Genes in panel
Regions in panel
Prev Next

Intellectual disability

Gene: OXR1

Amber List (moderate evidence)

OXR1 (oxidation resistance 1)
EnsemblGeneIds (GRCh38): ENSG00000164830
EnsemblGeneIds (GRCh37): ENSG00000164830
OMIM: 605609, Gene2Phenotype
OXR1 is in 2 panels

3 reviews

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

There is enough evidence for this gene to be rated GREEN at the next major review.
Created: 6 Aug 2020, 11:13 a.m. | Last Modified: 6 Aug 2020, 11:13 a.m.
Panel Version: 3.234
Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction. At least 4 variants reported in at least 3 unrelated cases, who all had epilepsy and global developmental delay.
Created: 6 Aug 2020, 11:13 a.m. | Last Modified: 6 Aug 2020, 11:13 a.m.
Panel Version: 3.234
Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction. At least 4 variants reported in at least 3 unrelated cases, who all had epilepsy and global developmental delay.
Created: 6 Aug 2020, 11:13 a.m. | Last Modified: 6 Aug 2020, 11:13 a.m.
Panel Version: 3.234

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Five individuals from three families.
Created: 9 Feb 2020, 10:27 a.m. | Last Modified: 9 Feb 2020, 10:27 a.m.
Panel Version: 3.0

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intellectual disability; seizures; cerebellar atrophy

Publications

Variants in this GENE are reported as part of current diagnostic practice

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Wang et al (2019 - https://doi.org/10.1016/j.ajhg.2019.11.002 ) report on 5 individuals (from 3 families) with biallelic OXR1 LoF variants.

Common features included hypotonia (4/5), severe global DD (5/5) and speech delay (5/5), ID (5/5), epilepsy (5/5) with cerebellar dysplasia/atrophy (5/5) and in some scoliosis.

All were investigated by exome sequencing and were found to harbor biallelic loss-of-function variants (2 splice-site, a stopgain and a frameshift one) either in homozygosity (2 consanguineous families) or in compound heterozygosity. In all cases parental segregation studies were compatible and in one family, an unaffected sib shown to be carrier.

Althouhgh OXR1 has been shown to affect several processes (among others DNA lesions induced by oxidative stress in E.coli, neuronal maintenance, mitochondrial morphology and DNA maintenance, etc), its mechanism of action is still not well defined. There are 6 RefSeq transcripts, the longest (NM_018002.3) encoding 3 protein domains (LysM, GRAM, TLDc). The TLDc domain is encoded by all transcripts.

Identified variants affected (probably all - fig1D) transcripts expressed in the CNS, namely NM_018002.3, NM_001198532.1, NM_181354.4. The 3 transcripts not expressed in the CNS are NM_001198533.1, NM_001198534.1 and NM_001198535.1.

Western blot with 2 different antibodies which would bind upstream of the truncation site failed to detect presence of truncated proteins in 2 affected individuals from 2 families.

The Drosophila homolog of OXR is mustard (mtd). The authors provide evidence that loss of mtd is lethal. This was however rescued by expression of an 80kb fly BAC clone covering mtd, or the fly mtd-RH isoform cDNA, or a short human OXR1 cDNA containing only the TLDc domain or a human NCOA7 cDNA. The latter is another human mtd homolog which also contains the TLDc domain. As a result the TLDc domain compensated sufficiently for loss of mtd.

Flies that survived displayed bang sensitivity and climbing defects the former assay being suggestive of susceptibility to seizures and the latter of impaired neurological/muscular function.

The authors provided evidence that mtd is broadly expressed in the fly CNS. RNAi mediated mtd knockdown specific to neurons (elav/nSyb-GAL4 expression of mtd RNAi) led to lethal eclosion defects for RNAis targeting most (18)/all(23) mtd isoforms. Lifespan was increased upon expression of human OXR1 cDNA. Neuronal loss and vacuolization was demonstrated and additional experiments in R7 photoreceptors showed presence of aberrant lysosomal structures (autolysosomes, autophagosomes and/or endolysosomes).

Aberrant lysosomal structures were also observed in fibroblasts from affected individuals (accumulation of lysosomes and/or presence of highly aberrant compartments with content typical of lysosomal dysfunction).

Overall the data presented suggest a critical role for OXR1 in lysosomal biology.

Although previous reports suggested that OXR1 is involved in oxidative stress resistance, studies performed by the authors suggested that oxidative stress is probably not the driver of the mutant fly defects.
Sources: Literature
Created: 1 Dec 2019, 11:14 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Central hypotonia; Global developmental delay; Delayed speech and language development; Intellectual disability; Seizures; Abnormality of the cerebellum

Publications

  • https://doi.org/10.1016/j.ajhg.2019.11.002

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay 213000
Tags
for-review
OMIM
605609
Clinvar variants
Variants in OXR1
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

6 Aug 2020, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: oxr1 has been classified as Amber List (Moderate Evidence).

6 Aug 2020, Gel status: 2

Added Tag

Sarah Leigh (Genomics England Curator)

Tag for-review tag was added to gene: OXR1.

6 Aug 2020, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: oxr1 has been classified as Amber List (Moderate Evidence).

6 Aug 2020, Gel status: 0

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: OXR1 were set to 31785787

6 Aug 2020, Gel status: 0

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for gene: OXR1 were changed from Central hypotonia; Global developmental delay; Delayed speech and language development; Intellectual disability; Seizures; Abnormality of the cerebellum to Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay 213000

6 Aug 2020, Gel status: 0

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: OXR1 were set to https://doi.org/10.1016/j.ajhg.2019.11.002

1 Dec 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: OXR1 was added gene: OXR1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: OXR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: OXR1 were set to https://doi.org/10.1016/j.ajhg.2019.11.002 Phenotypes for gene: OXR1 were set to Central hypotonia; Global developmental delay; Delayed speech and language development; Intellectual disability; Seizures; Abnormality of the cerebellum Penetrance for gene: OXR1 were set to Complete Review for gene: OXR1 was set to GREEN