Expanding the clinical and genetic spectrum of Heimler syndrome

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.

The peroxisomal disorder spectrum and Heimler syndrome: Deep phenotyping and review of the literature

“…There are a total of 26 probands in the literature, 11 of which had a variant in PEX1 (42%), 11 in PEX6 (42%), 2 in PEX26 (8%), and 2 had negative genetic testing (8%) (Gao et al, 2019; Mechaussier et al, 2019). Nineteen were missense variants (59%, 5 in PEX1 , 11 in PEX6 and 3 in PEX26 ), nine were copy number variants or insertion/deletion (29%, 5 in PEX1 and 4 in PEX6 ), two were splicing (6%, 1 in PEX1 and 1 in PEX6 ) and two were nonsense (6%, 1 in PEX1 and 1 in PEX6 ).…”

“…We did not find a genotype–phenotype correlation regarding particular alleles or regions of the proteins and HS. Gao et al proposed a genotype–phenotype correlation in which the patients that had ocular involvement (retinal degeneration or macular cysts) had at least one variant affecting the AAA domain in PEX1 or PEX6 (Gao et al, 2019 ) . We did not find this correlation in the three patients published by Mechaussier et al or here, where the six patients had retinal degeneration and only two had a variant in the AAA domain (Mechaussier et al, 2019).…”

“…These signs have been associated with a number of conditions (e.g., anemia, zinc deficiency, as an adverse effect of chemotherapy, microtrauma, Raynaud's syndrome) (Bodman, 2004). In a recent review, they were found in up to 40% of the patients with HS, therefore they do not appear to be a sensitive, specific component of the phenotyope (Gao et al, 2019). Lima et al found that patients with HS may also have retinal and macular dystrophies, causing decreased visual acuity (Lima et al, 2011).…”

“…Genetic testing is the most sensitive diagnostic method for HS, and oftentimes the only positive laboratory finding (79% of the patients reported to date have a molecular diagnosis) (Gao et al, 2019; Ratbi et al, 2015). Particularly, variants in PEX1 , PEX6 , and PEX26 have been associated with HS (Neuhaus et al, 2017; Ratbi et al, 2015).…”

Hereditary Hearing Impairment with Cutaneous Abnormalities

“…PBDs are a spectrum of autosomal recessive disorders of different severity, of which Zellweger syndrome (ZS) is the most severe form; neonatal adrenoleukodystrophy (NALD) presents with milder symptoms, and infantile Refsum disease (IRD) and Heimler syndrome constitute the mildest forms. The prevalence of PBDs is 1/50,000 and 1/500,000 in North America and Japan, respectively, while epidemiological figures on Heimler syndrome are to be determined [ 51 , 160 , 161 ]. PBDs result from pathogenic variants in peroxin-encoding genes, i.e., PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX11β, PEX12, PEX13, PEX14, PEX16, PEX19, and PEX26 [ 50 ].…”