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.
Whilst studying at University I became interested in genetic disorders that affect the heart and muscle. Some of these are particularly devastating as they can lead to sudden, often unexpected, death in the young.
Part of my job involves tutoring university medical and biomedical sciences students, and not too long ago I came across one student in particular who was always enthusiastic and hard working during sessions. In fact she often stayed late afterwards to continue chatting with me about the topics she was studying. She developed a keen interest in pursuing research after her degree, and I was pleased to be asked to write her a reference for a PhD studentship application.
Shortly after, I heard her application had been successful and I was extremely happy for her. She completed her undergraduate studies that year, and the summer break began. A few weeks before the start of the new term I received an email informing me that unfortunately one morning over the summer break she had not woken up from her sleep.
Her death was later attributed to a rare heart condition - one of those that I had been studying, and one which her and her family were unaware she was affected with. I felt helpless at the time, and in many ways still do, but recent successes in understanding the genetics of rare disease have spurred me on.
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; prenatal and pre-implantation diagnoses for prevention are also possible.
My research interest is now a much more personal one, and I am hoping to use my knowledge, and the advances that have been made in the field, to help as many families as possible.
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. I am particularly interested in those that affect muscle and the heart. 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 muscle and heart 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 $425. 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.
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.