Expanding the clinical and genetic spectrum of Heimler syndrome
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(2019) 14:290
RESEARCH
Open Access
Expanding the clinical and genetic spectrum of Heimler syndrome Feng-Juan Gao1,2,3†, Fang-Yuan Hu1,2,3†, Ping Xu1,2,3, Yu-He Qi1,2,3, Jian-Kang Li4,5, Yong-Jin Zhang1,2,3, Fang Chen4,6,7, Qing Chang1,2,3, Fang Song1, Si-Mai Shen8, Ge-Zhi Xu1,2,3* and Ji-Hong Wu1,2,3*
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: Heimler syndrome, Next-generation sequencing, Genetic diagnosis, PEX1, PEX6, Genotype–phenotype
Background Heimler syndrome (HS) was first reported in 1991 by A. Heimler as an inherited syndrome characterized by sensorineural hearing loss (SNHL), enamel hypoplasia, and nail abnormalities [1]. Biallelic mutations in the peroxisomal biogenesis factor 1 gene (PEX1; MIM*602136), peroxisomal biogenesis factor 6 gene (PEX6; MIM*601498), and peroxisomal biogenesis factor 26 gene (PEX26; MIM* 608666) are responsible for HS [2–4]. The proteins they encode function together to control peroxisomal matrix protein import, and mutations of these genes are implicated in peroxisome biogenesis disorders (MIM * Correspondence: [email protected]; [email protected] † Feng-Juan Gao and Fang-Yuan Hu contributed equally to this work. 1 Eye Institute, Eye and ENT Hospital, College of Medicine, Fudan University, Shanghai, China Full list of author information is available at the end of the article
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