Dataset Information

Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.

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.

SUBMITTER: Fasham J

PROVIDER: S-EPMC9933146 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.

Fasham James J Lin Siying S Ghosh Promita P Radio Francesca Clementina FC Farrow Emily G EG Thiffault Isabelle I Kussman Jennifer J Zhou Dihong D Hemming Rick R Zahka Kenneth K Chioza Barry A BA Rawlins Lettie E LE Wenger Olivia K OK Gunning Adam C AC Pizzi Simone S Onesimo Roberta R Zampino Giuseppe G Barker Emily E Osawa Natasha N Rodriguez Megan Christine MC Neuhann Teresa M TM Zackai Elaine H EH Keena Beth B Capasso Jenina J Levin Alex V AV Bhoj Elizabeth E Li Dong D Hakonarson Hakon H Wentzensen Ingrid M IM Jackson Adam A Chandler Kate E KE Coban-Akdemir Zeynep H ZH Posey Jennifer E JE Banka Siddharth S Lupski James R JR Sheppard Sarah E SE Tartaglia Marco M Triggs-Raine Barbara B Crosby Andrew H AH Baple Emma L EL

Genetics in medicine : official journal of the American College of Medical Genetics 20211130 3

<h4>Purpose</h4>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.<h4>Methods</h4>Clinical and genomic investigations were undertaken alongside molecular studies, including immunoblotting and immunofluorescence analyses of var ...[more]

PMID: 34906488

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Dataset Information

Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.

Purpose

Methods

Results

Conclusion

Publications

Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.

Similar Datasets

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