Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders

Abstract

PurposeGiven the rapid pace of discovery in rare disease genomics, it is likely that improvements in diagnostic yield can be made by systematically reanalysing previously generated genomic sequence data in light of new knowledge.MethodsWe tested this hypothesis in the UK-wide Deciphering Developmental Disorders Study, where in 2014 we reported a diagnostic yield of 27% through whole exome sequencing of 1133 children with severe developmental disorders and their parents. We reanalysed existing data using improved variant calling methodologies, novel variant detection algorithms, updated variant annotation, evidence-based filtering strategies, and newly discovered disease-associated genes.ResultsWe are now able to diagnose an additional 182 individuals, taking our overall diagnostic yield to 454/1133 (40%), and another 43 (4%) have a finding of uncertain clinical significance. The majority of these new diagnoses are due to novel developmental disorder-associated genes discovered since our original publication.ConclusionThis study highlights the importance of coupling large-scale research with clinical practice, and of discussing the possibility of iterative reanalysis and recontact with patients and health professionals at an early stage. We estimate that implementing parent-offspring whole exome sequencing as a first line diagnostic test for developmental disorders would diagnose >50% of patients.

A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders

“…Of note, 11 cases classified as nondiagnostic in this study were ultimately clinically diagnosed with multiple system atrophy, cerebellar type, and another case was identified with a VUS associated with increased risk for this condition (Gilman et al, ; Zhao et al, ). We also reclassified variants from our previously reported 76 cases (Fogel et al, ) based on current annotation, which has been shown to improve diagnosis over time (Alfares et al, ; Ewans et al, ; Fogel, ; Fogel, Lee, Strom, Deignan, & Nelson, ; Fogel et al, ; Nambot et al, ; Rexach et al, ; Wright et al, ). This resulted in four cases previously classified as nondiagnostic or having a reportable VUS being reclassified with a pathogenic/likely pathogenic genetic variant.…”

Reanalysis of exome sequencing data of intellectual disability samples: Yields and benefits

“…Williams et al 25 patients with ID, reanalysis of WES resulted in an additional 13% diagnostic rate 28 . In a study from Saudi Arabia, the authors reported a higher yield of finding a definitive cause (48%, n = 16).…”

Genomics for paediatricians: promises and pitfalls

“…Variant classification should be considered as a dynamic or iterative process and altered according to newly emerging clinical, family and/or molecular evidence 15. It is therefore important that scientists and clinicians work closely together to ensure evidence-based interpretation of variants, with the clinician then carefully reverse phenotyping the patient.…”