Advances in genomic testing have vastly improved clinicians’ ability to identify a molecular genetic cause for both common and rare diseases. But could such testing replace more conventional diagnostic modalities entirely? The study of Bourgon et al. suggests that prenatal exome sequencing may be sufficient to diagnose the cause of multiple congenital anomalies, without the need for post-mortem examination . In particular, the extra phenotypic information derived from fetal post-mortem did not substantially increase the diagnostic yield of exome sequencing. In the presence of multiple congenital anomalies, the prenatal phenotype identified through imaging may be sufficient to interpret exome sequencing.
Exome sequencing is a valuable diagnostic tool—but it does have limitations in the types of variant it can detect. A classic limitation of exome sequencing is limited coverage of deep intronic variants. Nicita et al. demonstrate this, and the need to use orthogonal techniques, such as RNA sequencing, to identify non-coding variants in a child with a biochemical diagnosis of Krabbe disease . Of course exome sequencing cannot detect repeat expansions or methylation status, of relevance to myotonic dystrophy type 1 . Perhaps the most significant limitation to exome sequencing is our ability to interpret the identified variants. Chopra et al. describe how publication of the protein structure of DNA polymerase delta was required to enable identification of a pathogenic variant in the POLD1 gene . Extensive exome sequencing studies have been unable to identify recurrent protein coding causes of cardiovascular laterality defects. Breuer et al. identify novel candidate genes in a series of individuals with laterality defects, but without significant replication in a larger cohort . Despite its limitations, trio exome sequencing is clearly a powerful diagnostic tool. In this issue, Brea-Fernández et al. identified a diagnostic yield of 25% from trio sequencing for intellectual disability, which is similar to the results of other studies . Exome sequencing also increases our understanding of clinical phenotypes. Al Shamsi et al. describe new cases of SLC25A32 deficiency presenting with hypoketotic hypoglycaemia without neuromuscular features .
Identification of causal genetic variants is the science of medicine. Helping families understand results and cope with them is part of the art. Firth et al. describe the role of a clinical psychologist in helping families come to terms with genetic conditions as part of a Clinical Genetics service .
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Firth C, Tripathi V, Kowalski Bellamy A, Somers N, Roos C, Tomlinson C. A unique service: how an embedded psychology team can help patients and genetics clinicians within a clinical genetics service. Eur J Hum Genet. 2022. https://doi.org/10.1038/s41431-022-01112-y
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McNeill, A. Exome sequencing—one test to rule them all?. Eur J Hum Genet 30, 869 (2022). https://doi.org/10.1038/s41431-022-01145-3