A single genetic test proposed for diagnosis early-onset dementia


By Mardi Chapman

18 Aug 2022

Whole-genome sequencing (WGS) has the potential to identify genetic variations associated with early-onset dementia and decrease the time to diagnosis, Victorian researchers say.

A timely genetic diagnosis would facilitate patient entry into clinical trials of therapeutic agents targeting particular genes or genetic pathways, they suggest.

Their study performed WGS on 50 participants with dementia diagnosed ≤65 years at the Royal Melbourne Hospital and Austin Hospital. Most were diagnosed with Alzheimer’s (42%) or frontotemporal dementia (34%) while the rest were mostly unspecified dementia.

Using a target panel of 117 dementia-associated genes and 119 genomic variants, the study was able to identify a definitive clinical cause in five patients (10%) and a further nine patients (18%) had an established risk factor allele (ERF).

“Variants in PSEN1 were identified in 2 of the 21 patients with Alzheimer’s disease (~10%),” the study authors said.

“The ERF genotype APOEε4/ε4 was found in 6 of the 21 (~29%) patients with a clinical diagnosis of AD as well as 1 patient where the clinical diagnosis was unclear (1 of 8, or ~12%).”

The study, published in the Journal of Neurology, Neurosurgery & Psychiatry (link) also found one patient with frontotemporal dementia had a pathogenic variant in GRN (~6%) and another patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) had a likely pathogenic variant in NOTCH3.

“Expanding the analysis from targeted panel to the Mendeliome approach detected multiple variants, but no pathogenic or likely pathogenic variants. Multiple variants of uncertain significance were detected.”

“Overall, we suggest that patients with Alzheimer’s dementia onset ≤65 years, especially with mGS [modified Goldman score] of ≤3, should be offered a minimum of a targeted panel genetic testing.”

“Patients with specific types of dementia, where a genetic diagnosis is very likely (eg, CADASIL), should be offered either single gene testing for the specific condition or a targeted dementia panel.”

The researchers, including senior investigator Professor Ingrid Winship from the Royal Melbourne Hospital, recommended WGS in patients with frontotemporal dementia or an unclear type of dementia “as it can detect C9orf72 expansions and other monogenic causes of dementia, including structural variants simultaneously.”

“Reducing the time to diagnosis using WGS may improve the quality of life for patients and their families but needs to be formally assessed by using quality-of-life assessment studies,” they said.

They also noted that WGS may be cost-prohibitive in some settings.

Regular re-analysis of WGS data was warranted to check if further evidence has led to newer diagnoses.

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