Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.

TitleElucidating the clinical spectrum and molecular basis of HYAL2 deficiency.
Publication TypeJournal Article
Year of Publication2022
AuthorsFasham, J, Lin, S, Ghosh, P, Radio, FClementina, 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, MChristine, 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
JournalGenet Med
Date Published2022 Mar
KeywordsAlleles, Animals, Cell Adhesion Molecules, Cleft Lip, Cleft Palate, Genetic Association Studies, GPI-Linked Proteins, Humans, Hyaluronoglucosaminidase, Mice, Phenotype

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.

Alternate JournalGenet Med
PubMed ID34906488
PubMed Central IDPMC9933146
Grant ListUM1 HG006542 / HG / NHGRI NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
MC_PC_15054 / MRC_ / Medical Research Council / United Kingdom
220600/Z/20/Z / WT_ / Wellcome Trust / United Kingdom
/ / Wellcome Trust / United Kingdom
TL1 TR001880 / TR / NCATS NIH HHS / United States

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