Deleterious, protein-altering variants in the X-linked transcriptional coregulator ZMYM3 in 22 individuals with a neurodevelopmental delay phenotype
Authors: Hiatt Susan M. , Trajkova Slavica , Sebastiano Matteo Rossi , Partridge E. Christopher , Abidi Fatima E. , Anderson Ashlyn , Ansar Muhammad , Antonarakis Stylianos E. , Azadi Azadeh , Bachmann-Gagescu Ruxandra , Bartuli Andrea , Benech Caroline , Berkowitz Jennifer L. , Betti Michael J. , Brusco Alfredo , Cannon Ashley , Caron Giulia , Chen Yanmin , Crenshaw Molly M. , Cuisset Laurence , Curry Cynthia J. , Darvish Hossein , Demirdas Serwet , Descartes Maria , Douglas Jessica , Dyment David A. , Elloumi Houda Zghal , Ermondi Giuseppe , Faoucher Marie , Farrow Emily G. , Felker Stephanie A. , Fisher Heather , Hurst Anna C. E. , Joset Pascal , Kmoch Stanislav , Leadem Benjamin R. , Macchiaiolo Marina , Magner Martin , Mandrile Giorgia , Mattioli Francesca , McEown Megan , Meadows Sarah K. , Medne Livija , Meeks Naomi J. L. , Montgomery Sarah , Napier Melanie P. , Natowicz Marvin , Newberry Kimberly M. , Niceta Marcello , Noskova Lenka , Nowak Catherine , Noyes Amanda G. , Osmond Matthew , Pullano Verdiana , Quélin Chloé , Rahimi-Aliabadi Simin , Rauch Anita , Redon Sylvia , Reymond Alexandre , Schwager Caitlin R. , Sellars Elizabeth A. , Scheuerle Angela , Shukarova-Angelovska Elena , Skraban Cara , Sullivan Bonnie R. , Tartaglia Marco , Thiffault Isabelle , Uguen Kevin , Umaña Luis A. , van Bever Yolande , van der Crabben Saskia N. , van Slegtenhorst Marjon A. , Waisfisz Quinten , Myers Richard M. , Cooper Gregory M. 
Published: September 2022

ABSTRACTNeurodevelopmental disorders (NDDs) often result from highly penetrant variation in one of many genes, including genes not yet characterized. Using the MatchMaker Exchange, we assembled a cohort of 22 individuals with rare, protein-altering variation in the X-linked transcriptional coregulator gene ZMYM3. Most (n=19) individuals were males; 15 males had maternally-inherited alleles, three of the variants in males arose de novo, and one had unknown inheritance. 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=21) are missense, two of which are recurrent. Three unrelated males were identified with inherited variation at R441, a site at which variation has been previously reported in NDD-affected males, and two individuals have de novo variation at R1294. 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 highly expressed in the brain, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one mutant, ZMYM3R1274W, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. 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 the presence of recurrent variation, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally-confirmed functional effects, strongly supports ZMYM3 as a novel NDD gene.