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.

中文翻译：

---

扩大Heimler综合征的临床和遗传谱。

背景Heimler综合征（HS）是一种罕见的遗传性系统性疾病，在临床上与Usher综合征部分重叠。到目前为止，我们对HS的了解非常有限，很多病例被误诊甚至根本无法诊断。这项研究旨在分析HS的临床和遗传特征，并评估潜在的表型与基因型的相关性。结果确定了两例由PEX1突变引起的HS病例，并发现了一个新的可能的致病突变PEX1 c.895_896insTATA。两名患者的主要眼科发现与色素性视网膜炎伴黄斑囊样水肿相一致，但也观察到眼轴短和远视是两种以前未报告的眼表型。文献分析表明，先前报道的29位HS患者中，有12位具有PEX6突变，10例有PEX1突变，两例有PEX26突变，其余患者未进行基因检测。从这些患者的分析中揭示了三种新的基因型-表型相关性。首先，每位HS患者的大多数基因型至少包含一个错义变体。其次，每位视网膜营养不良的HS患者中，PEX1或PEX6基因的至少一个突变会影响AAA-ATPase区域，提示AAA-ATPase区域是视网膜营养不良患者的高变区域。第三，与PEX1，PEX6-和PEX26相关的表型之间没有显着差异。结论下一代测序对HS的诊断很重要。这项研究扩大了HS的临床和遗传谱，并提供了有关基因型与表型相关性的其他见解，这对于准确的临床实践至关重要，