“I was surprised that such a recent publication would be incorporated into clinical reporting so rapidly. It is good practice that the latest evidence is incorporated.”
3billion Inc has developed an automated system to reflect the latest findings on genetic variants and diagnosed many patients suffering from the diagnostic odyssey for several years. After integrating this automated system, 3billion’s reanalysis solved 10% of undiagnosed cases.
There was a significant story of Dr. Alisdair McNeill. Without Dr. McNeill being aware, his academic effort took a great part in diagnosing four patients suffering from a diagnostic odyssey.
Profile of Dr. Alisdair McNeill
Affiliation: University of Sheffield, UK
Position: Senior Clinical Lecturer in Neurogenetics
Recent publication: SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect
Date of publication: 13 July 2020
Date of the first patient diagnosed: 6 December 2020
(This patient could not be diagnosed from the initial test. But through the continuous reanalysis, the patient finally got diagnosed based on Dr.McNeill's finding)
Interview with Dr. Alisdair McNeill
Q1: Please tell us who you are and your background.
I am a clinical academic, appointed as a Senior Clinical Lecturer in Neurogenetics. I spend half of my time as a consultant in Clinical Genetics and have undertaken neurogenetics research. My interests are identifying novel causes of neurogenetic disorders, defining the clinical phenotypes and understanding family experiences of living with rare diseases.
Q2: The process of identifying de novo mutations is extremely challenging. How did you start the research? And how did you make the approach for this research? (ex. the range of data: CNV or Transcriptome seq, etc)
In my work I identify candidate genes by 1. focusing on genes from within the smallest region of overlap in microdeletions and 2. Identifying genes which interact with known disease genes. I then identify candidate de novo variants in large scale exome and genome sequencing data from projects such as the UK Deciphering Developmental disorders study. Further work to classify any identified variants focuses on standard ACMG criteria.
Q3: Your research truly helped many patients suffering from rare diseases with neurodevelopmental problems, and it means a lot. There was a finding that the SLC12 gene is related to some diseases but the specific relationship was not clear until you published your research. Did you specifically target the SCL12 gene for the analysis or did you verify it with a newly revealed gene?
We identified an individual with an SLC12A2 variant and then identified a cohort via GeneMatcher and our network of collaborators.
Q4: You identified the candidate gene through Whole Exome Sequencing with multiple transcriptome and functional studies. What are the advantages of having WES tests? Since when did you use WES tests and why?
WES enables us to efficiently sequence multiple candidate genes which might be responsible for a patient's symptoms without having to undertake multiple panel or Sanger sequencing tests. There is ample evidence that WES is cost effective and enables a diagnosis to be made in 30-50% of undiagnosed patients.
Q5: Do you recommend WES to your colleagues or physicians?
Yes. It is not clear yet if whole genome sequencing will offer a significantly improved diagnostic rate so I believe WES should remain the first line test.
Q6: Based on your experience, what were the useful data to conduct your study? (ex. transcriptome data or in silico experiment)
Identification of protein coding variants which were de novo and rare in control populations. Ideally a pipeline such as exomiser would be applied, to interpret variants in the context of a patient's phenotype.
Q7: Did you get surprised when 3billion contacted you that patients are already having benefits because of your recent research?
Yes, I was surprised that such a recent publication would be incorporated into clinical reporting so rapidly. It is good practice that the latest evidence is incorporated.
Q8: There are still many undiagnosed patients in 3billion’s database. Would you consider collaborating with 3billion to reveal cases for your target genes?
Yes, I would very much value a research collaboration whereby we could identify if any patients in your database had variants in genes I am researching.
Q9: What do you recommend to do for physicians and medical experts in the industry to help reduce the number of undiagnosed patients?
Detailed phenotyping of patients. Early use of WES and application of a “phenotype aware” pipeline such as exomiser if possible or the pipeline developed by 3billion which seems to have similar effectiveness.