Monogenic hearing loss
Gene: ATP2B2
PMID: 30535804 - Smits et al 2019 as per previous review.
Heterozygous loss of function variants also reported in association with dominant hearing loss by Brownstein PMID: 33111345 p.(Gln345*) segregating in 8 affected family members and by Morgan PMID: 33105617 p.(Ser321*) - pedigree with 6 affected family members (unclear who else tested in family).
3 unrelated heterozygous cases also detected here at GOSH: p.(Arg777*), p.(Val441Cysfs*48) and p.(Val587Cysfs*44), the latter segregated in affected parent.
Phenotype of predominantly high frequency progressive hearing loss consistent across families, LoF variants reported across 7 different exons in 10 unrelated families.
Gene should be promoted to green.Created: 10 Mar 2023, 9:13 a.m. | Last Modified: 10 Mar 2023, 9:13 a.m.
Panel Version: 3.14
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Deafness, autosomal dominant 82
Publications
Comment on list classification: There is now enough evidence to show that variants in this gene can cause hearing loss so the recommendation is that this gene is rated Green following GMS review.Created: 9 May 2023, 4:06 p.m. | Last Modified: 9 May 2023, 4:06 p.m.
Panel Version: 4.9
Comment on list classification: Promoting from red to amber. PMID 30535804 reports 5 independent cases of autosomal dominant hearing impairment in individuals with truncating or splice site variants. Rare variants in CDH23 were considered unlikely to be causative. However, they cannot exclude a modifying effect of the CDH23 variants on Hearing impairment, therefore rating amber until further cases on monogenic hearing loss with ATP2B2 are reported.Created: 11 Jul 2019, 10:48 p.m. | Last Modified: 9 May 2023, 3:52 p.m.
Panel Version: 4.6
Comment on publications: PMID: 17234811 - Ficarella et al 2007 - A functional study of plasma-membrane calcium-pump isoform 2 mutants causing digenic deafness.Created: 11 Jul 2019, 10:37 p.m. | Last Modified: 11 Jul 2019, 10:37 p.m.
Panel Version: 1.120
Comment on mode of inheritance: The 5 cases described in PMID: 30535804 show a monoallelic pattern of inheritanceCreated: 11 Jul 2019, 10:34 p.m. | Last Modified: 11 Jul 2019, 10:34 p.m.
Panel Version: 1.118
PMID: 30535804 - Smits et al 2019 - report 5 independant cases. Whole exome sequencing in hearing impaired index cases of Dutch and Polish origins revealed five novel heterozygous (predicted to be) loss-of-function variants of ATP2B2. Two variants, c.1963G>T (p.Glu655*) and c.955delG (p.Ala319fs), occurred de novo. Three variants c.397+1G>A (p.?), c.1998C>A (p.Cys666*), and c.2329C>T (p.Arg777*), were identified in families with an autosomal dominant inheritance pattern of hearing impairment. In most cases HI was early onset, but in one individual hearing loss was reported around 55 years. Whole exome sequence (WES) data were analyzed for variants in a panel of 142 genes known to be associated with nonsyndromic hearing impairment (HI) and relatively common syndromic forms of HI. All variants affect exons, or their splice sites, that encode the ortholog of the rat PMCA2 w/a isoform. This isoform is highly abundant in stereocilia of outer hair cells (OHC) and to a lesser extent at the apical surface of inner hair cells of rats.
Although rare CDH23 variants cooccurred with ATP2B2 variants in all five index cases, they state their findings indicate that mono-allelic loss-of-function variants of ATP2B2 are the underlying cause of HI. However, variants in deep intronic regions or promoter regions were not addressed and can, therefore, not be excluded. CNVs of CDH23 can be excluded for the index cases only. They state they cannot exclude a modifying effect of the CDH23 variants on HI in the affected subjects in their study.Created: 11 Jul 2019, 10:33 p.m. | Last Modified: 11 Jul 2019, 10:33 p.m.
Panel Version: 1.117
After review with the NHS GMS hearing specialist group on 2019-02-13 it was decided to keep this gene red.Created: 18 Feb 2019, 10:19 a.m.
Publications
reported as a modifier of AR deafness 12, one case only other is v frequent variantCreated: 17 Feb 2019, 4:35 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
#601386:{Deafness, autosomal recessive 12, modifier of}[Hearing loss, profound prelingual sensorineural; No retinitis pigmentosa]
Publications
Gene: atp2b2 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: ATP2B2 were changed from {Deafness, autosomal recessive 12, modifier of} 601386 to {Deafness, autosomal recessive 12, modifier of}, OMIM:601386; Deafness, autosomal dominant 82, OMIM:619804; hearing loss, autosomal dominant 82, MONDO:0030719
Publications for gene: ATP2B2 were set to 30535804; 17234811
Tag Q2_23_promote_green tag was added to gene: ATP2B2. Tag Q2_23_NHS_review tag was added to gene: ATP2B2.
Gene: atp2b2 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: ATP2B2 were changed from to {Deafness, autosomal recessive 12, modifier of} 601386
Publications for gene: ATP2B2 were set to 30535804
Publications for gene: ATP2B2 were set to
Mode of inheritance for gene: ATP2B2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
ATP2B2 was added to Congenital hearing impairment (Profound/Severe)panel. Sources: UKGTN,Expert
ATP2B2 was added to Congenital hearing impairment (Profound/Severe)panel. Sources: UKGTN,Expert