Abstract

BackgroundHeimler syndrome (HS) is a rare hereditary systemic disorder, partial clinically overlapping with Usher syndrome. So far, our knowledge of HS is very limited, many cases are misdiagnosed or may not even be diagnosed at all. This study aimed to analyze the clinical and genetic characteristics of HS, and to evaluate potential phenotype–genotype correlations.ResultsTwo HS cases caused by PEX1 mutations were identified, and a novel likely pathogenic mutation, PEX1 c.895_896insTATA, was found. The main ophthalmic finding of the two patients was consistent with retinitis pigmentosa accompanied by cystoid macular edema, but short axial length and hyperopia were also observed as two previously unreported ocular phenotypes. Analysis of the literature showed that of the 29 HS patients previously reported, 12 had PEX6 mutations, 10 had PEX1 mutations, two had PEX26 mutations, and the remaining patients were not genetically tested. Three novel genotype–phenotype correlations were revealed from analysis of these patients. First, most genotypes of every HS patient include at least one missense variant; second, at least one mutation in PEX1 or PEX6 gene affects the AAA-ATPase region in every HS patient with retinal dystrophy, suggesting AAA-ATPase region is a hypermutable region in patients with a retinal dystrophy; third, there are no significant differences between PEX1-, PEX6-, and PEX26-associated phenotypes.ConclusionNext-generation sequencing is important for the diagnosis of HS. This study expands the clinical and genetic spectrum of HS, and provides additional insights into genotype–phenotype correlations, which is vital for accurate clinical practice, genetic counseling, and pathogenesis studies.

Highlights

  • Heimler syndrome (HS) is a rare hereditary systemic disorder, partial clinically overlapping with Usher syndrome

  • We found a genotype– phenotype relationship in HS patients with retinal dystrophy that at least one mutation in PEX1 or PEX6 gene affected the nucleotide sequence of the AAA-ATPase region in every patient, which is typically involved in binding of substrates or cofactors and is vital for the PEX function19–21

  • Genotype–phenotype analysis in this study revealed that HS is caused by genotypes including at least one missense variant, while Zellweger syndrome was caused by more deleterious genotypes, such as truncating stop or frameshift defects

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Summary

Introduction

Heimler syndrome (HS) is a rare hereditary systemic disorder, partial clinically overlapping with Usher syndrome. Our current knowledge of HS is very limited, with only 29 reported patients worldwide; 26 of these have genetic sequence information [1,2,3,4, 9,10,11,12,13,14]. The HS clinical phenotype varies, but includes acquired SNHL, amelogenesis imperfecta of the teeth, and retinal dystrophy, partially clinically overlapping with Usher syndrome that is characterized by congenital deafness, retinitis pigmentosa (RP), presence or absence of vestibular dysfunction, but no dental anomalies [4]. We further reviewed the varied phenotypes and genotypes of all previously reported cases, and uncovered novel genotype–phenotype correlations

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