Deleterious, protein-altering variants in the X-linked transcriptional coregulator ZMYM3 in 22 individuals with a neurodevelopmental delay phenotype

Abstract

Neurodevelopmental 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.

Skewed X-chromosome inactivation in unsolved neurodevelopmental disease cases can guide re-evaluation For X-linked genes

“…In the former category, LINKage-speci c-deubiquitylation-de ciency-induced embryonic defects (LINKED) syndrome, has been associated to pathogenic OTUD5 variants only in 2021,(31) whereas PDZD4 and ZMYM3 have been presently only proposed as a disease gene. (33,35) The microdeletion identi ed in ATRX (family 236) highlights the importance of searching for genomic rearrangements, exploiting exome data, or performing genome sequencing. In this case the deletion was missed by CMA due to lack of array probes in the deleted tract.…”

“…Furthermore, p.(Arg441Trp) variant was described by Philips et al 2014 in three male probands with ID and several dysmorphic features shared with proband II.1, and recently con rmed as a recurrent variant in a novel ZMYM3-associated NDD. (32,33) Other potentially causative ES-variants were excluded by functional analysis (de novo OSBPL8: c.1535T > C; p.(Val512Ala) that did not showed alteration of the protein activity (Prof. T. Balla, Bethesda NY, personal communication).…”