Marked yield of re‐evaluating phenotype and exome/target sequencing data in 33 individuals with intellectual disabilities

Abstract

The diagnosis of intellectual disability/developmental delay (ID/DD) benefits from the clinical application of target/exome sequencing. The yield in Mendelian diseases varies from 25% to 68%. The aim of the present study was to identify the genetic causes of 33 ID/DD patients using target/exome sequencing. Recent studies have demonstrated that reanalyzing undiagnosed exomes could yield additional diagnosis. Therefore, in addition to the normal data analysis, in this study, re-evaluation was performed prior to manuscript preparation after updating OMIM annotations, calling copy number variations (CNVs) and reviewing the current literature. Molecular diagnosis was obtained for 19/33 patients in the first round of analysis. Notably, five patients were diagnosed during the re-evaluation of the geno/phenotypic data. This study confirmed the utility of exome sequencing in the diagnosis of ID/DD. Furthermore, re-evaluation leads to a 15% improvement in diagnostic yield. Thus, to maximize the diagnostic yield of next-generation sequencing (NGS), periodical re-evaluation of the geno/phenotypic data of undiagnosed individuals is recommended by updating the OMIM annotation, applying new algorithms, reviewing the literature, sharing pheno/genotypic data, and re-contacting patients.

Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders

“…Several ES studies have focused on individuals with varying presentations of NDDs and have identified genetic causes in as many as 61% of cases. 1,11,12…”

Clinical sequencing yield in epilepsy, autism spectrum disorder, and intellectual disability: A systematic review and meta‐analysis

“…Sequencing studies that report the diagnostic yield (ie, percentage of pathogenic variant carriers identified in a cohort) in NDDs are few but are becoming increasingly common. Estimates of diagnostic yield vary considerably across individual studies (8% 5 –61% 6 ). This likely reflects differences in measurement, reporting, and clinical characteristics such as etiology and disorder type/subtype.…”

What do parents expect from a genetic diagnosis of their child with intellectual disability?

“…In addition, the probability of finding a diagnosis strongly depends on the diagnostic techniques that are available. The diagnostic yield has increased dramatically in the last few years (current range: 25%–68%) since NGS technologies were developed (Cherot et al, ; Deciphering Developmental Disorders Study, ; Evers et al, ; Vissers et al, ; Xiao et al, ). Therefore, it is important to explain to families that even in cases where a genetic cause of intellectual disability is strongly suspected, an aetiological clarification is not guaranteed.…”

“…The diagnostic yield has increased dramatically in the last few years (current range: 25%-68%) since NGS technologies were developed (Cherot et al, 2017;Deciphering Developmental Disorders Study, 2017;Evers et al, 2017;Vissers et al, 2017;Xiao et al, 2018).…”