Dataset Information

Longitudinal ophthalmic findings in a child with Helsmoortel-Van der Aa Syndrome.

ABSTRACT: Purpose:We present the first detailed ophthalmic description of a child with Helsmoortel-Van der Aa Syndrome (HVDAS), including longitudinal follow-up and analysis. Observations:After extensive workup, a young child with poor visual behavior, hypotonic cerebral palsy, intellectual disability, and global developmental delay was found to have a heterozygous de novo mutation in the ADNP gene and diagnosed with HVDAS. Ophthalmic findings were remarkable for progressive nystagmus, macular pigment mottling, mild foveal hypoplasia with abnormal macular laminations, persistent rod dysfunction with electronegative waveform, and progressive cone degeneration. Conclusions and importance:Patients with HVDAS are known to have abnormal visual behavior due to refractive or cortical impairment. However, we present the first description, to our knowledge, of an association with retinal mal-development and degeneration. Thus, patients with HVDAS should be referred for ophthalmic genetics evaluation, and HVDAS should be on the differential diagnosis for young children with global developmental delay who present with nystagmus, rod and cone dysfunction with electronegative waveform, and relative lack of severe structural degeneration on optical coherence tomography.

SUBMITTER: Gale MJ

PROVIDER: S-EPMC5956711 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Longitudinal ophthalmic findings in a child with Helsmoortel-Van der Aa Syndrome.

Gale Michael J MJ Titus Hope E HE Harman Gareth A GA Alabduljalil Talal T Dennis Anna A Wilson Jenny L JL Koeller David M DM Finanger Erika E Blasco Peter A PA Chiang Pei-Wen PW Karr Daniel J DJ Yang Paul P

American journal of ophthalmology case reports 20180313

<h4>Purpose</h4>We present the first detailed ophthalmic description of a child with Helsmoortel-Van der Aa Syndrome (HVDAS), including longitudinal follow-up and analysis.<h4>Observations</h4>After extensive workup, a young child with poor visual behavior, hypotonic cerebral palsy, intellectual disability, and global developmental delay was found to have a heterozygous <i>de novo</i> mutation in the <i>ADNP</i> gene and diagnosed with HVDAS. Ophthalmic findings were remarkable for progressive n ...[more]

PMID: 29780943

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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.

Dataset Information

Longitudinal ophthalmic findings in a child with Helsmoortel-Van der Aa Syndrome.

Publications

Longitudinal ophthalmic findings in a child with Helsmoortel-Van der Aa Syndrome.

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