Phenotype‐driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders

Abstract

About 6000 to 7000 different rare disorders with suspected genetic etiologies have been described and almost 4500 causative gene(s) have been identified. The advent of next-generation sequencing (NGS) technologies has revolutionized genomic research and diagnostics, representing a major advance in the identification of pathogenic genetic variations. This study presents a 3-year experience from an academic genetics center, where 400 patients were referred for genetic analysis of disorders with unknown etiology. A phenotype-driven proband-only exome sequencing (ES) strategy was applied for the investigation of rare disorders, in the context of optimizing ES diagnostic yield and minimizing costs and time to definitive diagnosis.Overall molecular diagnostic yield reached 53% and characterized 243 pathogenic variants in 210 cases, 85 of which were novel and 148 known, contributing information to the community of disease and variant databases. ES provides an opportunity to resolve the genetic etiology of disorders and support appropriate medical management and genetic counseling. In cases with complex phenotypes, the identification of complex genotypes may contribute to more comprehensive clinical management. In the context of effective multidisciplinary collaboration between clinicians and laboratories, ES provides an efficient and appropriate tool for first-tier genomic analysis.

Systematic analysis of inheritance pattern determination in genes that cause rare neurodevelopmental diseases

“…Lastly, 8.7% carried variants on the X chromosome with hemizygous status, making the proportion of inherited variants 33.4% ( Figure 1B ). This distribution of pathogenic variant inheritance is comparable to those reported in other studies using rare disease patients from outbred populations ( Yang et al, 2013 ; Wright et al, 2015 ; Kuperberg et al, 2016 ; Marinakis et al, 2021 ).…”

“…We conducted WES analysis to reveal genetic etiology for 1,180 undiagnosed patients in the KND cohort. Previously reported diagnostic rates of WES vary substantially among studies, ranging from 25% to 56% ( Yang et al, 2013 ; Iglesias et al, 2014 ; Lee et al, 2014 ; Yang et al, 2014 ; Wright et al, 2015 ; Retterer et al, 2016 ; Jalkh et al, 2019 ; Marinakis et al, 2021 ). Herein, we report that the diagnostic yield for definitive pathogenic variant findings in KND patients was 50.8%.…”

Genome sequencing as a first-line diagnostic test for hospitalized infants

“…Finally, individuals with neurological-/muscular-associated features were 2.7 times (P = .003) more likely to receive a VUS, perhaps reflecting the fact that some neurological features are not observable in infancy. 30 Although others have conducted similar analyses, 31,32 future, larger studies may help to further delineate clinical features most predictive of GS diagnostic potential. It is also important to note that some phenotypes in infants with a DD/LD result may not be obviously related to the GS-identified variant (Table 4), and conversely, not all phenotypes associated with a specific DD/LD result were observed in the affected patients.…”

De novo interstitial deletion of 11q14.3q22 in a boy with mild intellectual disability and short stature

“…Genomic libraries were prepared using Twist Human Core Exome Kit (Twist Bioscience South San Francisco California USA) and paired-end sequencing was performed on an Illumina NextSeq 500 system (Illumina San Diego California USA) with a 150× mean sequencing depth (4.90 Gb). The generated raw data in the FASTQ file format was uploaded to the SOPHiA DDM platform where the variant filtering and interpretation steps were performed as previously described (Marinakis et al ., 2021).…”