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

Abstract

Purpose: Given the rapid pace of discovery in rare disease genomics, it is likely that improvements in diagnostic yield can be made by systematically reanalyzing previously generated genomic sequence data in light of new knowledge.

Methods: We tested this hypothesis in the United Kingdom-wide Deciphering Developmental Disorders study, where in 2014 we reported a diagnostic yield of 27% through whole-exome sequencing of 1,133 children with severe developmental disorders and their parents. We reanalyzed existing data using improved variant calling methodologies, novel variant detection algorithms, updated variant annotation, evidence-based filtering strategies, and newly discovered disease-associated genes.

Results: We are now able to diagnose an additional 182 individuals, taking our overall diagnostic yield to 454/1,133 (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.

Conclusion: This 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.

Keywords: diagnostic yield; exome sequencing; reanalysis; reclassification; recontact.

Figure 1. Outline of DDD variant filtering and reporting workflow.

Details of thresholds are outlined in the Methods section. The entire workflow is automated until the final stage, which requires detailed clinical review of any candidate variants in light of the child’s specific developmental phenotype.

Figure 2. Summary of reported and diagnostic variants in 1133 trios.

The total number of candidate variants per proband using the 2017 analysis pipeline is indicated (black bars), along with the number of full or partially diagnostic variants per proband in 2017 (striped dark grey bars) and 2014 (light grey bars).

Figure 3. Pathogenicity assessments of reported variants by inheritance class.

All variants (including SNVs, indels, CNVs, SVs, UPD and aneuploidies) that were classified by clinical teams as definitely/likely pathogenic were considered diagnostic, while those considered uncertain/likely benign/benign were not. The likelihood that a rare, functional de novo mutation in a dominant DDG2P gene is considered pathogenic is >80%, while the diagnostic yield from reported inherited variants is substantially less (10-30%). Note that variants of unknown and mosaic inheritance are excluded from the diagram due to low numbers (n<10).