Abstract
PurposeWe 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. MethodsClinical 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. ResultsTen 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. ConclusionThese 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.
Highlights
We first identified abnormalities in HYAL2 function through studies of a novel syndromic form of orofacial clefting in 5 Amish and 2 Saudi Arabian individuals[1] associated with 2 distinct homozygous HYAL2 missense variants
HYAL2 is a cell-surface protein proposed to act as a hyaluronidase enzyme in concert with HYAL1, the other major mammalian hyaluronidase acting in somatic tissues, catalyzing the degradation of the high molecular weight glycosaminoglycan polymer hyaluronan.[2,3]
HYAL1 alterations are associated with mucopolysaccharidosis type IX (OMIM 601492), which is characterized by short stature, craniofacial dysmorphism, submucosal cleft palate, and joint abnormalities.[12]
Summary
We first identified abnormalities in HYAL2 function through studies of a novel syndromic form of orofacial clefting in 5 Amish and 2 Saudi Arabian individuals[1] associated with 2 distinct homozygous HYAL2 missense variants. Affected individuals displayed a remarkably consistent pattern of craniofacial dysmorphism involving bilateral/unilateral cleft lip and palate, penetrant in all but 1 Saudi Arabian child, along with more variable features, including congenital cardiac anomalies (cor triatriatum sinister), myopia with staphyloma, cataract, conductive/ sensorineural hearing loss, pectus excavatum, and single palmar creases. Consistent with the human condition, Hyal2–/– mice displayed similar craniofacial abnormalities with submucosal cleft palate, and in a proportion of mice, cor triatriatum sinister and hearing loss were identified.[1] To date, no further affected individuals have been described. We describe the clinical, genetic, and molecular findings associated with putative HYAL2 pathogenic variants in 10 individuals from 6 families of Amish, Romanian, Italian, and North European ancestry
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