期刊
NPJ GENOMIC MEDICINE
卷 6, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41525-021-00214-8
关键词
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资金
- National Eye Institute [R01EY012910, R01EY026904, P30EY014104]
- Jurg Tschopp MD-Ph.D. Scholarship
- Swiss National Science Foundation [31003A_176097]
- Foundation Fighting Blindness [EGI-GE-1218-0753-UCSD, BR-GE-0214-0639-TECH]
- Curing Kids Foundation
- National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust
- UCL Institute of Ophthalmology
- Moorfields Eye Charity
- Retina UK
- Swiss National Science Foundation (SNF) [31003A_176097] Funding Source: Swiss National Science Foundation (SNF)
The study validates the association between INPP5E gene mutations and non-syndromic IRD, as well as the wide phenotypic spectrum, demonstrating the involvement of genetic modifiers. Additionally, the research identifies 12 rare INPP5E variants not previously reported.
Pathogenic variants in INPP5E cause Joubert syndrome (JBTS), a ciliopathy with retinal involvement. However, despite sporadic cases in large cohort sequencing studies, a clear association with non-syndromic inherited retinal degenerations (IRDs) has not been made. We validate this association by reporting 16 non-syndromic IRD patients from ten families with bi-allelic mutations in INPP5E. Additional two patients showed early onset IRD with limited JBTS features. Detailed phenotypic description for all probands is presented. We report 14 rare INPP5E variants, 12 of which have not been reported in previous studies. We present tertiary protein modeling and analyze all INPP5E variants for deleteriousness and phenotypic correlation. We observe that the combined impact of INPP5E variants in JBTS and non-syndromic IRD patients does not reveal a clear genotype-phenotype correlation, suggesting the involvement of genetic modifiers. Our study cements the wide phenotypic spectrum of INPP5E disease, adding proof that sequence defects in this gene can lead to early-onset non-syndromic IRD.
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