Not the end of the road: Achieving diagnoses following non-diagnostic exome sequencing: experiences at a clinical site of the Undiagnosed Diseases Network.

PURPOSE: Most participants who undergo exome sequencing (ES) remain undiagnosed. Since clinical ES reanalysis and clinical genome sequencing (GS) provide incremental diagnoses in only 5-15%, better resolution approaches to non-diagnostic ES are needed.

METHODS

Retrospective review of non-diagnostic NGS (ES/GS), at one site of the Undiagnosed Diseases Network (UDN), to assess the diagnostic approaches of ES/GS research reanalysis, clinical GS, non-ES/GS genetic testing and achieving diagnoses from clinical information.

RESULTS

77/192 (40%) participants with prior non-diagnostic NGS (ES/GS) obtained 80 diagnoses, including known disorders (n=50) and novel gene-disease associations (n=30). Research reanalysis of raw data from prior ES and UDN GS yielded the highest diagnoses (54%), followed by clinical ES/GS (27%), genetic testing other than ES/GS (11%) and clinical diagnoses (8%). Most causal variants were single nucleotide variants (SNVs- 78%) and most were coding (88%). Most (72%) genetic diagnoses should have occurred with prior ES; frequent reasons for diagnoses being overlooked were the prior laboratory not prioritizing: (a) novel gene variants (53%) and, (b) variants in known disorder genes due to perceived phenotypic mismatch (17%).

CONCLUSIONS

An individualized approach to non-diagnostic NGS increased the diagnosis rate beyond reflexive GS. Most subsequent diagnoses and novel gene discoveries were from prioritization of variants amenable to ES.