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Exome sequencing technologies are constantly evolving, with exome capture systems covering more coding bases, and the continual development of improved alignment and variant-calling programmes. At the same time, new genes are frequently being implicated in Mendelian genetic disease. In many cases, therefore, the generation of extra coverage, updating of alignment and variant calling tools and regular inspection for novel gene-disease associations emerging in the literature will yield a diagnosis that was not found in the initial analysis.
The rates of diagnosis with exome sequencing range from 25% to 40%.1 The diagnosis rate depends on various factors including how patients are selected, the degree of genetic prescreening, the age and ancestry of the population and what is defined as a probable diagnosis. Some of those that remain undiagnosed will not, in fact, have a Mendelian genetic disorder, for example, those with disorders due to mutations in mitochondrial genes, somatic mutations and those with oligogenic or more complex genetic disorders. However, there are many ways that patients with a relevant Mendelian pathogenic genetic variant may not obtain a diagnosis in the initial analysis. These can be divided into two broad classes.
The variant is not identified. The simplest reason for patients remaining undiagnosed is that the pathogenic variant is not identified. This may be because it is in a region not included in the exome sequence, for example, intronic or intergenic variants, or because that site is just poorly covered in that individual due to fluctuations in coverage.2 Other variant sites may be well covered but the variants themselves are not easily discoverable by current bioinformatic tools, for example, repeat polymorphisms and structural variants, or single nucleotide variants or small insertion/deletion polymorphisms in regions of local genomic complexity.
The variant is …
Contributors VS and KS helped to interpret the exome data and contributed to the writing of the paper, SP, DBG and ACN contributed to the re-analysis of the exome data and the writing of the paper.
Competing interests None declared.
Ethics approval Duke IRB.
Provenance and peer review Not commissioned; externally peer reviewed.