Dataset Information

De novo 2.3 Mb microdeletion of 1q32.2 involving the Van der Woude Syndrome locus.

ABSTRACT: BACKGROUND:Van der Woude syndrome is the most common among syndromes which include cleft lip and/or cleft palate as one of the presentations. It is usually caused by mutations in the interferon regulatory factor 6 (IRF6) gene. CASE PRESENTATION:We previously reported on a patient with suspected deletion of the IRF6 gene. Using the Affymetrix Human SNP 6.0 Array, the interstitial deletion has been confirmed and found to be approximately 2.327-2.334 Mb within the 1q32.2 region. Although several known genes were deleted, the patient has no other phenotype apart from the orofacial presentations typical of VWS. The same deletion was not present in either parent and his two siblings were also phenotypically normal. CONCLUSIONS:Other than IRF6, the genes which are deleted in this patient appear to be insensitive to copy number and haploinsufficiency. We compared the deletion in this patient with another case which was also mapped by high resolution array but had additional phenotypic features.

SUBMITTER: Tan EC

PROVIDER: S-EPMC3751720 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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De novo 2.3 Mb microdeletion of 1q32.2 involving the Van der Woude Syndrome locus.

Tan Ene-Choo EC Lim Eileen Cp EC Lee Seng-Teik ST

Molecular cytogenetics 20130806

<h4>Background</h4>Van der Woude syndrome is the most common among syndromes which include cleft lip and/or cleft palate as one of the presentations. It is usually caused by mutations in the interferon regulatory factor 6 (IRF6) gene.<h4>Case presentation</h4>We previously reported on a patient with suspected deletion of the IRF6 gene. Using the Affymetrix Human SNP 6.0 Array, the interstitial deletion has been confirmed and found to be approximately 2.327-2.334 Mb within the 1q32.2 region. Alth ...[more]

PMID: 23915469

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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

De novo 2.3 Mb microdeletion of 1q32.2 involving the Van der Woude Syndrome locus.

Publications

De novo 2.3 Mb microdeletion of 1q32.2 involving the Van der Woude Syndrome locus.

Similar Datasets

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