Dataset Information

Surgical, Speech, and Audiologic Outcomes in Patients With Orofacial Cleft and Van der Woude Syndrome.

ABSTRACT: OBJECTIVE:The purpose of this study was to investigate the surgical, speech, and audiologic outcomes in patients with Van der Woude syndrome (VWS) and compare them to patients with nonsyndromic cleft palate with or without cleft lip (NS-CP?±?L) treated at the same institution. DESIGN:Retrospective chart review. SETTING:A single children's hospital at a major academic institution. PATIENTS:The records of 18 patients with VWS who had been treated at a single institution from 1989 to 2017 have been retrospectively examined. Thirty-eight patients with NS-CP?±?L who were also treated at the same institution during that same time frame were selected to closely match sex and date of birth. MAIN OUTCOME MEASURES:Demographic, clinical, surgical, and speech pathology data were gathered from medical charts. RESULT:By age 4, 88% of subjects with VWS and 76% of subjects with NS-CP?±?L (P?=?0.732) had been, or were actively involved in, speech therapy. By age 10, 100% of remaining subjects with VWS and 58% of remaining subjects with NS-CP?±?L remained involved in speech therapy (P?=?0.027).About 33% of patients with VWS and 16% of patients with NS-CP?±?L had a secondary procedure for velopharyngeal dysfunction (VPD) (P?=?0.171). CONCLUSION:The VWS group had more than twice the rate of secondary procedures for VPD repair, and a higher rate of continuing involvement for speech therapy at age 10. No differences were found in the rate of participation in speech therapy at or by age 4.

SUBMITTER: Kitchin S

PROVIDER: S-EPMC6636358 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Surgical, Speech, and Audiologic Outcomes in Patients With Orofacial Cleft and Van der Woude Syndrome.

Kitchin Spencer S Grames Lynn L Naidoo Sybill D SD Skolnick Gary G Schoenborn Alyssa A Snyder-Warwick Alison A Patel Kamlesh K

The Journal of craniofacial surgery 20190701 5

<h4>Objective</h4>The purpose of this study was to investigate the surgical, speech, and audiologic outcomes in patients with Van der Woude syndrome (VWS) and compare them to patients with nonsyndromic cleft palate with or without cleft lip (NS-CP ± L) treated at the same institution.<h4>Design</h4>Retrospective chart review.<h4>Setting</h4>A single children's hospital at a major academic institution.<h4>Patients</h4>The records of 18 patients with VWS who had been treated at a single institutio ...[more]

PMID: 31299749

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Project description:IntroductionVan der Woude Syndrome (VWS) is an autosomal dominant disorder responsible for 2% of all syndromic orofacial clefts (OFCs) with IRF6 being the primary causal gene (70%). Cases may present with lip pits and either cleft lip, cleft lip with cleft palate, or cleft palate, with marked phenotypic discordance even among individuals carrying the same mutation. This suggests that genetic or epigenetic modifiers may play additional roles in the syndrome's etiology and variability in expression. We report the first DNA methylation profiling of 2 pairs of monozygotic twins with VWS. Our goal is to explore epigenetic contributions to VWS etiology and variable phenotypic expressivity by comparing DNAm profiles in both twin pairs. While the mutations that cause VWS in these twins are known, the additional mechanism behind their phenotypic risk and variability in expression remains unclear.MethodsWe generated whole genome DNAm data for both twin pairs. Differentially methylated positions (DMPs) were selected based on: (1) a coefficient of variation in DNAm levels in unaffected individuals < 20%, and (2) intra-twin pair absolute difference in DNAm levels >5% (delta beta > | 0.05|). We then divided the DMPs in two subgroups for each twin pair for further analysis: (1) higher methylation levels in twin A (Twin A > Twin B); and (2) higher methylation levels in twin B (Twin B >Twin A).Results and discussionGene ontology analysis revealed a list of enriched genes that showed significant differential DNAm, including clef-associated genes. Among the cleft-associated genes, TP63 was the most significant hit (p=7.82E-12). Both twin pairs presented differential DNAm levels in CpG sites in/near TP63 (Twin 1A > Twin 1B and Twin 2A < Twin 2B). The genes TP63 and IRF6 function in a biological regulatory loop to coordinate epithelial proliferation and differentiation in a process that is critical for palatal fusion. The effects of the causal mutations in IRF6 can be further impacted by epigenetic dysregulation of IRF6 itself, or genes in its pathway. Our data shows evidence that changes in DNAm is a plausible mechanism that can lead to markedly distinct phenotypes, even among individuals carrying the same mutation.

Project description:BackgroundLoss-of-function mutations in interferon regulatory factor-6 (IRF6) are responsible for about 70% of cases of Van Der Woude Syndrome (VWS), an autosomal dominant developmental disorder characterized by pits and/or sinuses of the lower lip and cleft lip, cleft palate, or both.MethodsWe collected a Chinese Han VWS pedigree, performed sequencing and screening for the causal gene mutant. Initially, species conservation analysis and homology protein modeling were used to predict the potential pathogenicity of mutations. To test whether a VWS family-derived mutant variant of IRF6 retained function, we carried out rescue assays in irf6 maternal-null mutant zebrafish embryos. To assess protein stability, we overexpressed reference and family-variants of IRF6 in vitro.ResultsWe focused on a VWS family that includes a son with bilateral lip pits, uvula fissa and his father with bilateral cleft lip and palate. After sequencing and screening, a frameshift mutation of IRF6 was identified as the potential causal variant (NM.006147.3, c.1088-1091delTCTA; p.Ile363ArgfsTer33). The residues in this position are strongly conserved among species and homology modeling suggests the variant alters the protein structure. In irf6 maternal-null mutant zebrafish embryos the periderm differentiates abnormally and the embryos rupture and die during gastrulation. Injection of mRNA encoding the reference variant of human IRF6, but not of the frame-shift variant, rescued such embryos through gastrulation. Upon overexpression in HEK293FT cells, the IRF6 frame-shift mutant was relatively unstable and was preferentially targeted to the proteasome in comparison to the reference variant.ConclusionIn this VWS pedigree, a novel frameshift of IRF6 was identified as the likely causative gene variant. It is a lost function mutation which could not rescue abnormal periderm phenotype in irf6 maternal-null zebrafish and which causes the protein be unstable through proteasome-dependent degradation.

Dataset Information

Surgical, Speech, and Audiologic Outcomes in Patients With Orofacial Cleft and Van der Woude Syndrome.

Publications

Surgical, Speech, and Audiologic Outcomes in Patients With Orofacial Cleft and Van der Woude Syndrome.

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