Latest research round up: November 2023

The field of genomics is always evolving. With a constant stream of new research, discoveries and developments, it can be difficult to keep up.

This blog features some exciting genomics studies from the past few months, from both within and outside of our research network here at Genomics England.

From our research community

Here, we showcase some recent research papers that use data from our National Genomic Research Library (NGRL).

Cherry-picked by our Research Management team, these studies show that participants – many of whom are from the 100,000 Genomes Project - have played a vital role in research discoveries by volunteering their data to the NGRL.

Whole genome sequencing reveals which genetic changes affect a patient’s response to immune checkpoint cancer therapy

Some cancer cells make high levels of checkpoint proteins. These proteins stop our immune cells from attacking the cancer, almost like pressing a stop button. Checkpoint inhibitor (CPI) therapy is a type of immunotherapy that blocks the checkpoint proteins. It acts to keep our immune cells switched on, allowing them to attack the cancer.

CPI therapies are revolutionary treatments for advanced cancers. They have been approved for use in many tumour types. This study by Litchfield et al., uses whole genome sequencing data from the 100,000 Genomes Project to investigate the survival of 318 patients with various tumour types receiving CPI therapy.

The research marks the first ever cross-cancer study to use whole genome sequencing data to investigate CPI therapy survival. It found several factors associated with patient survival, such as genetic changes related to tobacco use or UV exposure, as well as some related to previous chemotherapy. This information could be very useful for predicting patient outcome.

The results here highlight the value of whole genome sequencing for predicting which patients will respond well to CPI therapy. This has great value for clinical practice, helping us to find the best possible treatment for each individual patient.

Find the full paper by Litchfield K, Simpson B, Cha H, et al.,

Genetic changes in the NOP56 gene cause a rare, inherited brain condition in the British population

Spinocerebellar ataxias are a group of genetic disorders affecting the brain and nervous system. They cause problems with muscle coordination and movement control, in turn affecting stability, hearing, speech, and eye movement.

One example of this is spinocerebellar ataxia 36 (SCA36). This type is caused by a ‘repeat expansion’ in the NOP56 gene. A repeat expansion is when a section of DNA is repeated several times, which can sometimes cause a genetic disorder.

SCA36 has mainly been reported in East Asian and Western European patients. The study here uses new tools to detect repeat expansions in whole genome sequencing data from the 100,000 Genomes Project. The researchers analysed the NOP56 expansion in 1,257 British patients with inherited ataxia, and 7,506 unrelated controls.

The researchers found disease-causing NOP56 expansions in 7 patients from 5 different families. These patients represent the first White British-descent patients with SCA36, serving as evidence that SCA36 can cause hereditary ataxia in the British population.

Find the full paper by Tanya Lam, Clarissa Rocca, Kristina Ibanez, et al.,

Identifying genetic causes of kidney disease in young infants

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder, affecting 1 in every 400 to 1,000 individuals. .

Usually, the condition doesn’t present itself until later in life, and is mostly diagnosed in adulthood when fluid-filled cysts progressively damage the kidneys. In very rare cases, ADPKD can present during infancy, or when a foetus is still in the womb.

The genetic mechanisms behind these early-onset cases are unclear, however, they are likely caused by specific genetic changes in genes called PKD1 and PKD2. For example, inheriting a non-functioning version of the gene alongside a ‘hypomorphic', meaning a version that is faulty but still has some of its normal function.

Identifying these hypomorphic alleles is very important, but also challenging, as when inherited on their own they have no ill affect. Consequently, they are present in the healthy population and are often overlooked as potential causes of disease and excluded from normal diagnostic processes.

In this paper, researchers use data from the 100,000 Genomes Project and other datasets to identify a hypomorphic version of PKD1 which likely contributes to early onset disease and infant death when inherited alongside a non-functioning copy.

Researchers also analysed data from UK Biobank and the GnomAD database, confirming that adults carrying a hypomorphic and a normal version of the PKD1 gene experienced normal kidney function. This suggests that it would typically be overlooked when searching for disease-causing gene variants.

These findings highlight the role of hypomorphic variants in causing ADPKD. They show the importance of including these variants during the standard diagnostic process and in genetic counselling for affected families.

Find the full paper by Durkie, Watson, Winship et al.,

Looking at structural and non-coding gene variants provides answers to patients with rare genetic conditions

Genetic testing has greatly enhanced our ability to diagnose, understand, and treat rare conditions. However, rates of diagnosis are often still low.

This is partly due to limitations in the current way we investigate and analyse genes, and the difficulties we often face when interpreting genetic test results.

Finding and understanding ‘structural’ and ‘non-coding’ genetic variation could greatly improve our ability to diagnose patients. Structural variation refers to changes in the structure of our DNA, for example new sections of DNA getting inserted or removed. Non-coding variation refers to changes in DNA that does not code for proteins, sometimes known as DNA dark matter.

In this recent study, researchers investigated the whole genome sequences of 31 participants in the 100,000 Genomes Project, each of whom had a suspected inherited condition. By focussing on structural and non-coding variants, researchers successfully pinpointed potential disease-causing genes in 8 of the 31 unsolved cases.

This approach greatly improved the accuracy of diagnosis for the patients in the group, showing the importance of looking at structural and non-coding variants. The researchers also emphasised the importance of close collaboration between the data analysts and colleagues in the clinic, describing how this could increase diagnosis from whole genome sequencing, providing more answers to those with suspected inherited disorders.

Read the full paper by Moore, Yu, Pei et al.,

Research for your reading list

Here we highlight some recent research favorites selected by Matt Brown, Chief Scientific Officer here at Genomics England.

Though we may not play a direct part in these research studies, they are certainly relevant to the work that we do.

Unanticipated disease risks in newborn genomic screening

A big question for the Generation Study in our Newborn Genomes Programme, is the proportion of newborns who will be shown to carry genetic variants that can be potentially treated. We call these genetic variants ‘actionable’.

This paper reports on findings from the US BabySeq Project, which recruited apparently healthy children from newborn nurseries (NBN), or unwell infants from neonatal intensive care (NICU). They used a type of genetic screening known as whole exome sequencing, and reported up disease-causing or likely disease-causing genetic variants in 954 genes that were considered to be actionable.

17 of the 159 infants studied (10.7%) were found to have an actionable variant. 3 babies with cancer genes were identified, leading to screening for other members on their families. 3 mothers ended up having risk reduction surgery as a result.

The paper does not report which infants were recruited from NBN vs NICU, and the list of genes reported is different from those that will be reported in the Generation Study. It is not clear how this experience relates to what the Generation Study will find, and it very likely overestimates the proportion of infants that Generation Study will need to report back on. But it gives a glimpse of the future impact as this type of sequencing gets rolled out, both for the babies and their families.

Read the full paper by Green, Shah, Genetti et al.,

Exploring why mitochondrial DNA is only inherited from mothers

OK, just a short fun one. Mitochondria are the so-called ‘power-houses’ of the cells in our body, producing energy for the cell to survive. They contain small amounts of DNA, passed down from mother to child. It is well known that mitochondrial genetic disorders are inherited exclusively down the maternal line.

This had been thought to be related to the low levels of mitochondrial in sperm, but actually, sperm do carry some mitochondria. However, turns out that these mitochondria have no mitochondrial DNA.

This is because mitochondria in sperm lack a crucial protein called ‘TFAM’, which is required to produce and protect mitochondrial DNA. For TFAM to get imported into mitochondria, it uses specific sequence called the ‘pre-sequence’ of the protein. In sperm cells, this pre-sequence has been altered, causing the protein to head off to a different part of the cell instead of the mitochondria, resulting in elimination of the mitochondrial DNA. Fascinating.

The authors also suggest that deficiency of TFAM may play a role in some cases of male infertility, so this may end up being relevant in the clinic.

Read the full paper by Lee, Zamudio-Ochoa, Buchel et al.,

And there you have it, the latest research round-up. Have something you'd like to add? Leave it in a comment below!

In the meantime, catch up with other news at Genomics England in our other blogs.