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Hearing loss

Gene: COL9A3

Amber List (moderate evidence)

COL9A3 (collagen type IX alpha 3 chain)
EnsemblGeneIds (GRCh38): ENSG00000092758
EnsemblGeneIds (GRCh37): ENSG00000092758
OMIM: 120270, Gene2Phenotype
COL9A3 is in 16 panels

3 reviews

Eleanor Williams (Genomics England Curator)

Green List (high evidence)

Comment on list classification: Leaving the rating as amber, but there are now 4 cases with homozygous variants in this gene in patients with hearing loss. 2 cases are reported with Stickler syndrome. In the other 2 cases Stickler syndrome was not excluded. The phenotype needs to be reviewed to decide whether to encompass Stickler syndrome genes on this panel.
Created: 3 Mar 2021, 12:24 p.m. | Last Modified: 3 Mar 2021, 12:24 p.m.
Panel Version: 2.151
Comment on mode of inheritance: Leaving as Biallelic mode of inheritance as 4 cases reported with this inheritance pattern. However PMID: 15917166 also reports two cases with an AD pattern of inheritance, but no segregation data to support this.
Created: 3 Mar 2021, 12:20 p.m. | Last Modified: 3 Mar 2021, 12:20 p.m.
Panel Version: 2.150
PMID: 33078831 - Wonkam et al 2020 - report 2 unrelated patients from Cameroon with autosomal recessive non-syndromic hearing impairment and a homozygous c.G406A, p.G136S variant in COL9A3. This variant is rare (ExAC_AFR MAF = 0, ExAC_ASI MAF = 0.001, Cameroonian controls MAF (N = 129) = 0). However, the authors report that further investigation of these patients is needed to exclude Stickler syndrome.

PMID: 15917166 - Asamura et al 2005 - direct-sequencing of COL9A3 gene in 159 non-syndromic sensorineural deafness patients (Japanese and Korean) and 150 normal controls. 2 possible disease-causing mutations were identified in patients with moderate progressive bilateral sensorineural hearing impairment in all frequencies. : a homozygous in-frame deletion of three amino acid residues (G181-P183 del) in one patient (with consanguineous parents) and a heterozygous missense mutation (D617E) found in 2 independent autosomal dominant families. No segregation data.
Created: 3 Mar 2021, 12:17 p.m. | Last Modified: 3 Mar 2021, 12:17 p.m.
Panel Version: 2.149
Removed the for-review tag as this gene is not a candidate for promoting to green as there are only two cases. However, once a decision is made about including Stickler syndrome green genes (e.g. COL9A1) or not on this panel, this gene may need further revision as regards to rating.
Created: 20 Jan 2021, 2:23 p.m. | Last Modified: 20 Jan 2021, 2:23 p.m.
Panel Version: 2.146
Comment on list classification: Promoting this gene from red to amber. 2 cases of a Stickler syndrome phenotype reported, which includes hearing loss.
Created: 20 Sep 2020, 7:56 a.m. | Last Modified: 20 Sep 2020, 7:56 a.m.
Panel Version: 2.85
Not associated with any relevant phentoype in OMIM.

PMID: 31090205 - Nixon et al 2019 - report one consanguineous family where the 2 probands with Stickler syndrome were identified as having a a novel homozygous variant in COL9A3: c.1411C>T, p.(Arg471Ter). The parents were heterozygous. Both probands had high‐frequency sensorineural hearing loss. One had severe arthropathy in shoulders and hip and had undergone spinal scoliosis surgery. The variant was present in gnomAD at a frequency of 3/270000.

PMID: 24273071 - Faletra et al 2014 - report a Moroccan family with first‐cousins healthy parents and 3 affected siblings with hearing loss, visual defects, bone abnormalities and ID. Based on the regions of homology shared by all 3 siblings, DNA from COL9A3, NEUROD2, NLGN1, and SLC4A10 were analysed and a homozygous frameshift mutation was found in COL9A3 the 3 siblings: c.1176_1198del (NP_001844.3: p.Gln393Cysfs*25). The parents were heterozygous for this variant. The intellectual disability in the patients is not explained by the COL9A3 variant.
Created: 20 Sep 2020, 7:53 a.m. | Last Modified: 20 Sep 2020, 7:53 a.m.
Panel Version: 2.81

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Stickler syndrome; non-syndromic sensorineural deafness

Publications

Maria Bitner-Glindzicz (UCL)

Red List (low evidence)

Jun Shen (Harvard Medical School)

Red List (low evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
#600969:Epiphyseal dysplasia, multiple, 3[Short stature, mild; Hip arthrosis; OsteoarthritisSmall, irregular epiphysesLate ossifying epiphyses; Normal handsShort metacarpals; Proximal muscle weakness; Mild variability in muscle fiber size; Mildly elevated creatine phosphokinase (CPK)]; #603932:{Intervertebral disc disease, susceptibility to}

Publications

History Filter Activity

3 Mar 2021, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: col9a3 has been classified as Amber List (Moderate Evidence).

3 Mar 2021, Gel status: 2

Set mode of inheritance

Eleanor Williams (Genomics England Curator)

Mode of inheritance for gene: COL9A3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal

3 Mar 2021, Gel status: 2

Added Tag

Eleanor Williams (Genomics England Curator)

Tag Q2_21_phenotype tag was added to gene: COL9A3.

20 Sep 2020, Gel status: 2

Added Tag

Eleanor Williams (Genomics England Curator)

Tag for-review tag was added to gene: COL9A3.

20 Sep 2020, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: col9a3 has been classified as Amber List (Moderate Evidence).

20 Sep 2020, Gel status: 1

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: COL9A3 were changed from to Stickler syndrome

20 Sep 2020, Gel status: 1

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: COL9A3 were set to

20 Sep 2020, Gel status: 1

Set mode of inheritance

Eleanor Williams (Genomics England Curator)

Mode of inheritance for gene: COL9A3 was changed from to BIALLELIC, autosomal or pseudoautosomal

24 Jun 2015, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

COL9A3 was added to Congenital hearing impairment (Profound/Severe)panel. Sources: Expert