NGS and phenotypic ontology-based approaches increase the diagnostic yield in syndromic retinal diseases

Abstract

Syndromic retinal diseases (SRDs) are a group of complex inherited systemic disorders, with challenging molecular underpinnings and clinical management. Our main goal is to improve clinical and molecular SRDs diagnosis, by applying a structured phenotypic ontology and next-generation sequencing (NGS)-based pipelines. A prospective and retrospective cohort study was performed on 100 probands with an a priori diagnosis of non-Usher SRDs, using available clinical data, including Human Phenotype Ontology annotation, and further classification into seven clinical categories (ciliopathies, specific syndromes and five others). Retrospective molecular diagnosis was assessed using different molecular and bioinformatic methods depending on availability. Subsequently, uncharacterized probands were prospectively screened using other NGS approaches to extend the number of analyzed genes. After phenotypic classification, ciliopathies were the most common SRD (35%). A global characterization rate of 52% was obtained, with six cases incompletely characterized for a gene that partially explained the phenotype. An improved characterization rate was achieved addressing prospective cases (83%) and well-recognizable syndrome (62%) subgroups. The 27% of the fully characterized cases were reclassified into a different clinical category after identification of the disease-causing gene. Clinical-exome sequencing is the most appropriate first-tier approach for prospective cases, whereas whole-exome sequencing and bioinformatic reanalysis increases the diagnosis of uncharacterized retrospective cases to 45%, mostly those with unspecific symptoms. Our study describes a comprehensive approach to SRDs in daily clinical practice and the importance of thorough clinical assessment and selection of the most appropriate molecular test to be used to solve these complex cases and elucidate novel associations.

Prioritization of new candidate genes for rare genetic diseases by a disease-aware evaluation of heterogeneous molecular networks

“…On the other hand, DNAH5 has been proposed as a candidate gene for retinal dystrophies using a different method based on the aggregation of variants in unsolved cases compared to controls (1). In a second case, we found a monoallelic variant in the recessive gene GLI1, which explains partially the patient's phenotype (68). Further analyses are needed to reach a conclusive diagnostic in both cases.…”

Prioritization of New Candidate Genes for Rare Genetic Diseases by a Disease-Aware Evaluation of Heterogeneous Molecular Networks

“…On the other hand, DNAH5 has been proposed as a candidate gene for retinal dystrophies using a different method based on the aggregation of variants in unsolved cases compared to controls [ 1 ]. In a second case, we found a monoallelic variant in the recessive gene GLI1 , which explains partially the patient’s phenotype [ 68 ]. Further analyses are needed to reach a conclusive diagnostic in both cases.…”

Five years’ experience of the clinical exome sequencing in a Spanish single center

“…It is known that this increased DR is mainly due to the discovery of new disease-genes, the use of better bioinformatics tools, such as large databases and improved pipelines that help in the reclassification of variants, as previously demonstrated by our group 30 , 31 , and the availability of additional phenotype data, among others 16 . In this line, prioritized features and genes using Human Phenotype Ontology terminology have been proposed as a helping diagnostic tool 32 , 33 . In addition, good communication with the clinicians ordering tests and an continuous genomic data sharing, is essential for the discovery of new genes -as already demonstrated with the GeneMatcher tool 34 – 36 -and for a better interpretation of variants that will definitely improve our diagnosis process 3 .…”