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

Diagnostic approaches after non-diagnostic next-generation sequencing (research reanalysis, clinical genome sequencing, other genetic tests, clinical diagnosis) and the reasons why diagnoses had been missed

Most participants who undergo exome sequencing (ES) remain undiagnosed, and since clinical ES reanalysis and clinical genome sequencing (GS) provide incremental diagnoses in only 5 to 15% of cases, better approaches are needed. This retrospective review, carried out at one site of the Undiagnosed Diseases Network (UDN), examined the diagnostic approaches applied to non-diagnostic next-generation sequencing (ES/GS): research reanalysis of ES/GS, clinical GS, genetic testing other than ES/GS, and diagnosis from clinical information. In 77 of 192 participants (40%) with prior non-diagnostic sequencing, 80 diagnoses were obtained, including 50 known disorders and 30 novel gene-disease associations; research reanalysis of raw data from prior ES and UDN GS yields the largest share of diagnoses (54%), ahead of clinical ES/GS (27%), genetic testing other than ES/GS (11%) and clinical diagnoses (8%). Most causal variants are single nucleotide variants (78%) and coding (88%), and 72% of genetic diagnoses should have been made with the prior ES, the most frequent reasons being that the laboratory had not prioritised variants in novel genes (53%) or variants in known disease genes because of a perceived phenotypic mismatch (17%). The authors conclude that an individualised approach to non-diagnostic sequencing increases the diagnosis rate beyond reflexive GS, most subsequent diagnoses and novel gene discoveries coming from prioritisation of variants amenable to ES.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The most instructive result is not the overall yield but its origin: 72% of genetic diagnoses were already within reach of the initial exome, missed because variants in not-yet-established genes were not prioritised (53%) or because the phenotype seemed discordant with the known gene (17%). It is an argument against the reflex of systematic genome sequencing after a negative exome and in favour of an individualised re-reading of existing data, phenotype in hand. Extrapolation is nevertheless limited: a single site of the network, participants recruited into a research programme, and a level of validation of the 30 novel gene-disease associations that the abstract does not specify.

Analysis by Dr Thibaut Benquey