Automated Clinical Exome Reanalysis Reveals Novel Diagnoses

Abstract

Clinical exome sequencing (CES) has a reported diagnostic yield of 20% to 30% for most clinical indications. The ongoing discovery of novel geneedisease and variantedisease associations are expected to increase the diagnostic yield of CES. Performing systematic reanalysis of previously nondiagnostic CES samples represents a significant challenge for clinical laboratories. Here, we present the results of a novel automated reanalysis methodology applied to 300 CES samples initially analyzed between June 2014 and September 2016. Application of our reanalysis methodology reduced reanalysis variant analysis burden by >93% and correctly captured 70 of 70 previously identified diagnostic variants among 60 samples with previously identified diagnoses. Notably, reanalysis of 240 initially nondiagnostic samples using information available on July 1, 2017, revealed 38 novel diagnoses, representing a 15.8% increase in diagnostic yield. Modeling monthly iterative reanalysis of 240 nondiagnostic samples revealed a diagnostic rate of 0.57% of samples per month. Modeling the workload required for monthly iterative reanalysis of nondiagnostic samples revealed a variant analysis burden of approximately 5 variants/month for proband-only and approximately 0.5 variants/month for trio samples. Approximately 45% of samples required evaluation during each monthly interval, and 61.3% of samples were reevaluated across three consecutive reanalyses. In sum, automated reanalysis methods can facilitate efficient reevaluation of nondiagnostic samples using up-to-date literature and can provide significant value to clinical laboratories. (J Mol Diagn 2019, 21: 38e48; https://doi.

Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer

“…BRPF1 variants are present in 40 cases of syndromic intellectual disability ( Figs. 3 and 4) (12,(33)(34)(35)(36) and one individual with autism (43). As reported for H3K23 acetylation (12,33), these variants impaired BRPF1 in activating KAT6A (and perhaps also KAT6B) for H3K23 propionylation (Fig.…”

“…2), we then investigated the clinical relevance of these findings. We and others have reported 28 clinical cases of syndromic intellectual disability due to de novo or inherited BRPF1 variants (12,(33)(34)(35). We have now identified 12 previously unreported cases ( Fig.…”

“…Known cases with KAT6B variants have also exceeded 60 (32). We and others have just identified BRPF1 variants in 28 individuals with syndromic intellectual disability (12,(33)(34)(35)(36). The variants cause deficient H3K23 acetylation (12,33).…”

“…intellectual disability-associated germline variants (previously reported) Functional impact of BRPF1 variants associated with neurodevelopmental disorders. (A) Cartoon representation of variants previously identified in 29 individuals with syndromic intellectual disability(12,(33)(34)(35)(36) or autism(43). SeeFig.…”

Bibliome Variant Database: Automated Identification and Annotation of Genetic Variants in Primary Literature

“…Additionally, use of the BVdb can promote variant classification harmonization by ensuring all users have access to the same open access literature during variant interpretation (Garber et al 2016). Furthermore, the BVdb can also facilitate variant reanalysis, by allowing easy identification of newly published literature describing previously evaluated variants (Baker et al 2019).…”