Monogenic hearing loss

Gene: SLC52A2

Green List (high evidence)

Comment on classification of this gene: The rating for this gene should be GREEN, as this gene has been implicated in hearing loss, as identified from biallelic loss-of-function variants from >20 unrelated individuals/ families from multiple ethnicities and supported by results from functional studies. Several of these patients with biallelic variants in SLC52A2 gene and treated with oral riboflavin responded well to the treatment.

Unrelated individuals carrying homozygous variants (e.g. c.916G>A/ p.Gly306Arg) and compound heterozygous variants (e.g. c.368T>C/ p.Leu123Pro & c.1016T>C/ p.Leu339Pro) were reported with Brown-Vialetto-Van Laere syndrome-2. According to report from Foley et al (2014), patients were presented with ataxia (9 out of 18 patients), hearing loss (all 18 patients), limb/ muscle weakness (17 patients), optic atrophy/ impaired vision (14 of 15 patients), tongue fasciculations (11 of 18 patients) and axonal sensorimotor neuropathy (all 18 patients). The onset of ataxia ranged from 1.5 to 8 years of age and some of these patients were confined to a wheelchair in their childhood (ranging from 1.5 to 8 years old). Respiratory insufficiency developed in 13 patients (PMID:24253200). One patient from this study and patient from Ciccolella et al (2012) bearing compound heterozygous variants were hospitalized for respiratory failure and died at 3-4 years of age (PMID:24253200; PMID:23243084).

A report on an eight year old patient with already identified homozygous variant (c.916G>A/ p.Gly306Arg) was presented with progressive ataxia since the age of 2.5 years and cerebellar atrophy and peripheral polyneuropathy despite the absence of other common symptoms of Brown-Vialetto-Van Laere syndrome including motor neuropathy, bulbar palsy, optic atrophy, and sensorineural hearing loss (PMID:30377535).

A recent review and statistical analysis by Zhou et al reports data of 62 BVVL type 2 patients from 43 different families, of which 40 patients had homozygous and 22 patients had compound heterozygous variants. A total of 32 variants have been reported to date, with the most common being missense variants. The symptoms of BVVL type 2 appear at the earliest shortly after birth and at the latest at 10 years of age. The most common symptoms are hearing loss (83.9%), muscle weakness (80.6%), visual impairment (64.5%), and ataxia (61.3%). In addition, this study also suggests that homozygous pattern was more likely to present with ataxia as the first symptom in patients with missense mutations (p < 0.05), while compound heterozygous pattern was more likely to develop respiratory insufficiency during the course of disease (p < 0.001) (PMID:36186484).

Transfection and overexpression of SLC52A2 gene containing mutant alleles in HEK293 showed that the riboflavin uptake activity was abolished in certain mutants and moderately reduced in others. In addition, the expression levels of mutants were decreased (in correlation with the reduction in activity) with the exception of only one mutant tested (PMID:22864630; PMID:24253200).

Created: 11 Dec 2022, 7:20 p.m. | Last Modified: 11 Dec 2022, 7:20 p.m.

Panel Version: 3.1

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867; Sensorineural hearing loss disorder, MONDO:0020678

Publications

• 22740598
• 22864630
• 23243084
• 24253200
• 30343981
• 30377535
• 31868069
• 35608644
• 36186484

Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.

Created: 20 Oct 2020, 8:02 a.m. | Last Modified: 20 Oct 2020, 8:02 a.m.

Panel Version: 2.95

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

Created: 3 Mar 2022, 1:19 p.m. | Last Modified: 3 Mar 2022, 1:19 p.m.

Panel Version: 2.221

Comment on list classification: Changing rating from red to green. More than 3 cases reported in patients with Brown-Vialetto-Van Laere syndrome 2 and variants in this gene. Expert reviewer reports that hearing loss may be the first presentation.

Created: 11 May 2020, 12:02 p.m. | Last Modified: 11 May 2020, 12:02 p.m.

Panel Version: 2.18

Associated with Brown-Vialetto-Van Laere syndrome 2 #614707 (AR) in OMIM. Early childhood onset of sensorineural deafness is a feature along with bulbar dysfunction, and severe diffuse muscle weakness and wasting of the upper and lower limbs and axial muscles, resulting in respiratory insufficiency.

Numerous cases have been reported with variants in the SLC52A2 gene and Brown-Vialetto-Van Laere syndrome 2:

PMID: 22740598 Johnson et al 2012 - used linkage and exome sequencing to identify a novel mutation (p.G306R (c.916G>A)) in SLC52A2 in an extended Lebanese Brown-Vialetto-Van Laere kindred. The same homozygous mutation was identified in one additional subject from the UK, from 44 screened.

PMID: 22864630 Haack et al 2012 - exome sequencing of a single case with Brown-Vialetto-Van Laere syndrome showed compound heterozygosity for two pathogenic mutations in the SLC52A2 gene. Overexpression studies confirmed that the gene products of both mutant alleles have reduced riboflavin transport activities.

PMID: 23243084 Ciccolella et al 2013 - 1 case of a severe BVVL patient with two novel compound heterozygous mutations in SLC52A2 (c.155C>T, p.S52F and c.1255G>A, p.G419S). Functional studies show that these variants impair the gene expression of the corresponding transporter, resulting in a significant reduction of riboflavin transport.

PMID: 24253200 Foley et al 2014 - using exome and sanger sequencing identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy, hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression.

Created: 11 May 2020, 11:59 a.m. | Last Modified: 11 May 2020, 11:59 a.m.

Panel Version: 2.14

Gene suggested for panel by Dr Julia Rankin (Royal Devon and Exeter NHS Foundation Trust). Sensorineural deafness is the presenting feature in cases presenting after infancy with other neurology a year or 2 later – treatment with Riboflavin can be effective.
Sources: Expert list

Created: 11 May 2020, 9:59 a.m. | Last Modified: 11 May 2020, 10:01 a.m.

Panel Version: 2.9

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Brown-Vialetto-Van Laere syndrome 2 #614707

Publications

• 22740598
• 22864630
• 23243084
• 24253200