Yalda Jamshidi, PhD
Two individuals share as much as 99.9% of the same genetic code or "DNA", and differ in only 0.1% of it. Yet we know that a single letter change can result in a life-threatening genetic disorder.
For rich countries genetic advances are allowing the identification of differences between individuals' genes that could be responsible for disease. For families affected by rare diseases this knowledge allows the clinical teams to make informed choices about potential therapeutic approaches, helps discussion about recurrence risk for future pregnancies and family planning decisions, and provides insight into how and why the disease occurs thereby aiding future drug development.
Unfortunately there are many doctors and families for whom lack of available expertise, technology, funds, or insurance prohibit access to this genomics revolution. However the tests can be carried out on a simple blood sample, which can be shipped across the world such that there are no travel costs/invasive procedures required, analyzed remotely and findings reported back to the local genetic centres for easy confirmation.
The funds we raise through this project will directly allow us to try and identify mutations causing disease in families who have no other means of getting this testing done. The project will enable us to share our knowledge and expertise of gene finding in rare disease families, and help address some of the inequalities across the world.
Rare diseases are often misdiagnosed or detected too late for meaningful therapies to be administered. New technologies mean that we can screen individuals much more rapidly, and much more cheaply to try and identify the underlying cause.
Research on these conditions has a global impact on the diagnosis and understanding of the disease. The identification of genes and mutations has led to new diagnostic tests, which inform clinical management in terms of expected disease course and choice of the most effective drugs for even more families.
Even with the best doctors, the nature of rare diseases is that they are very difficult to diagnose. Families can spend years – sometimes more than a decade – searching to uncover the cause behind their childs illness. Two common questions asked by parents of children with any rare genetic diseases is: “why did this happen to our child?” and “will this happen again in future pregnancies?”.
1 in 25 children are born with a genetic disorder. These conditions often occur in young children, and can be devastating for the entire family. A large number of these individuals do not have a diagnosis, as scientists are yet to discover all the genes that could be responsible.
The Genetic Code is stored as DNA made up of an "alphabet" of letters (Adenine (A), Guanine (G), Cytosine (C) and Thymine (T)). These letters are used to write "code words" or genes. Genes tell the cell what to do, and provide instructions for how the body works. We each have 25,000 genes and a fault in just one of these can cause disease.
We and others have shown that the technique of "whole-exome DNA sequencing" can successfully be used to identify the cause of both inherited (passed down in a family) and spontaneous (new) genetic disorders. Using this technique we can pinpoint a change in the sequence of DNA letters that can lead to a faulty gene, and start to answer some of the most important questions asked by the family.
Unfortunately however we get many requests from doctors and families who due to the lack of funds or insurance, or even which town they live in, cannot access this technology. Importantly as the test is carried out on a blood sample, which can be shipped to us fairly easily, there are no travel costs/invasive procedures required.
Why is this important?
Making a genetic diagnosis is important for several reasons: first, it provides families and healthcare professional’s the potential to improve the management and treatment of these conditions. It also helps discussion about recurrence risk for future pregnancies and family planning decisions. Finally, it allows insight into how and why the disease occurs and provides avenues for drug development.
Our approach uses the latest DNA sequencing technology, which can now be carried out in a much reduced time frame, and within a reasonable budget.
Following our recent identification of a new form of muscular dystrophy, a muscle wasting condition that starts soon after birth, Robert Meadowcroft, Chief Exec Muscular Dystrophy UK said "Early stage research identifying genes for muscle-wasting conditions, such as this, gives us valuable insight into better understanding these complex and rare conditions. We know families find it extremely difficult living in limbo without a precise diagnosis". Click here to find out more.
Who will benefit?
The results of these studies will provide immense benefit to families with these conditions by providing accurate genetic counseling as well as opportunities for genetic testing. The sooner we have an accurate diagnosis for the families, the sooner doctors can develop an appropriate course of management and treatment for the patients. The results will reveal new molecules and pathways essential for normal development. This will help other scientists working on similar problems, as well as providing opportunities for studies leading to strategies for therapies aimed at treating these disorders.
BudgetWe already have funding for analysis of the data once we receive it, and laboratory personnel for evaluation and confirmation of findings. We are hoping to raise enough money to try and provide a diagnosis for at least 8 families by being able to pay for genetic sequencing of their DNA. For each new family it costs approximately $1500 to sequence the DNA of an affected child and their parents. An important first step is to sequence the DNA of the affected child. This costs $325. Once we identify a mutation we can offer genetic testing in other members of the family and for this we budget $225/family. If we exceed our funding target we will be able to try and provide a genetic diagnosis for more affected children. Thank you for your support!
New form of hereditary spastic paraplegia
Thank you to everyone who has supported us so far! It really can make a difference. In fact I thought it would be nice to share some of our results as they happen.
We have been investigating a family with four children affected by hereditary spastic paraplegia (HSP). It's thought to affect about 3 in every 100,000 people. Affected children develop leg stiffness and problems walking, such as stumbling and tripping, particularly on uneven ground. Some may eventually need to use a walking cane or a wheelchair to help them get around. At present it isn't possible to prevent, slow or reverse HSP.
Using exome sequencing we have identified a new form of HSP, and excitingly through discussions with other researchers and doctors interested in the condition have found another 3 families who appear to have similar symptoms, and the same faulty gene.
(Publication: Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia. Wagner M et al. Nat Commun. 2019 Oct 21;10(1):4790)
We're now working to put together a summary of our findings to share with the medical and scientific community to increase awareness, help other undiagnosed families, and start the path towards developing new treatments.
Through your donations we hope to continue this work and help more families with children suffering from genetic conditions.