Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency
Fasham, J; Lin, S; Ghosh, P; et al.Radio, FC; Farrow, EG; Thiffault, I; Kussman, J; Zhou, D; Hemming, R; Zahka, K; Chioza, BA; Rawlins, LE; Wenger, OK; Gunning, AC; Pizzi, S; Onesimo, R; Zampino, G; Barker, E; Osawa, N; Rodriguez, MC; Neuhann, TM; Zackai, EH; Keena, B; Capasso, J; Levin, AV; Bhoj, E; Li, D; Hakonarson, H; Wentzensen, IM; Jackson, A; Chandler, KE; Coban-Akdemir, ZH; Posey, JE; Banka, S; Lupski, JR; Sheppard, SE; Tartaglia, M; Triggs-Raine, B; Crosby, AH; Baple, EL
Date: 30 November 2021
Genetics in Medicine
Elsevier / American College of Medical Genetics and Genomics
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. ...
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.
Institute of Biomedical & Clinical Science
College of Medicine and Health
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Except where otherwise noted, this item's licence is described as © 2021 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).