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 Xu9,10,11, Ji-Hong Wu12,13,14. 1. Eye Institute, Eye and ENT Hospital, College of Medicine, Fudan University, Shanghai, China. 2. Shanghai Key Laboratory of Visual Impairment and Restoration, Science and Technology Commission of Shanghai Municipality, Shanghai, China. 3. Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, National Health Commission, Shanghai, China. 4. BGI-Shenzhen, Shenzhen, China. 5. Department of Computer Science, City University of Hong Kong, 83 Tat Chee Ave, Kowloon, Hong Kong. 6. Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark. 7. Shenzhen Engineering Laboratory for Birth Defects Screening, BGI-Shenzhen, Shenzhen, China. 8. Sichuan University, Chengdu, China. 9. Eye Institute, Eye and ENT Hospital, College of Medicine, Fudan University, Shanghai, China. drxugezhi@163.com. 10. Shanghai Key Laboratory of Visual Impairment and Restoration, Science and Technology Commission of Shanghai Municipality, Shanghai, China. drxugezhi@163.com. 11. Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, National Health Commission, Shanghai, China. drxugezhi@163.com. 12. Eye Institute, Eye and ENT Hospital, College of Medicine, Fudan University, Shanghai, China. jihongwu@fudan.edu.cn. 13. Shanghai Key Laboratory of Visual Impairment and Restoration, Science and Technology Commission of Shanghai Municipality, Shanghai, China. jihongwu@fudan.edu.cn. 14. Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, National Health Commission, Shanghai, China. jihongwu@fudan.edu.cn.
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.
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 HSpatients 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 HSpatient include at least one missense variant; second, at least one mutation in PEX1 or PEX6 gene affects the AAA-ATPase region in every HSpatient 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.
Authors: Malena Daich Varela; Priyam Jani; Wadih M Zein; Precilla D'Souza; Lynne Wolfe; Jennifer Chisholm; Christopher Zalewski; David Adams; Blake M Warner; Laryssa A Huryn; Robert B Hufnagel Journal: Am J Med Genet C Semin Med Genet Date: 2020-08-31 Impact factor: 3.359