Early onset or syndromic epilepsy

Gene: OTUD7A

This gene is not currently associated with a disease phenotype in OMIM, but checked PMID:31997314 to make sure it is the same gene listed in the publication as on this panel and it is, so added the gene-checked tag.

Created: 16 Oct 2023, 7:36 p.m. | Last Modified: 16 Oct 2023, 7:36 p.m.

Panel Version: 4.118

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.

Created: 11 Oct 2023, noon | Last Modified: 11 Oct 2023, noon

Panel Version: 4.110

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Comment on list classification: There is sufficient evidence (three unrelated cases with biallelic variants and supportive functional evidence from mouse models) for this gene to be promoted to green at the next major review.

Created: 17 Apr 2023, 6:27 a.m. | Last Modified: 17 Apr 2023, 6:27 a.m.

Panel Version: 4.14

PMID:31997314 reported a patient presenting with severe global developmental delay, language impairment and epileptic encephalopathy and was identified with homozygous variant in OTUD7A gene (c.697C>T)/ p.Leu233Phe).

PMID:33381903 reported a patient with profound hypotonia, severe intellectual disability, and seizures and identified with biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del/ p.Glu375Aspfs*11.

PMID:36180924 reported a patient (patient #4) presenting with severe neurodevelopmental diseases and dysmorphic features and identified with hemizygous OTUD7A frameshift variant allele c.2023_2066del/ p.D675Hfs*188 in trans with the recurrent 15q13.3 BP4-BP5 deletion.

OTUD7A knockout mice exhibited reduced body weight, developmental delay, abnormal electroencephalography patterns and seizures, reduced ultrasonic vocalisations, decreased grip strength, impaired motor learning/motor coordination, and reduced acoustic startle (PMID:29395075). The function evidence also suggest that OTUD7A may be the critical “driver gene” in the 15q13.3 deletion syndrome.

This gene has been reported in the DD panel of Gene2Phenotype (with 'limited' rating), but has not yet been associated with phenotypes in OMIM.

Created: 17 Apr 2023, 6:25 a.m. | Last Modified: 17 Apr 2023, 6:30 a.m.

Panel Version: 4.14

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
developmental and epileptic encephalopathy, MONDO:0100062

Publications

• 29395075
• 31997314
• 33381903
• 36180924

Green List (high evidence)

Second case and third case with DD and seizures and biallelic variant reported in 36180924 and 31997314, in addition to the previously mentioned 31997314.

Created: 8 Oct 2022, 11 p.m. | Last Modified: 8 Oct 2022, 11 p.m.

Panel Version: 2.597

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 36180924
• 31997314
• 31997314

Red List (low evidence)

Review by Zornitza Stark on Intellectual disability panel https://panelapp.genomicsengland.co.uk/panels/285/: One patient with severe global developmental delay, language impairment and epileptic encephalopathy reported. Homozygous OTUD7A missense variant (c.697C>T, p.Leu233Phe), predicted to alter an ultraconserved amino acid, lying within the OTU catalytic domain. Its subsequent segregation analysis revealed that the parents, presenting with learning disability, and brother were heterozygous carriers. Biochemical assays demonstrated that proteasome complex formation and function were significantly reduced in patient‐derived fibroblasts and in OTUD7A knockout HAP1 cell line. Gene lies in the chromosome 15q13.3 region. Heterozygous microdeletions of chromosome 15q13.3 show incomplete penetrance and are associated with a highly variable phenotype that may include intellectual disability, epilepsy, facial dysmorphism and digit anomalies. Mouse model and other data support the role of this gene in neurodevelopmental phenotypes but nevertheless, single family to date.

Created: 9 Jul 2020, 5:20 p.m. | Last Modified: 9 Jul 2020, 5:20 p.m.

Panel Version: 2.119

Not associated with phenotype in OMIM or in Gen2Phen, Although the region ISCA-46295-Loss, which encompasses the OTUD7A locus, is associated with seizures 20236110, mental retardation 22775350, dysmorphic features, developmental delay and severe epileptic encephalopathy. PMID 31997314 report a homozygous variant in a case of severe global developmental delay, language impairment and epileptic encephalopathy; segregation and functional studies support this gene disease association.
Sources: Literature

Created: 9 Jul 2020, 5:17 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Epileptic encephalopathy, intellectual disability

Publications

• 31997314
• 29395075
• 29395074