Study linking 28 genes to developmental disorders to mean diagnoses for
about 500 families
Researchers estimate another 1,000 genes linked to developmental
disorders still to be found

Date:
October 14, 2020
Source:
Wellcome Trust Sanger Institute
Summary:
Research into the causes of developmental disorders has identified
285 genes linked to these conditions, including 28 newly-associated
genes.

The study will enable diagnoses for around 500 families living with
children who have rare conditions. The authors collated anonymised
healthcare and research data to create the largest available genetic
resource for developmental disorders. They estimate about 1,000
genes linked to developmental disorders remain to be discovered,
requiring more open access to healthcare data.



FULL STORY ========================================================================== Research into the causes of developmental disorders has identified
285 genes linked to these conditions, including 28 newly-associated
genes. Published today (14 October 2020) in Nature, the study by
researchers at the Wellcome Sanger Institute, Radboud University Medical Center, OPKO Health's GeneDx and their collaborators will enable diagnoses
for around 500 families living with children who have rare conditions.


==========================================================================
The authors collated anonymised healthcare and research data to create the largest available genetic resource for developmental disorders. Analysis
of the data estimates that around 1,000 genes linked to developmental
disorders remain to be discovered. Finding them all will require ten times
the amount of data currently available, which will only be possible with
more open access to healthcare data.

Globally, around 400,000 babies are born every year with new, spontaneous
DNA changes -- known as de novo mutations * -- that interfere with their development. These developmental disorders can lead to conditions such
as intellectual disability, epilepsy, autism or heart defects.

The de novo mutations in genes that create proteins are a well-established cause of developmental disorders, but to date many of the genes linked
to these disorders remain unknown. Every person is born with around 60
de novo mutations on average, though the vast majority do not lead to
health problems.

Ongoing initiatives, such as the Deciphering Developmental Disorders
(DDD) study, have discovered associated genes by looking for patterns in
the genomes of people with these disorders. But because many conditions
are extremely rare, the statistical analysis used to locate these genes requires large volumes of anonymised patient data that has not always
been easily accessible.

For this study, the researchers analysed 31,058 exome sequence
'trios'. Each trio includes sequences from a child with a developmental disorder, plus both of their parents.



==========================================================================
The sample was created by combining existing research and clinical
datasets from the Wellcome Sanger Institute, Radboud University Medical
Center and GeneDx.

The scale of the dataset greatly increased the statistical power available
to search for previously undiscovered mutations. The authors then used
an improved statistical test to determine whether individuals in the
study had more mutations in the same gene than they would expect to
occur by chance.

Dr Kaitlin Samocha, a first author of the study from the Wellcome Sanger Institute, said: "From previous studies we know that certain genes and
types of mutation are more strongly linked to developmental disorders,
which has allowed us to narrow our search. Combined with a much larger
dataset, this has enabled us to identify 28 novel genes associated with developmental disorders." Dr Helen Firth, Consultant Clinical Geneticist
at Addenbrooke's Hospital, said: "Caring for a child with a developmental disorder can be extremely challenging for a family, particularly
when their child's doctors don't know what is causing their condition
and are unable to make a diagnosis. A diagnosis can help families to
access support networks, inform treatment for their child and help
them to understand the risk for any further children they might have."
The study also applied statistical modelling to the data to estimate that approximately 1,000 more development disorder-associated genes remain undiscovered. Around 60 per cent of children born with a disorder do
not have a diagnosis and the authors estimate that around 50 per cent
of these children will have a mutation in one of these unknown genes.

Professor Matthew Hurles, lead author of the study from the Wellcome
Sanger Institute, said: "This study has really shown the benefits of
access to healthcare data, not least to the approximately 500 families
living with a developmental disorder who had not been able to get a
diagnosis until now. But our findings also estimate that we require
ten times as much data to be able to identify all the genes linked to developmental disorders. As such, greater access to anonymised patient
data is crucial to our understanding of these conditions and our ability
to help the families living with them." Kyle Retterer, Senior Vice
President, Chief Technology Officer, and lead author of the study from
GeneDx, said: "As a global leader in clinical exome sequencing and rare
disease diagnostics, GeneDx is committed to helping end the diagnostic
odyssey not only through diagnostic testing but through collaborative
research projects like this one. By combining data and efforts across institutions, we are able to provide more patients and families with
answers." Professor Sir Mark Caulfield, Chief Scientist at Genomics
England, said: "This study demonstrates the value of combining genomic
data with healthcare data in gaining novel gene insights that improve
patient outcomes. It also shows that, rather than being something that
just takes place in a lab, genomics is bringing about tangible advances in healthcare that directly impact patients and their families. It should
serve as a call to action that more must be done to make anonymised
patient data available for research."

========================================================================== Story Source: Materials provided by Wellcome_Trust_Sanger_Institute. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Joanna Kaplanis, Kaitlin E. Samocha, Laurens Wiel, Zhancheng
Zhang, Kevin
J. Arvai, Ruth Y. Eberhardt, Giuseppe Gallone, Stefan H. Lelieveld,
Hilary C. Martin, Jeremy F. McRae, Patrick J. Short, Rebecca
I. Torene, Elke de Boer, Petr Danecek, Eugene J. Gardner, Ni
Huang, Jenny Lord, In~igo Martincorena, Rolph Pfundt, Margot
R. F. Reijnders, Alison Yeung, Helger G. Yntema, Lisenka
E. L. M. Vissers, Jane Juusola, Caroline F.

Wright, Han G. Brunner, Helen V. Firth, David R. FitzPatrick,
Jeffrey C.

Barrett, Matthew E. Hurles, Christian Gilissen, Kyle
Retterer. Evidence for 28 genetic disorders discovered by
combining healthcare and research data. Nature, 2020; DOI:
10.1038/s41586-020-2832-5 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201014114638.htm

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