Early onset non-syndromic retinal degeneration due to variants in INPP5E: phenotypic expansion of the ciliary gene previously associated with Joubert syndrome

Author:

Sangermano Riccardo,Deitch Iris,Peter Virginie G.,Ba-Abbad Rola,Place Emily M.,Wagner Naomi E.,Fulton Anne B.,Coutinho-Santos Luisa,Rosin Boris,Dunet Vincent,AlTalbishi Ala’a,Banin Eyal,Sousa Ana Berta,Neves Mariana,Larson Anna,Quinodoz Mathieu,Michaelides Michel,Ben-Yosef Tamar,Pierce Eric A.,Rivolta Carlo,Webster Andrew R.,Arno Gavin,Sharon Dror,Huckfeldt Rachel M.,Bujakowska Kinga M.

Abstract

ABSTRACTPurposePathogenic variants in INPP5E cause Joubert syndrome, a systemic disorder that can manifest with retinal degeneration among other clinical features. We aimed to evaluate the role of INPP5E variants in non-syndromic inherited retinal degenerations (IRDs) of varying severity.MethodsTargeted or genome sequencing were performed in 12 unrelated non-syndromic IRD families from multiple research hospitals. Detailed clinical examination was conducted in all probands. The impact of new likely pathogenic variants was modeled on a tertiary INPP5E protein structure and all the new and published variants were analyzed for their deleteriousness and phenotypic correlation.ResultsFourteen INPP5E rare alleles were detected, 12 of which were novel. Retinal degeneration in all 12 probands was clinically distinguishable on the basis of onset and severity into Leber congenital amaurosis (n=4) and a milder, later-onset rod-cone dystrophy (n=8). Two probands showed mild ciliopathy features that resolved in childhood. Analysis of the combined impact of both alleles in syndromic and non-syndromic INPP5E patients did not reveal clear genotype-phenotype correlation, suggesting involvement of genetic modifiers.ConclusionsThe study expands the phenotypic spectrum of disorders due to pathogenic variants in INPP5E and describes a new disease association with previously underdiagnosed forms of early-onset non-syndromic IRD.

Publisher

Cold Spring Harbor Laboratory

Reference40 articles.

1. Retinal Information Network (RetNet). https://sph.uth.edu/retnet/home.htm. Accessed April 1, 2020.

2. Ciliopathies

3. Signaling through the Primary Cilium

4. Photoreceptor Cilia and Retinal Ciliopathies

5. Joubert Syndrome and related disorders

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