Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD
Abstract 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 associati...
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Nature Portfolio
2021
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oai:doaj.org-article:e208f44c488745faa67e41d6e10b7aa12021-12-02T16:31:55ZBroadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD10.1038/s41525-021-00214-82056-7944https://doaj.org/article/e208f44c488745faa67e41d6e10b7aa12021-06-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00214-8https://doaj.org/toc/2056-7944Abstract 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.Riccardo SangermanoIris DeitchVirginie G. PeterRola Ba-AbbadEmily M. PlaceErin ZampaglioneNaomi E. WagnerAnne B. FultonLuisa Coutinho-SantosBoris RosinVincent DunetAla’a AlTalbishiEyal BaninAna Berta SousaMariana NevesAnna LarsonMathieu QuinodozMichel MichaelidesTamar Ben-YosefEric A. PierceCarlo RivoltaAndrew R. WebsterGavin ArnoDror SharonRachel M. HuckfeldtKinga M. BujakowskaNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-10 (2021) |
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DOAJ |
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DOAJ |
| language |
EN |
| topic |
Medicine R Genetics QH426-470 |
| spellingShingle |
Medicine R Genetics QH426-470 Riccardo Sangermano Iris Deitch Virginie G. Peter Rola Ba-Abbad Emily M. Place Erin Zampaglione Naomi E. Wagner Anne B. Fulton Luisa Coutinho-Santos Boris Rosin Vincent Dunet Ala’a AlTalbishi Eyal Banin Ana Berta Sousa Mariana Neves Anna Larson Mathieu Quinodoz Michel Michaelides Tamar Ben-Yosef Eric A. Pierce Carlo Rivolta Andrew R. Webster Gavin Arno Dror Sharon Rachel M. Huckfeldt Kinga M. Bujakowska Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD |
| description |
Abstract 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. |
| format |
article |
| author |
Riccardo Sangermano Iris Deitch Virginie G. Peter Rola Ba-Abbad Emily M. Place Erin Zampaglione Naomi E. Wagner Anne B. Fulton Luisa Coutinho-Santos Boris Rosin Vincent Dunet Ala’a AlTalbishi Eyal Banin Ana Berta Sousa Mariana Neves Anna Larson Mathieu Quinodoz Michel Michaelides Tamar Ben-Yosef Eric A. Pierce Carlo Rivolta Andrew R. Webster Gavin Arno Dror Sharon Rachel M. Huckfeldt Kinga M. Bujakowska |
| author_facet |
Riccardo Sangermano Iris Deitch Virginie G. Peter Rola Ba-Abbad Emily M. Place Erin Zampaglione Naomi E. Wagner Anne B. Fulton Luisa Coutinho-Santos Boris Rosin Vincent Dunet Ala’a AlTalbishi Eyal Banin Ana Berta Sousa Mariana Neves Anna Larson Mathieu Quinodoz Michel Michaelides Tamar Ben-Yosef Eric A. Pierce Carlo Rivolta Andrew R. Webster Gavin Arno Dror Sharon Rachel M. Huckfeldt Kinga M. Bujakowska |
| author_sort |
Riccardo Sangermano |
| title |
Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD |
| title_short |
Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD |
| title_full |
Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD |
| title_fullStr |
Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD |
| title_full_unstemmed |
Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD |
| title_sort |
broadening inpp5e phenotypic spectrum: detection of rare variants in syndromic and non-syndromic ird |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/e208f44c488745faa67e41d6e10b7aa1 |
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