Expanding the clinical and genetic spectrum of Heimler syndrome

Abstract

Background: Heimler 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.

Results: Two 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.

Conclusion: Next-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.

Keywords: Genetic diagnosis; Genotype–phenotype; Heimler syndrome; Next-generation sequencing; PEX1; PEX6.

Fig. 1

Pedigrees (a) and identified mutations (a). a Circles represent females, and squares represent males. Filled symbols represent affected patients, and empty symbols represent unaffected family members. b Sequencing results of the mutations in the PEX1 gene. Arrows indicate the position of the mutated nucleotide

Fig. 2

Ocular features of patient 1. a Ultra wide-field pseudocolor images showing retinal atrophy in the mid and far periphery combined with significant bone spicule-like pigmentation and mottling in both eyes. b SD-OCT shows small macular cysts in the inner nuclear layer, a thickened retina, and an atrophic photoreceptor layer with preservation of the ellipsoid zone (EZ) and the external limiting membrane (ELM). c Visual field shows peripheral visual field loss, with small central loss. d mfERG shows that amplitudes in the posterior-pole of both eyes were significantly reduced, more seriously in the right eye

Fig. 3

Ocular features of patient 2. a Ultra wide-field pseudocolor images showing retinal atrophy in the mid and far periphery combined with significant bone spicule-like pigmentation, mottling in both eyes. b SD-OCT shows bilateral cystoid macular edema, which mainly involved the outer nuclear layer (ONL). The foveal and peripheral macular ellipsoid zone (EZ) was disrupted and almost absent. c Visual field shows peripheral visual field loss except for the superior nasal quadrant. d mfERG shows undetectable rod ERG, subnormal bright flash ERG, and subnormal and delayed cone ERG

Fig. 4

Follow-up of central foveal thickness in patient 2

Fig. 5

Location of HS-associated variants in PEX1, PEX6 and PEX26. Black: missense mutation. Blue: splicing mutation. Red: frameshift mutation. Green: nonsense mutation