Document Type
Article
Publication Date
3-2022
Identifier
DOI: 10.1016/j.gim.2021.10.014
Abstract
PURPOSE: We previously defined biallelic HYAL2 variants causing a novel disorder in 2 families, involving orofacial clefting, facial dysmorphism, congenital heart disease, and ocular abnormalities, with Hyal2 knockout mice displaying similar phenotypes. In this study, we better define the phenotype and pathologic disease mechanism.
METHODS: Clinical and genomic investigations were undertaken alongside molecular studies, including immunoblotting and immunofluorescence analyses of variant/wild-type human HYAL2 expressed in mouse fibroblasts, and in silico modeling of putative pathogenic variants.
RESULTS: Ten newly identified individuals with this condition were investigated, and they were associated with 9 novel pathogenic variants. Clinical studies defined genotype-phenotype correlations and confirmed a recognizable craniofacial phenotype in addition to myopia, cleft lip/palate, and congenital cardiac anomalies as the most consistent manifestations of the condition. In silico modeling of missense variants identified likely deleterious effects on protein folding. Consistent with this, functional studies indicated that these variants cause protein instability and a concomitant cell surface absence of HYAL2 protein.
CONCLUSION: These studies confirm an association between HYAL2 alterations and syndromic cleft lip/palate, provide experimental evidence for the pathogenicity of missense alleles, enable further insights into the pathomolecular basis of the disease, and delineate the core and variable clinical outcomes of the condition.
Journal Title
Genetics in medicine : official journal of the American College of Medical Genetics
Volume
24
Issue
3
First Page
631
Last Page
644
MeSH Keywords
Alleles; Animals; Cell Adhesion Molecules; Cleft Lip; Cleft Palate; GPI-Linked Proteins; Genetic Association Studies; Humans; Hyaluronoglucosaminidase; Mice; Phenotype
Keywords
Congenital heart disease; Facial dysmorphism; Hyaluronidase; Myopia; Orofacial clefting
Recommended Citation
Fasham J, Lin S, Ghosh P, et al. Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency. Genet Med. 2022;24(3):631-644. doi:10.1016/j.gim.2021.10.014
Comments
Grant support
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Publisher's Link: https://www.gimjournal.org/article/S1098-3600(21)05366-1/fulltext