Otago University-led research delivers more certainty for genetic test diagnoses

Findings from a new international study look set to improve rates of diagnosis for patients undergoing genetic testing in Aotearoa New Zealand and around the world.

The research, published in one of the world’s most prestigious medical journals, could pave the way for earlier intervention in the treatment of patients with genetic diseases and possibly prevent such diseases developing in patients and their whānau.

Associate Professor Logan Walker from the University of Otago, Christchurch’s Department of Pathology and Biomedical Science, was a leading member amongst 8 international researchers tasked with improving RNA diagnostics for laboratories worldwide.

“The study will help people undergoing genetic testing to have more certainty – whether changes to their DNA increase their risk of disease or whether those changes have no medical relevance at all,” says Associate Professor Walker.

Published in The American Journal of Human Genetics, Associate Professor Walker was joined by fellow New Zealand researcher Dr George Wiggins (University of Otago, Christchurch) alongside other colleagues in the United States, Australia and Spain.

“Genetic testing enables disease-associated DNA changes to be identified so patients can receive the best treatment or preventative therapies. However, many identified genetic changes are still an enigma, with scientists struggling to understand whether they cause harm or not. This lack of certainty causes anxiety for patients and their whānau, and prevents doctors from providing the best health care,” Associate Professor Walker says.

The Health Research Council-funded project focused on a developing area known as RNA Diagnostics. This involves scientists examining how changes to DNA affect a similar but different molecule called RNA. Understanding if and how the RNA molecule is altered by a DNA variant can help diagnose the clinical relevance of that variant. Analysing changes to RNA molecules also helps reduce reliance on population-based genetic methods which are susceptible to ethnic biases (which create inequity in healthcare).

The research team collated and organised a large amount of genetic testing information from both published scientific literature as well as commercial companies dedicated to advancing genetic healthcare. Careful analysis of these large datasets enabled the team to develop important recommendations for diagnostic and research laboratories when using RNA-based assays and computational methods to examine a new DNA variant.

“There is much discordance in the way different laboratories examine the RNA molecule and draw their conclusions. Our study will act as an instruction manual for these laboratories to help improve and standardise their diagnostic methods. We’ve already received positive feedback from different diagnostic labs which is extremely encouraging,” says Associate Professor Walker.

Decision tree for application of bioinformatic codes and RNA-splicing assay results for variant interpretation

(A) Alternative prediction tools/thresholds may be appropriate for variants that impact sites other than GT-AT donor-acceptor motifs. (B) LP variants at the canonical positions should only be used as evidence if additional supporting clinical evidence is present. (C) Silent (excluding last 3 nucleotides of exon and first nucleotide of exon) and intronic variants at or beyond the +7 and −21 positions (conservative designation for donor/acceptor splice region) or otherwise at or beyond the +7 and −4 positions (less conservative designation for the minimal donor/acceptor splice region). (D) If multiple impacts are observed from a splicing assay, use flowchart for the most conservative application of PVS1 based on experimental data. (E) We recommend that these thresholds be refined and applied in a disease- and gene-specific manner, including advice from VCEPs. Categorization as complete or near complete needs to consider multiple factors, including assay/technique, RNA source, and validation of assay weights using established controls. Examples of laboratory-specific approaches and suggested operational thresholds have been reported previously.

The project was affiliated with the National Institutes of Health (NIH)-funded Clinical Genome (ClinGen) Resource, a US-based international body of expert investigators tasked with building a genomic knowledge base to improve patient care, and help standardise the clinical annotation and interpretation of genomic variants.

The introduction of new cost-effective DNA sequencing technologies for genetic testing will continue to increase the number of such tests being undertaken around the world.

Interpreting the results of genetic tests remains a major challenge for health care professionals.

Associate Professor Walker hopes this study will guide the activities of more than 50 international specialist groups affiliated with ClinGen tasked with developing guidelines for their own disease specific genes.

SourceUniversity of Otago

Walker LC, Hoya M, Wiggins GAR, Lindy A, Vincent LM, Parsons MT, Canson DM, Bis-Brewer D, Cass A, Tchourbanov A, Zimmermann H, Byrne AB, Pesaran T, Karam R, Harrison SM, Spurdle AB; ClinGen Sequence Variant Interpretation Working Group. (2023) Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup. Am J Hum Genet 110(7):1046-1067. [article]

Leave a Reply

Your email address will not be published. Required fields are marked *


Time limit is exhausted. Please reload CAPTCHA.