn A Ansar Muhammad M Antonarakis Stylianos E SE Azadi Azadeh A Bachmann-Gagescu Ruxandra R Bartuli Andrea A Benech Caroline C Berkowitz Jennifer L JL Betti Michael J MJ Brusco Alfredo A Cannon Ashley A Caron Giulia G Chen Yanmin Y Cochran Meagan E ME Coleman Tanner F TF Crenshaw Molly M MM Cuisset Laurence L Curry Cynthia J CJ Darvish Hossein H Demirdas Serwet S Descartes Maria M Douglas Jessica J Dyment David A DA Elloumi Houda Zghal HZ Ermondi Giuseppe G Faoucher Marie M Farrow Emily G EG Felker Stephanie A SA Fisher Heather H Hurst Anna C E ACE Joset Pascal P Kelly Melissa A MA Kmoch Stanislav S Leadem Benjamin R BR Lyons Michael J MJ Macchiaiolo Marina M Magner Martin M Mandrile Giorgia G Mattioli Francesca F McEown Megan M Meadows Sarah K SK Medne Livija L Meeks Naomi J L NJL Montgomery Sarah S Napier Melanie P MP Natowicz Marvin M Newberry Kimberly M KM Niceta Marcello M Noskova Lenka L Nowak Catherine B CB Noyes Amanda G AG Osmond Matthew M Prijoles Eloise J EJ Pugh Jada J Pullano Verdiana V Quélin Chloé C Rahimi-Aliabadi Simin S Rauch Anita A Redon Sylvia S Reymond Alexandre A Schwager Caitlin R CR Sellars Elizabeth A EA Scheuerle Angela E AE Shukarova-Angelovska Elena E Skraban Cara C Stolerman Elliot E Sullivan Bonnie R BR Tartaglia Marco M Thiffault Isabelle I Uguen Kevin K Umaña Luis A LA van Bever Yolande Y van der Crabben Saskia N SN van Slegtenhorst Marjon A MA Waisfisz Quinten Q Washington Camerun C Rodan Lance H LH Myers Richard M RM Cooper Gregory M GM

American journal of human genetics 20221230 2

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 i ...[more]

PMID: 36586412

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Project description: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 gene ZMYM3, located on the X chromosome. Most (n=24) individuals were males, 17 of which have a maternally inherited variant and four of which have 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 with variants that have arisen independently at the same codon at least two times. Four unrelated probands were identified with inherited variation at Arg441 (Arg441Trp or Arg441Gln), a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation at Arg1294 (Arg1294Cys). 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 mutant, Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. Similarly, RNA-seq comparing mutant cells to reference revealed numerous expression changes. Such changes were not seen in edited cells harboring a likely benign variant, Arg688His. While we are unable to perform statistical evaluations to support a conclusive causative role for variation in ZMYM3 in disease, the totality of the evidence, including 27 affected individuals, recurrent variation affecting at least two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally-confirmed functional effects strongly support ZMYM3 as a novel NDD gene.

Dataset Information

Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype.

Publications

Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype.

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