Clefting
Gene: HYAL2
The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 3 Mar 2022, 4:45 p.m. | Last Modified: 3 Mar 2022, 4:45 p.m.
Panel Version: 2.63
Comment on list classification: Promoting this gene from grey to amber but with recommendation for green rating following GMS review. This is based on 2 reported unrelated cases with different proposed causative variants in HYAL2, plus a mouse knockout model which replicates the human phenotype and some functional data reporting the effect of patient variants on protein levels.Created: 19 Jan 2021, 7:26 p.m. | Last Modified: 19 Jan 2021, 7:26 p.m.
Panel Version: 2.14
As reported by expert reviewer PMID: 28081210 (Muggenthaler et al 2017) report 2 unrelated consanguineous extended families (Amish and Arab). In pedigree 1 (Amish) 5/5 analysed individuals had cleft lip and palate. All had a homzogyous c.443A>G, p.K148R variant which segregated with the disorder in the pedigree. It was found in a heterozygous state at a frequency of 0.013 in the Amish population, but was not found in 1000 Genomes or ExAC databases. In pedigree 2 (Arab) 1/2 analysed individuals had cleft lip and a palate and both were found to have a homozygous c.749C>T; p.P250L variant following whole genome SNP mapping. This variant was found in 2 individuals in the ExAC database in heterozygous state. Transient expression of the patient variants in mouse embryonic fibroblasts showed a large decrease in protein levels compared to wild type. Hyal2-/- mice showed craniofacial abnormalities, including submucosal cleft palate.Created: 19 Jan 2021, 7:22 p.m. | Last Modified: 19 Jan 2021, 7:22 p.m.
Panel Version: 2.13
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
cleft lip/palate MONDO:0016044
Publications
This entry is based on finding of homozygous HYAL2 variants in two inbred families with cleft lip and palate (CLP) in PMID:28081210. Five Amish individuals aged 4–16 years affected by a syndromic form of CLP were reported with a homozygous variant K148R in HYAL2 gene and two children aged 7 and 12 years from an extended consanguineous Arab family were reported with a homozygous P250L variant in HYAL2 gene. Reduced expression of the HYAL2 protein consequental to the two missense variants was shown in functional assays (PMID:28081210). Study of Hyal2 knock-out mice has also shown underdeveloped central palate bones and absence/reduction of ethmoid bone.
The entry is based on this single study, therefore currently leaving this at Red level of evidence.
Sources: LiteratureCreated: 6 Oct 2020, 3:12 p.m. | Last Modified: 6 Oct 2020, 3:21 p.m.
Panel Version: 2.3
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Cleft lip and palate, cor triatriatum
Publications
Tag gene-checked tag was added to gene: HYAL2.
Tag for-review was removed from gene: HYAL2.
Source Expert Review Green was added to HYAL2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag for-review tag was added to gene: HYAL2.
Phenotypes for gene: HYAL2 were changed from Cleft lip and palate, cor triatriatum to cleft lip/palate MONDO:0016044; triatrial heart MONDO:0015450
Gene: hyal2 has been classified as Amber List (Moderate Evidence).
gene: HYAL2 was added gene: HYAL2 was added to Clefting. Sources: Literature Mode of inheritance for gene: HYAL2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HYAL2 were set to 28081210 Phenotypes for gene: HYAL2 were set to Cleft lip and palate, cor triatriatum Penetrance for gene: HYAL2 were set to unknown Review for gene: HYAL2 was set to RED