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.
Highlights
Inherited retinal degenerations (IRDs) are a group of genetically and clinically heterogeneous disorders characterized by progressive photoreceptor loss due to genetic defects in ~270 genes, inherited in all Mendelian modes[1]
Rare Inositol Polyphosphate-5-Phosphatase E gene (INPP5E) variants associated with non-syndromic earlyonset IRD
We report non-syndromic IRD patients from ten families and two mildly syndromic Joubert syndrome (JBTS) cases with rare variants in INPP5E
Summary
Inherited retinal degenerations (IRDs) are a group of genetically and clinically heterogeneous disorders characterized by progressive photoreceptor loss due to genetic defects in ~270 genes, inherited in all Mendelian modes[1]. A total of 34 pathogenic INPP5E variants have been reported, 28 of which in patients with JBTS or MORM (Mental retardation, truncal obesity, retinal dystrophy, and micropenis) syndrome (OMIM #610156)[9,10,11,12,13,14,15,16,17,18,19,20,21,22,23]. These JBTS cases include eleven patients with no signs of IRD10,15,16,18,20,21,23. Our study substantiates the involvement of INPP5E variants in non-syndromic retinal disease
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