Young‐onset dementia diagnosis, management and care

To the Editor: Loi and colleagues1 recently published a comprehensive review on young‐onset dementia (YOD). The review discussed genomic diagnostics, which has an increasing role to play in dementia care. Genetic diagnosis will lead to better outcomes for patients and their families, with greatest benefits for families found to have known pathogenic mutations in established monogenic causes of dementia.

At least 15% of YOD is caused by autosomal dominant genetic mutations.1 The most important genetic cause of frontotemporal dementia, a type of YOD, is the C9orf72 repeat expansion, discovered in 2011. Loi and colleagues outline in their article that the detection of repeat expansions, such as the C9orf72 repeat expansion, is not possible with widely available, short‐read whole genome sequencing (WGS). We contend that this is not correct.

In the past six years, several tools for the detection of repeat expansions from standard WGS have been developed.2 These methods are highly sensitive and specific, as demonstrated by applications to large clinical cohorts3,4 and by their ability to identify the causes of disease in families with no known genetic risk factors for YOD.5 These computational methods identify all known repeat expansions with a single diagnostic assay (WGS). This is in contrast to the currently used repeat expansion detection methods, which are laborious, locus by locus tests, using methods such as repeat primed polymerase chain reaction (PCR) and Southern blots. These new computational methods are thus able to detect rare repeat expansions not routinely tested, which can be unusual causes of dementia, such as the coding CAG (cytosine, adenine, guanine) expansion in the HTT gene, which causes Huntington disease. The only caveat to these powerful new diagnostic tools is that repeat expansion sizing is not accurate when the repeat expansion exceeds 150 base pairs.3 For this purpose, it is still current practice to confirm all detected repeat expansions using National Association of Testing Authority (NATA), or similarly accredited, repeat expansion tests.

Greater use of WGS in YOD is warranted because repeat expansion detection is not only possible but will also improve diagnostics. This will deliver precise and timely diagnostics for more patients with YOD, providing important clinical information for treating physicians.