Purpose: To characterize the retinal phenotype associated with INTS11-related neurodevelopmental disorder, expanding the phenotypic and genotypic spectrum of this newly described condition.
Methods: Four affected individuals with biallelic INTS11 variants from two unrelated families were evaluated through comprehensive ophthalmic and systemic clinical assessments, including multimodal retinal imaging and electrophysiology. Genetic testing involved genome or exome sequencing and segregation analysis, with novel variants assessed for pathogenicity. Two individuals (A-1 and A-2) had been reported previously and were noted to have retinal dystrophy, but no retinal imaging or electrophysiological findings were described; this study provides the first detailed characterization of their ocular phenotype.
Results: All four affected individuals exhibited a neurodevelopmental phenotype consistent with INTS11-associated disease. A similar retinal phenotype was observed across all four patients. Fundus examination demonstrated mild optic disc pallor; retinal pseudocolor and autofluorescence imaging were otherwise unremarkable. Optical coherence tomography revealed severe thinning of the inner retinal layers with preserved outer retinal layers. Electroretinography demonstrated generalized rod and cone system dysfunction localized to the inner retina or post-phototransduction. Individuals A-1 and A-2 harbored biallelic missense INTS11 variants c.34G > A; p.(Gly12Ser) and c.1219C > T; p.(Pro407Ser), as previously described. Novel missense INTS11 variants (c.721G > A, p.(Ala241Thr) and c.983T > A, p.(Leu328Gln)) were identified in individuals B-3 and B-4.
Conclusions: This study consolidates retinopathy as a feature of INTS11-associated neurodevelopmental disorders and provides a detailed characterization of a distinctive retinal phenotype. While most monogenic retinopathies affect the outer retina, this disease leads to thinning of the inner retinal layers. The findings underscore the importance of comprehensive ophthalmic evaluations in such cases. Furthermore, the study expands both the phenotypic and genotypic spectrum of INTS11-associated disorders.