Monogenic hearing loss

Gene: USP48

Green List (high evidence)

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

Green List (high evidence)

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: Literature

Created: 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

• 34059922