Abstract
Inherited syndromic retinopathies are a highly heterogeneous group of diseases that involve retinal anomalies and systemic manifestations. They include retinal ciliopathies, other well-defined clinical syndromes presenting with retinal alterations and cases of non-specific multisystemic diseases. The heterogeneity of these conditions makes molecular and clinical characterization of patients challenging in daily clinical practice. We explored the capacity of targeted resequencing and copy-number variation analysis to improve diagnosis of a heterogeneous cohort of 47 patients mainly comprising atypical cases that did not clearly fit a specific clinical diagnosis. Thirty-three likely pathogenic variants were identified in 18 genes (ABCC6, ALMS1, BBS1, BBS2, BBS12, CEP41, CEP290, IFT172, IFT27, MKKS, MYO7A, OTX2, PDZD7, PEX1, RPGRIP1, USH2A, VPS13B, and WDPCP). Molecular findings and additional clinical reassessments made it possible to accurately characterize 14 probands (30% of the total). Notably, clinical refinement of complex phenotypes was achieved in 4 cases, including 2 de novo OTX2-related syndromes, a novel phenotypic association for the ciliary CEP41 gene, and the co-existence of biallelic USH2A variants and a Koolen-de-Vries syndrome–related 17q21.31 microdeletion. We demonstrate that combining next-generation sequencing and CNV analysis is a comprehensive and useful approach to unravel the extensive phenotypic and genotypic complexity of inherited syndromic retinopathies.
Highlights
Inherited syndromic retinopathies are a highly heterogeneous group of diseases that involve retinal anomalies and systemic manifestations
The genes were selected based on previous associations with Inherited syndromic retinopathies (ISR) reported in the literature, many of which showed a high proportion of associated phenotypes and appeared to be functionally related (Supplementary Fig. S1)
Patients were classified into 4 major phenotypic categories based on clinical features and suspected clinical diagnosis (Fig. 1): i) ciliopathies, including cases with Alström, Bardet-Biedl syndrome (BBS), or Joubert syndrome; ii) ciliopathy-like, including patients with retinal dystrophies (RD) and some ciliopathy-related systemic anomalies; iii) other known syndromic retinopathies, a total of 5 patients with a clear diagnosis of either PBDs, Stickler syndrome, or pseudoxanthoma elasticum (PXE); iv) miscellanea, including 21 cases with heterogeneous phenotypes involving retinal disease with 1 or more non-specific systemic features, such as congenital malformations, ataxia, dwarfism, intellectual disability (ID), or neuroendocrine alterations
Summary
Inherited syndromic retinopathies are a highly heterogeneous group of diseases that involve retinal anomalies and systemic manifestations. They include retinal ciliopathies, other well-defined clinical syndromes presenting with retinal alterations and cases of non-specific multisystemic diseases. The heterogeneity of these conditions makes molecular and clinical characterization of patients challenging in daily clinical practice. Patients present with diverse non-specific systemic symptoms and signs in which a clear clinical diagnosis cannot be achieved[13]. Our results provide new insights into the genetic complexity of these diseases
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