Monogenic hearing loss
Gene: USP48
The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.Created: 30 Jan 2023, 10:16 a.m. | Last Modified: 30 Jan 2023, 10:16 a.m.
Panel Version: 3.7
Comment on list classification: Promoting from red to amber, with a recommendation for green rating following GMS review. 3 cases, 1 with segregation data (incomplete penetrance), plus supportive zebrafish model.Created: 7 Oct 2021, 1:14 p.m. | Last Modified: 7 Oct 2021, 1:14 p.m.
Panel Version: 2.191
PMID: 34059922 - Bassani et al 2021 - 3 cases reported with variants in USP48 and non syndromic hearing loss. They first analysed 4-generation Italian family with 6 individuals with hearing loss. The only rare variant segregating with the disease was a missense variant in USP48 (NM_032234.7:c.1216G > A, NP_115612.4:p.(Gly406Arg)). The variant is present in GnomAD v2.1.1 with a minor allele frequency (MAF) of 6.7 × 10−5 (17 allele out of 251 304 with no homozygotes). They also observed one hearing individual in the family who was heterozygous for the variant, suggesting incomplete penetrance.
In a Dutch family the found by exome sequencing a missense variant in USP48 (NM_032236.7:c.2215_2216delinsTT, NP_115612.4:p.(Thr739Leu)). The probands mother and uncle were also affected by no sequence data was available for analysis.
In a French family a proband is reported with right profound sensorineural hearing impairment (at 12 months), but normal left hearing (at 6 years old). The patient is heterozygote for a de novo splice variant in USP48 (NM_032236.7:c.3058 + 2 T > C, NP_115612.4:p.?;) which is not found in GnomAD and is predicted to result in a frameshift resulting in either NMD or a truncated protein.
In functional experiments they showed that the two missense variants found in the Italian and Dutch families, and a shortened protein as predicted for the variant found in the French variant, showed an impaired ability to cleave tetra-ubiquitin into tri-, di- and mono-ubiquitin. Using immunohistology, they show that the human USP48 protein is present in fetal inner ear specimens.
In addition zebrafish lacking usp48 showed a significant decrease of auditory response in acoustic startle response assays at 600 and 800 Hz wavelengths.Created: 7 Oct 2021, 1:12 p.m. | Last Modified: 7 Oct 2021, 1:12 p.m.
Panel Version: 2.187
Conference talk/abstract from ESHG2020 - C06.2 - Whole Exome Sequencing, Molecular Assays, Immunohistology and Animal Models associate USP48 to Hereditary Hearing Loss - Bassani et al. Report 1 large Italian family, and 2 unrelated Dutch families with non-syndromic hearing loss and potentially pathogenic missense variants in USP48. A 4th case with unilateral cochlear nerve aplasia and a de novo splice variant in the same gene is reported. A zebrafish knockout for the USP48 paralog showed delayed primary motoneurons development and behaviour indicative of vestibular dysfunction and hearing impairment and acoustic startle response assays revealed a reduced auditory response.
No publication relating to this work could be found in PubMed at this time.
Sources: LiteratureCreated: 12 Jun 2020, 8 p.m. | Last Modified: 13 Jun 2020, 7:24 a.m.
Panel Version: 2.19
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
nonsyndromic genetic deafness, MONDO:0019497
Publications
Tag Q4_21_rating was removed from gene: USP48.
Source NHS GMS was added to USP48. Source Expert Review Green was added to USP48. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag watchlist was removed from gene: USP48. Tag Q4_21_rating tag was added to gene: USP48.
Gene: usp48 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: USP48 were changed from non-syndromic hearing loss to non-syndromic hearing loss; nonsyndromic genetic deafness, MONDO:0019497
Publications for gene: USP48 were set to
Mode of inheritance for gene: USP48 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Tag watchlist tag was added to gene: USP48.
gene: USP48 was added gene: USP48 was added to Hearing loss. Sources: Literature Mode of inheritance for gene: USP48 was set to Unknown Phenotypes for gene: USP48 were set to non-syndromic hearing loss Review for gene: USP48 was set to RED