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Hearing loss

Gene: LMX1A

Amber List (moderate evidence)

LMX1A (LIM homeobox transcription factor 1 alpha)
EnsemblGeneIds (GRCh38): ENSG00000162761
EnsemblGeneIds (GRCh37): ENSG00000162761
OMIM: 600298, Gene2Phenotype
LMX1A is in 1 panel

3 reviews

Eleanor Williams (Genomics England Curator)

Green List (high evidence)

Comment on list classification: Changing rating from red to amber but with a recommendation for a green rating following GMS review.
Created: 25 Nov 2020, 4:54 p.m. | Last Modified: 25 Nov 2020, 4:54 p.m.
Panel Version: 2.120
Comment on mode of inheritance: Setting MOI to Monoallelic as only one case of biallelic reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.
Created: 25 Nov 2020, 4:52 p.m. | Last Modified: 25 Nov 2020, 4:52 p.m.
Panel Version: 2.119
Associated with Deafness, autosomal dominant 7 #601412 (AD) in OMIM.

As reported by Zornitza Stark, 3 families with monoallelic missense variants and 1 family with biallelic. Mouse model and some functional data showing decreased transcriptional activity as a result of the reported variants.

PMID: 29754270- Wesdorp et al 2018 - report 2 families of Dutch origin with progressive nonsyndromic hearing impairment. Using WES they identified heterozygous variants in LMX1A in both families. In family one, c.721G > C; p.Val241Leu was found in 3 generations. In the second family, c.290G > C;p.Cys97Ser was found in the affected mother and 3 affected children. Age of onset ranged from birth to 35 years.

PMID: 29971487 - Schrauwen et al 2018 - report a consanguineous Pakistani family with severe-to-profound hearing impairment that is inherited in an autosomal recessive manner. They identified a homozygous missense variant c.1106T>C:p.Ile-369Thr in LMX1A in 2 affected children using exome sequencing. The parents were heterozygous carriers.

PMID: 32840933 - Lee et al 2020 - report a 3 month year old proband with severe-to-profound hearing loss from birth, in which a de novo, heterozygous, missense variant (c.595A > G; p.Arg199Gly) in LMX1A was identified by exome sequencing. Functional studies to measure the transcriptional activity of the 3 heterozygous LMX1A variants showed the greatest reduction with p.Arg199Gly, followed by p.Cys97Ser and p.Val241Leu which are associated with a less severe phenotype. The activity of the p.Ile-369Thr variant (found in the biallelic case) was only slightly reduced.

Mouse models - PMID: 19540218 and PMID:18985389 both report LMX1A knockout mouse have ear defects.
Created: 25 Nov 2020, 4:36 p.m. | Last Modified: 25 Nov 2020, 4:36 p.m.
Panel Version: 2.116

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

Phenotypes
Deafness, autosomal dominant 7 OMIM:601412; autosomal dominant nonsyndromic deafness 7 MONDO:0011074

Publications

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Now 3 families with monoallelic missense variants (2 with dominant inheritance and 1 de novo), and a single biallelic family. Supporting mouse model and in vitro functional assays.
Created: 5 Oct 2020, 9:04 a.m. | Last Modified: 5 Oct 2020, 9:04 a.m.
Panel Version: 2.94
Two families described with mono-allelic variants and dominant pattern of deafness; one family with bi-allelic. Mouse model.
Created: 2 Jan 2020, 4:58 a.m. | Last Modified: 2 Jan 2020, 4:58 a.m.
Panel Version: 2.4

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Deafness, autosomal recessive and autosomal dominant

Publications

Jun Shen (Harvard Medical School)

Red List (low evidence)

LMX1A is not associated with a phenotype entry in OMIM.
Created: 9 Feb 2016, 10:07 a.m.
LMX1A is not associated with a phenotype entry in OMIM.
Created: 7 Feb 2016, 3:43 p.m.

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
  • Expert
Phenotypes
  • Deafness, autosomal dominant 7 OMIM:601412
  • autosomal dominant nonsyndromic deafness 7 MONDO:0011074
Tags
watchlist for-review
OMIM
600298
Clinvar variants
Variants in LMX1A
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

25 Nov 2020, Gel status: 2

Added Tag, Added Tag

Eleanor Williams (Genomics England Curator)

Tag watchlist tag was added to gene: LMX1A. Tag for-review tag was added to gene: LMX1A.

25 Nov 2020, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: lmx1a has been classified as Amber List (Moderate Evidence).

25 Nov 2020, Gel status: 1

Set mode of inheritance

Eleanor Williams (Genomics England Curator)

Mode of inheritance for gene: LMX1A was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

25 Nov 2020, Gel status: 1

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: LMX1A were changed from to Deafness, autosomal dominant 7 OMIM:601412; autosomal dominant nonsyndromic deafness 7 MONDO:0011074

25 Nov 2020, Gel status: 1

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: LMX1A were set to

24 Jun 2015, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

LMX1A was added to Congenital hearing impairment (Profound/Severe)panel. Sources: Expert