Familial non syndromic congenital heart diseaseGene: HYAL2
Comment on list classification: Promoting to green after further consultation with the Genomics England clinical team. 2 cases which both report a cardiac phenotype, and mouse model which also re-capitulates the cardiac phenotype, so should be rated green.
Created: 31 Jan 2021, 1:13 p.m. | Last Modified: 31 Jan 2021, 1:13 p.m.
Panel Version: 1.57
Comment on list classification: Promoting from red to amber. 2 cases reported with supporting data from mouse. Cardiac phenotype is not fully penetrant. Awaiting confirmation of further cases before promoting to green.
Created: 27 Jan 2021, 3:58 p.m. | Last Modified: 27 Jan 2021, 3:58 p.m.
Panel Version: 1.56
PMID: 28081210 (Muggenthaler et al 2017) report 2 unrelated consanguineous extended families (Amish and Arab) who have an orofacial clefting phenotype with cardiac anomalies are also reported.
In pedigree 1 (Amish) 5/5 analysed individuals had cleft lip and palate. 3/5 had congenital cardiac malformations including left cor triatriatum and dilated coronary sinus consistent with persistent left superior vena cava. 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 palate and 1/2 had an abnormal mitral valve with accessory tissue. 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.
They report that valvular thickening and atrial dilatation are found in all Hyal2-/- mice (PMID: 23172227) and that Cor triatriatum sinister has been detected in 50% of Hyal2-/- mice (PMID: 26515055).
Created: 27 Jan 2021, 3:56 p.m. | Last Modified: 27 Jan 2021, 3:57 p.m.
Panel Version: 1.55
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
cor triatriatum; congenital cardiac malformations
Gene: hyal2 has been classified as Green List (High Evidence).
Gene: hyal2 has been classified as Amber List (Moderate Evidence).
gene: HYAL2 was added gene: HYAL2 was added to Familial non syndromic congenital heart disease. Sources: Literature Mode of inheritance for gene: HYAL2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HYAL2 were set to 28081210; 23172227; 26515055 Phenotypes for gene: HYAL2 were set to cor triatriatum; congenital cardiac malformations Review for gene: HYAL2 was set to AMBER