PXD082880

PXD082880 is an original dataset announced via ProteomeXchange.

Title	A two-exon deletion and hypomorphic missense variant in GEMIN5 causes autosomal recessive ataxia
Description	Neurodegenerative and neuromuscular disorders are genetically heterogeneous, and many patients remain without a genetic diagnosis after multiple rounds of clinical gene panels or exome sequencing. These approaches often fail to detect structural variants (SVs), contributing to missed diagnoses. We investigated 286 individuals with neurodegenerative or neuromuscular diseases who previously received an uninformative report from diagnostic testing. Short-read genome sequencing (srGS) was used for single nucleotide variant/indel, copy number variant, and SV calling with variant prioritisation in seqr. Findings were corroborated by long-read sequencing, orthogonal validation (PCR/MLPA/Sanger), transcriptomics, and proteomics. We also assessed the utility of Talos (an automated variant prioritisation tool) to find clinically relevant SVs. Overall, 65/286 cases (22.7%) were solved; SVs accounted for 11/65 solved cases (16.9%). Four of these would not be detectable with targeted panel or exome sequencing. We describe 10 illustrative diagnoses spanning diverse SV classes: an intronic interspersed duplication disrupting SPAST (SPG4); SVs supporting phenotype expansions associated with SPG11 (neuronal ceroid lipofuscinosis), heterozygous large in-frame deletions in TTN (distal arthrogryposis), and SPTAN1 (autosomal-dominant hereditary spastic paraplegia); an intergenic balanced translocation downstream of FOXG1; and a pathogenic SVA insertion in TAF1 detected as breakends in srGS. Talos prioritised seven of 10 SV diagnoses. SVs contribute substantially to diagnoses in neurogenetic disease cohorts and can evade panel/exome pipelines due to intronic breakpoints, balanced rearrangements, microhomology, and partial-exon events. srGS combined with automated reanalysis can shorten diagnostic timelines and improve diagnostic equity through a single, genome-wide test, although the clinical interpretation of SVs remains a significant challenge.
HostingRepository	PRIDE
AnnounceDate	2026-08-27
AnnouncementXML	Submission_2026-08-27_05:36:43.725.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Gavin Monahan
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2026-08-20 00:01:24	ID requested
⏵ 1	2026-08-27 05:36:44	announced

Dataset with its publication pending

submitter keyword: Human, PBMCs, ataxia, neurodegeneration

Gina Ravenscroft
contact affiliation	Harry Perkins Institute of Medical Research, Centre for Medical Research, The University of Western Australia, Nedlands, WA, 6009, Australia
contact email	gina.ravenscroft@perkins.uwa.edu.au
lab head
Gavin Monahan
contact affiliation	Harry Perkins Institute of Medical Research
contact email	gavin.monahan@perkins.org.au
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/08/PXD082880

PRIDE project URI

• PRIDE
  1. PXD082880
     1. Label: PRIDE project
     2. Name: A two-exon deletion and hypomorphic missense variant in GEMIN5 causes autosomal recessive ataxia