PMC:4596894 / 19480-26025 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4596894","sourcedb":"PMC","sourceid":"4596894","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4596894","text":"Discussion\nPEX1 and PEX6 encode two interacting proteins that belong to the peroxisomal import machinery and that are involved in the shuttling of PEX5, the cytosolic receptor for peroxisomal matrix proteins.32,33 Biallelic pathogenic variants in PEX1, PEX5, PEX6, or any of the other 11 PEX genes result in a PBD, which is characterized by defective peroxisome assembly due to impaired import of proteins into the peroxisomal matrix or membrane.25 Peroxisomes are found in virtually all human cells and play a crucial role in a number of metabolic pathways.34 PBDs usually have a severe progressive multi-systemic clinical presentation, including developmental delay, seizures, SNHL, retinopathy, peripheral neuropathy, leukodystrophy, and skeletal, craniofacial, and liver abnormalities.35–37 Dependent on the underlying genetic defect, however, the clinical presentation and survival of individuals with a PBD can show a wide variability ranging from the severe, early-childhood lethal Zellweger syndrome to milder phenotypes, including isolated progressive ataxia.26,27 To reflect this clinical variability, the PBDs are often referred to as Zellweger spectrum disorders. Accounting for 60% and 16%, respectively, of diagnosed cases,19 mutations in PEX1 and PEX6 represent the most common causes of PBDs. Our combined findings show that HS is caused by compound heterozygosity for a loss-of-function allele and a hypomorphic allele in PEX1 or PEX6. Alternatively, in family 1 a homozygous hypomorphic allele also results in the HS phenotype. Consequently, although PBD-affected individuals with mild or normal peroxisome functions in blood and fibroblasts and normal intellect have been described before, HS represents a discrete phenotypic entity at the mildest end of the PBD clinical spectrum. The characteristic presentation overlaps some of the clinical features observed in affected individuals with PBDs.38,39 Indeed, SNHL is a common feature of PBDs, and tooth and nail abnormalities have been described in PBD-affected individuals with prolonged survival, but always in association with additional and more severe features.40–44 Importantly, in contrast to individuals with PBDs at the severe end of the clinical spectrum, the individuals with HS showed no identifiable dysmorphic or additional neurological features. Other evidence of clinical effect due to peroxisome dysfunction was not investigated, given that there was no clinical indication. However, future assessments of individuals with HS should consider other features well described in individuals with PBDs, including brain imaging, testing for adrenal insufficiency, liver-function tests, and clinical assessment for evidence of (progressive) peripheral neuropathy. Compound heterozygosity of the hypomorphic PEX6 c.1802G\u003eA allele has been reported previously in seven individuals with a Zellweger spectrum disorder.20,23 In all reported individuals, the p.Arg601Gln allele was in trans with a severe PEX6 allele that, when homozygous or in trans with another severe PEX6 allele, causes a severe peroxisomal phenotype (six individuals) or that is predicted to be deleterious (one individual). For three of the seven individuals, who were diagnosed at an advanced adult age, studies in fibroblasts revealed peroxisomal mosaicism at 37°C and slightly elevated C26:C22 levels (unpublished results). Other peroxisomal parameters were normal. No clinical data are available for determining whether these individuals showed a HS-like phenotype. However, these findings suggest that the PEX6 c.1802G\u003eA allele is a risk allele for mild PBD when in trans with a severe PEX6 allele. Because the PEX6 c.1802G\u003eA allele has a frequency of 0.41% in the European population (see ExAC Browser in the Web Resources), we expect that future WES studies will identify additional individuals who have a mild PBD due to compound heterozygosity of the PEX6 c.1802G\u003eA allele and a severe PEX6 allele and who have not been suspected of or analyzed for a peroxisomal disorder on the basis of clinical diagnosis.\nBecause standard biochemical screening of blood for evidence of a peroxisomal disorder would not have provided a diagnosis in the individuals with HS, our study used a genomic approach to diagnose a rare inborn error of metabolism. Our findings could also be relevant for the development of future therapy for PBDs, because they indicate that partial restoration of the function of altered PEX proteins would lead to a phenotype consistent with HS. Notably, the normal intellectual development and lack of severe hepatic and neurological impairment should be instructive in the expected outcomes of future therapeutic trials. Because of the SNHL and retinal pigmentation, HS is also an important differential diagnosis for Usher syndrome (MIM: 276900). Our study allows precise molecular differentiation of the two diagnoses and indicates that all individuals with SNHL and retinal pigmentation are candidates for mutation analysis of PEX genes. Our data indicate that HS is a clinically and genetically heterogeneous condition due to biallelic variants in PEX1 or PEX6. We did not identify PEX variants in families 7 or 8, nor did we find another genetic cause. However, there are phenotypic differences between these families and those in whom PEX1 or PEX6 variants were identified. Although amelogenesis imperfecta was present in all affected individuals in families 7 and 8, the SNHL in the individuals in family 7 was less severe than in the other affected individuals. In the previously reported affected individual in family 8, the SNHL was unilateral, whereas it was bilateral in all the other affected individuals. In addition, only individual F8-II:1 presented with subtle Beau’s lines, individuals in family 7 did not show any nail abnormalities, and ocular features were not present in any of the individuals in families 7 or 8. So, these phenotypic differences might account for the lack of PEX1 or PEX6 mutations, indicating both clinical and genetic heterogeneity.\nThe development of genomic medicine has stimulated an active debate about the interpretation of sequence variants and the challenges of pleiotropy.45 Our data highlight the complexity of the clinical interpretation of genomic data by showing that different mutations in PEX1 and PEX6 result in strikingly different clinical outcomes. In addition, the results of this study further emphasize the power of functional laboratory tests in the evaluation of rare variants in known disease-associated genes.","divisions":[{"label":"title","span":{"begin":0,"end":10}},{"label":"p","span":{"begin":11,"end":4063}},{"label":"p","span":{"begin":4064,"end":6043}}],"tracks":[{"project":"2_test","denotations":[{"id":"26387595-22079764-2046290","span":{"begin":211,"end":213},"obj":"22079764"},{"id":"26387595-25016021-2046290","span":{"begin":211,"end":213},"obj":"25016021"},{"id":"26387595-22871920-2046291","span":{"begin":446,"end":448},"obj":"22871920"},{"id":"26387595-16756494-2046292","span":{"begin":558,"end":560},"obj":"16756494"},{"id":"26387595-23798008-2046293","span":{"begin":792,"end":794},"obj":"23798008"},{"id":"26387595-23622381-2046293","span":{"begin":792,"end":794},"obj":"23622381"},{"id":"26387595-22483868-2046293","span":{"begin":792,"end":794},"obj":"22483868"},{"id":"26387595-17534573-2046294","span":{"begin":1071,"end":1073},"obj":"17534573"},{"id":"26387595-20695019-2046294","span":{"begin":1071,"end":1073},"obj":"20695019"},{"id":"26387595-21031596-2046295","span":{"begin":1237,"end":1239},"obj":"21031596"},{"id":"26387595-21862673-2046296","span":{"begin":1918,"end":1920},"obj":"21862673"},{"id":"26387595-11873320-2046296","span":{"begin":1918,"end":1920},"obj":"11873320"},{"id":"26387595-15098231-2046297","span":{"begin":2139,"end":2141},"obj":"15098231"},{"id":"26387595-20033294-2046297","span":{"begin":2139,"end":2141},"obj":"20033294"},{"id":"26387595-22591434-2046297","span":{"begin":2139,"end":2141},"obj":"22591434"},{"id":"26387595-21703082-2046297","span":{"begin":2139,"end":2141},"obj":"21703082"},{"id":"26387595-10607947-2046297","span":{"begin":2139,"end":2141},"obj":"10607947"},{"id":"26387595-19877282-2046298","span":{"begin":2897,"end":2899},"obj":"19877282"},{"id":"26387595-19105186-2046298","span":{"begin":2897,"end":2899},"obj":"19105186"},{"id":"26387595-24481117-2046299","span":{"begin":6191,"end":6193},"obj":"24481117"}],"attributes":[{"subj":"26387595-22079764-2046290","pred":"source","obj":"2_test"},{"subj":"26387595-25016021-2046290","pred":"source","obj":"2_test"},{"subj":"26387595-22871920-2046291","pred":"source","obj":"2_test"},{"subj":"26387595-16756494-2046292","pred":"source","obj":"2_test"},{"subj":"26387595-23798008-2046293","pred":"source","obj":"2_test"},{"subj":"26387595-23622381-2046293","pred":"source","obj":"2_test"},{"subj":"26387595-22483868-2046293","pred":"source","obj":"2_test"},{"subj":"26387595-17534573-2046294","pred":"source","obj":"2_test"},{"subj":"26387595-20695019-2046294","pred":"source","obj":"2_test"},{"subj":"26387595-21031596-2046295","pred":"source","obj":"2_test"},{"subj":"26387595-21862673-2046296","pred":"source","obj":"2_test"},{"subj":"26387595-11873320-2046296","pred":"source","obj":"2_test"},{"subj":"26387595-15098231-2046297","pred":"source","obj":"2_test"},{"subj":"26387595-20033294-2046297","pred":"source","obj":"2_test"},{"subj":"26387595-22591434-2046297","pred":"source","obj":"2_test"},{"subj":"26387595-21703082-2046297","pred":"source","obj":"2_test"},{"subj":"26387595-10607947-2046297","pred":"source","obj":"2_test"},{"subj":"26387595-19877282-2046298","pred":"source","obj":"2_test"},{"subj":"26387595-19105186-2046298","pred":"source","obj":"2_test"},{"subj":"26387595-24481117-2046299","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#ec93cd","default":true}]}]}}