Monogenic hearing loss

Gene: PTPRQ

Comment on publications: Previous publications listed: "PMID: 20346435 report a homozygous variant resulting in Tyr497Ter in 2 Dutch siblings with AR nonsyndromic hearing loss, and not found in matched controls. A homozygous variant resulting in Arg457Gly identified in 2 Moroccan siblings with AR nonsyndromic hearing loss, was also not found in matched controls."

Created: 7 Nov 2023, 2:49 p.m. | Last Modified: 7 Nov 2023, 2:49 p.m.

Panel Version: 4.21

Green List (high evidence)

The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 5 Dec 2024, 8:33 p.m. | Last Modified: 5 Dec 2024, 8:33 p.m.

Panel Version: 4.62

Comment on mode of inheritance: As there are sufficient cases/ variants reported with monoallelic inheritance and hearing loss, the MOI should be changed from "BIALLELIC, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" in the next major review.

Created: 26 Jul 2023, 5:50 p.m. | Last Modified: 26 Jul 2023, 5:50 p.m.

Panel Version: 4.10

PMID:29309402 - A heterozygous nonsense variant (c.6881G>A; p.Trp2294Ter) was identified in a four-generation German family with nonsyndromic mild to severe hearing loss of the mid- to high frequencies and onset from early childhood to second decade in seven members.

PMID:31655630 - The same variant (c.6881G>A; p.Trp2294Ter) was identified in a five-generation Polish family with autosomal dominant non-syndromic hearing loss (ADNSHL). Using genome-wide linkage analysis, the authors also found that the studied Polish family and the original German family derive from a common ancestor.

PMID:33229591 - PTPRQ variants p.Gly383Glu and p.Arg841Trp were identified in multiplex family age-related hearing loss (mARHL) cases, while p.Ser1022Arg, c.4286-1G>T and p.Leu879Argfs*20 were identified with simplex/sporadic age-related hearing loss (sARHL) cases. However, p.Ser321Cys was identified in control cases with normal hearing.

This gene has been associated with hearing loss caused by both autosomal dominant (MIM #617663) and autosomal recessive (MIM #613391) inheritance in OMIM.

Created: 26 Jul 2023, 5:45 p.m. | Last Modified: 26 Jul 2023, 5:58 p.m.

Panel Version: 4.10

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Deafness, autosomal dominant 73, OMIM:617663; Deafness, autosomal recessive 84A, OMIM:613391

Publications

• 29309402
• 31655630
• 33229591

Green List (high evidence)

This gene was identified in 2017/2018 as causing autosomal dominant non-syndromic hearing loss (DFNA73, OMIM: #617663, Eisenburger et al., 2018, PMID: 29309402) due to a heterozygous nonsense variant in PTPRQ (NM_001145026.1:c.6881G>A, p.(Trp2294Ter)) segregating in a four generation German family. Affected individuals in the family had sloping/flat (one ear)/U-shaped (one ear) audiograms with evidence variable severity and age of onset. Due to the variant residing in the last exon (exon 45), NMD-escape was predicted and the authors suspected dominant negative disease mechanism.
In 2019, Ozieblo et al. published a second confirmatory Polish family, proven to derive from a common ancestor of the German family, with the identical nonsense variant. The variant segregated in three generations. Hearing loss was further characterized as progressive and most severely affected high frequencies (sloping audiograms).
The recognition of the dominant inheritance pattern in PTPRQ in a gene that was previously associated with autosomal recessive hearing impairment (DFNB84A) is important. The identification of other variants being linked to autosomal dominant hearing impairment still remains to be clarified (other entries about likely pathogenic variants associated with autosomal dominat hearing loss are in ClinVar, but lack further details).

Created: 11 Aug 2022, 8:10 a.m. | Last Modified: 11 Aug 2022, 8:10 a.m.

Panel Version: 2.247

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
DEAFNESS, AUTOSOMAL DOMINANT 73; DFNA73

Publications

• PMID: 29309402, PMID: 31655630

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
#613391:Deafness, autosomal recessive 84A[Hearing loss, bilateral sensorineural, progressiveVestibular dysfunction; Mildly delayed motor development due to vestibular dysfunction]

Publications

• PMID:12802008
• 12837292
• 14534255
• 20346435
• 9727007

Comment on list classification: Probable DD gene for deafness, autosomal recessive.

Created: 1 Mar 2016, 12:42 p.m.

Comment on list classification: Internal discussion decided that this gene should be promoted from amber to green - PMC4412678 compares reports of variants from 4 families from different ethnicities...Dutch, Moroccan, Palestinian and Chinese.

Created: 1 Mar 2016, 12:41 p.m.

I don't know

2 families with very similar phenotypes; little functional data

Created: 14 Oct 2015, 8:33 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal