Effectiveness of whole-exome sequencing for the identification of causal mutations in patients with suspected inherited ocular diseases

Abstract

Background: Genetic eye disorders, affecting around one in 1000 people, encompass a diverse group of diseases causing severe visual deficiency. The recent adoption of next-generation sequencing techniques, including whole-exome sequencing (WES), in medicine has greatly enhanced diagnostic rates of genetically heterogeneous diseases. Objectives: The objectives of the study were to assess the diagnostic yield of WES in a cohort of Mexican individuals with suspected genetic eye disorders and to evaluate the improvement of diagnostic rates by reanalysis of WES data in patients without an initial molecular diagnosis.Methods: A total of 90 probands with ocular anomalies of suspected genetic origin were ascertained. Patients underwent WES in leukocytic DNA. Bioinformatics analysis and Sanger sequencing were used to confirm the disease-causing variants. Only variants identified as pathogenic or likely pathogenic were considered as causal. Results: Initial analysis revealed causal mutations in 46 cases (51%). Reanalysis of WES data 12 months after first analysis resulted in the identification of additional causal variants in 6 patients (7%), increasing the molecular diagnostic yield to 58%. The highest diagnostic rates by disease categories corresponded to hereditary retinal dystrophies (77%) and to anomalies of the anterior segment of the eye (47%). Conclusion: Our study demonstrates that WES is an effective approach for genetic diagnosis of genetic ocular diseases and that reanalysis of WES data can improve the diagnostic yield.

Deciphering the etiology of undiagnosed ocular anomalies along with systemic alterations in pediatric patients through whole exome sequencing

“…The WES genomic testing conducted in this cohort of ten patients with complex ocular and systemic manifestations yielded a diagnosis in 40% of the patients, which is slightly similar to the reported diagnostic yield in the literature for Mexico (47%) 16 . Among the three disease-causing genotypes identified in Patients 1–3, the LPV of TRRAP p.(Ala1043Thr), identified in Patient 3, is the only genotype previously reported in five individuals with syndromic intellectual disability (ID) with malformations.…”