Whole genome sequencing increases diagnosis of rare disorders by nearly
a third

Date:
November 4, 2021
Source:
University of Cambridge
Summary:
Whole Genome Sequencing from a single blood test picks up 31% more
cases of rare genetic disorders than standard tests, shortening the
'diagnostic odyssey' affected families experience and providing
huge opportunities for future research.



FULL STORY ========================================================================== Whole Genome Sequencing from a single blood test picks up 31% more
cases of rare genetic disorders than standard tests, shortening the
'diagnostic odyssey' affected families experience and providing huge opportunities for future research.


========================================================================== Mitochondrial disorders affect around 1 in 4300 people and cause
progressive, incurable diseases. They are amongst the most common
inherited diseases but are difficult for clinicians to diagnose, not
least because they can affect many different organs and resemble many
other conditions.

Current genetic testing regimes fail to diagnose around 40% of patients,
with major implications for patients, their families and the health
services they use.

A new study, published today in the BMJ, offers hope to families with
no diagnosis, and endorses plans for the UK to establish a national
diagnostic programme based on whole genome sequencing (WGS) to make more diagnoses faster.

While previous studies based on small, highly selected cohorts have
suggested that WGS can identify mitochondrial disorders, this is the first
to examine its effectiveness in a national healthcare system -- the NHS.

The study, led by researchers from the MRC Mitochondrial Biology
Unit and Departments of Clinical Neuroscience and Medical Genetics
at the University of Cambridge, involved 319 families with suspected mitochondrial disease recruited through the 100,000 Genomes Project
which was set up to embed genomic testing in the NHS, discover new
disease genes and make genetic diagnosis available for more patients.



==========================================================================
In total, 345 participants -- aged 0 to 92 with a median age of 25
years -- had their whole genome sequenced. Through different analyses,
the researchers found that they could make adefinite or probable genetic diagnosis for 98 families (31%). Standard tests, which are often more
invasive, failed to reach these diagnoses. Six possible diagnoses (2% of
the 98 families) were made. A total of 95 different genes were implicated.

Surprisingly, 62.5% of the diagnoses were actually non-mitochondrial
disorders, with some having specific treatments. This happened because
so many different diseases resemble mitochondrial disorders, making it
very difficult to know which are which.

Professor Patrick Chinnery from the MRC Mitochondrial Biology Unit and the Department of Clinical Neurosciences at the University of Cambridge, said:
"We recommend that whole genome sequencing should be offered early and
before invasive tests such as a muscle biopsy. All that patients would
need to do is have a blood test, meaning that this could be offered
across the whole country in an equitable way. People wouldn't need to
travel long distances to multiple appointments, and they would get their diagnosis much faster." Dr Katherine Schon from the MRC Mitochondrial
Biology Unit and the Departments of Clinical Neuroscience and Medical
Genetics, said: "A definitive genetic diagnosis can really help patients
and their families, giving them access to tailored information about
prognosis and treatment, genetic counselling and reproductive options
including preimplantation genetic diagnosis or prenatal diagnosis."


==========================================================================
The researchers made 37.5% of their diagnoses in genes known to cause mitochondrial disease. These diagnoses were nearly all unique to a
particular participant family, reflecting the genetic diversity found
in these disorders.

The impairment of mitochondrial function tends to affect tissues with
high energy demand such as the brain, the peripheral nerves, the eye,
the heart and the peripheral muscles. The study offers a valuable new
resource for the discovery of future mitochondrial disease genes.

The majority of the team's diagnoses (62.5%) were, however, of non- mitochondrial disorders which had features resembling mitochondrial
diseases.

These disorders would have been missed if the participants had only been investigated for mitochondrial disorders through muscle biopsy and/or a specific mitochondrial gene panel. These participants were living with a
range of conditions including developmental disorders with intellectual disability, severe epileptic conditions and metabolic disorders, as well
as heart and neurological diseases.

Chinnery said: "These patients were referred because of a suspected mitochondrial disease and the conventional diagnostic tests are
specifically for mitochondrial diseases. Unless you consider these
other possibilities, you won't diagnose them. Whole genome sequencing
isn't restricted by that bias." A small number of newly diagnosed
participants are already receiving treatments as a result. The team
identified potentially treatable disorders in six participants with
a mitochondrial disorder and nine with a non-mitochondrial disorder,
but the impact of the treatments has yet to be determined.

Chinnery said: "Diagnostic services are fragmented and unevenly
distributed across the UK, and that creates major challenges for people
with rare diseases and their families. By delivering a national programme
based on this genome- wide approach, you can offer the same level of
service to everyone.

Schon said: "If we can create a national platform of families with rare diseases, we can give them the opportunity to engage in clinical trials
so we can get definitive evidence that new treatments work." The study
points out that the relatively high number of patients with probable or possible diagnoses reflects the need for greater investment into the
analysis of functional effects of new genetic variants which could be
the cause of disease, but it is not certain at present.

It also argues that rapid trio whole genome sequencing should be offered
to all acutely unwell individuals with suspected mitochondrial disorders,
so that results can help guide clinical management. Currently in the UK,
this is only available for acutely unwell children.

========================================================================== Story Source: Materials provided by University_of_Cambridge. The original
text of this story is licensed under a Creative_Commons_License. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. K. R. Schon et al. Use of whole genome sequencing to determine the
genetic basis of suspected mitochondrial disorders: a cohort
study. BMJ, 2021 DOI: 10.1136/_bmj-2021-066288 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211104115351.htm

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