Hearing lossGene: LMX1A
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
Deafness, autosomal dominant 7 OMIM:601412; autosomal dominant nonsyndromic deafness 7 MONDO:0011074
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
Deafness, autosomal recessive and autosomal dominant
Tag watchlist tag was added to gene: LMX1A. Tag for-review tag was added to gene: LMX1A.
Gene: lmx1a has been classified as Amber List (Moderate Evidence).
Mode of inheritance for gene: LMX1A was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: LMX1A were changed from to Deafness, autosomal dominant 7 OMIM:601412; autosomal dominant nonsyndromic deafness 7 MONDO:0011074
Publications for gene: LMX1A were set to
LMX1A was added to Congenital hearing impairment (Profound/Severe)panel. Sources: Expert