GEO series

Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype [RNA-seq]

GSE259222 Homo sapiens (human) RNA-seq (gene expression) 12 samples Submitted 2024/03/02 Platform GPL18573

At a glance

RNA-seq (gene expression) · human · 12 samples

What it is: RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism: Homo sapiens (human)
Samples: 12 samples: 3 × HepG2_R1274W_Control vs 3 × HepG2_R1274W_Variant vs 3 × HepG2_R688H_Control vs 3 × HepG2_R688H_VariantGroups are read from the sample names, not from the paper. Check the list below.
Data you can get: A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper: Probabilistic association of differentially expressed genes with cis-regulatory elementsGenome research · 2024

Summary (written by the submitters)

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.

Read the full summary ↓

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.

Published in

Probabilistic association of differentially expressed genes with cis-regulatory elements

Roberts BS, Anderson AG, Partridge EC et al. · Genome research 2024 · PMID 38631728 · doi:10.1101/gr.278598.123

This dataset

Open GSE259222 in finder → Find more human RNA-seq datasets →

Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓

2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE259222_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓

3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1080482 and SRA study SRP491702. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 38631728) ↗

Study design

3 × HepG2_R1274W_Control vs 3 × HepG2_R1274W_Variant vs 3 × HepG2_R688H_Control vs 3 × HepG2_R688H_Variant

Supports a between-group comparison across 12 samples.

How we read this: 4 replicated groups read from 12 sample titles; they account for 12 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study

GSM8111625 HepG2_R1274W_Control_1 HepG2_R1274W_Control
GSM8111626 HepG2_R1274W_Control_2 HepG2_R1274W_Control
GSM8111627 HepG2_R1274W_Control_3 HepG2_R1274W_Control
GSM8111628 HepG2_R1274W_Variant_1 HepG2_R1274W_Variant
GSM8111629 HepG2_R1274W_Variant_2 HepG2_R1274W_Variant
GSM8111630 HepG2_R1274W_Variant_3 HepG2_R1274W_Variant
GSM8111631 HepG2_R688H_Control_1 HepG2_R688H_Control
GSM8111632 HepG2_R688H_Control_2 HepG2_R688H_Control
GSM8111633 HepG2_R688H_Control_3 HepG2_R688H_Control
GSM8111634 HepG2_R688H_Variant_1 HepG2_R688H_Variant
GSM8111635 HepG2_R688H_Variant_2 HepG2_R688H_Variant
GSM8111636 HepG2_R688H_Variant_3 HepG2_R688H_Variant

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