Newborn Screening Programme in UK

Interview with Meena Balasubramanian

My name is Meena Balasubramanian. I am a clinician-scientist specialising in bone genetics at the University of Sheffield and Sheffield Children’s Hospital in the UK. I have worked in Sheffield over the last 15 years. I started here as a Clinical Genetics trainee having previously worked as a paediatrician and did my higher research degree on atypical presentations of OI. I subsequently started as a Consultant Clinical Geneticist in the Highly specialised OI service in Sheffield looking after a number of children with OI. I set up the bone genetics clinic in 2012 to streamline diagnostic pathways and address the diagnostic odyssey that some families go through when trying to get a genetic diagnosis of OI. Those were the days when access to genetic testing was limited and expensive, so my work was around ensuring robust clinical pathways to ensure equitable access to such testing across the highly specialised services in England.

In addition, realising there was lack of continuity with Genetics services when children were transitioned to the adult services, I set up links with the adult metabolic bone clinic in Sheffield. This led to setting up a regular Genetics-metabolic bone team meeting since 2015 to discuss shared families and referrals to Genetics for young adults to access genetic testing prior to starting a family.

My research over the last 15 years has been on improving diagnostic outcomes in OI especially the more rare, atypical presentations. I previously led studies on applying advanced genetic technologies in unresolved OI families where a diagnosis was uncertain and developing pathways for robust interpretation of genetic variants identified on testing. I was able to identify and publish a novel cause of bone fragility/OI which led me to establishing a lab working on zebrafish models for bone fragility.

6 People Standing on Grass in front of a brick building

Are you working on any other OI-related research?

Yes, I have a number of OI-related research projects which transcends the clinical and translational science. Most of my research ideas have always started with a child or family with OI that I care for. In the clinical space, my research is around understanding the natural history of the rarer forms of OI and mining genomics data for identifying new genes causing OI. In addition to this, we are working on a project to better understand why some adults develop significant fractures at a young age but clearly do not have OI as we understand it.

In the translational space, I am very interested in bench-to-bedside medicine, taking knowledge from the lab back into clinic like my work on zebrafish models for bone fragility. I also work with a number of colleagues in other disciplines such as engineering (looking at collagen orientation in OI vs control cells) and stem cell biology (developing iPSC models for gene therapy in OI). I have a PhD student working on reclassification of variants of uncertain significance identified on OI testing and another project on drug repurposing in OI. So quite a lot of research happening in this space.

Another major area of my research is on neurodevelopmental disorders where children present with seizures and developmental delay. I am working on developing gene therapies for specific conditions in this space and using all the knowledge gained from this work to apply to OI. As it happens, I have also identified a number of children in my clinic with significant fractures who have faults within genes causing severe developmental delay, so currently looking into the association with bone and brain so called BRONE association.

Do you think all people with OI should have the offer to get tested to know their mutation?

Yes, with the latest advances in genomic technologies, testing has got more accessible and cheaper which means there should be a discussion around genetic testing and what this means for the individual regardless of their consideration around family planning. There is some data on correlating the genetic variant on what the evolving phenotype would be, so this would be another reason to consider testing in individuals with OI. The longer I do this job, the lesser I second-guess whether testing would be useful or not and always discuss this as an option in all the families and adults I see in clinic with OI.

A newnorn kissed by a woman

OI has been listed on Genomics England’s published list of conditions that will be screened for as part of the New-born Genomes Programme research study (“the Generation Study”). Normally the new-born screening programmes have been only for diagnoses, where it is important to start an advanced treatment very early. What is the rationale of including more conditions (incl. OI)?

The Generation study is a research study to explore the benefits, challenges, and practicalities in use of whole genome sequencing to look for rare genetic conditions in new-borns, to see if this is feasible and can help enable early treatments to be instituted. The conditions include those were there are treatment options available, and an early diagnosis could change outcomes. The decision about which conditions are screened for was decided following a wide-ranging consultation.

Why are only the genes Col1A1/A2/ IFITM5 chosen?

OI is included as there are treatments available as a pilot and it may show us what the challenges are and what the uptake is. I guess the genes were chosen based on how common they are as a cause of OI as we know genes encoding type 1 collagen (COL1A1/A2) account for >85% of OI. IFITM5 has been included, I suspect, because it is part of the autosomal dominant OI panel of genes.

Graphic showing OI genes in different colours

Based on your opinion – what are the pros and cons for including OI?

The pros are the using power of genome sequencing and harnessing the advances in genomic technologies to inform management of children born with OI long before they sustain a fracture and diagnostic odyssey that many families suffer from. The cons are that early diagnosis in the newborn period may come with its own challenges about knowing what the course of the condition might be and the uncertainty in these situations.

Will we find many “hidden” OIs, that would never have gotten their diagnosis until much later in life?

That is possible, just by nature of the study but I suspect most of the severe presentations in OI would have been picked up by prenatal scans. Some of the ‘hidden’ OI may have normally been picked up after a child sustains their first fracture, but involving in this study may allow an earlier diagnosis to be made.

Can this prevent accusations of child abuse?

As I mentioned above, that is possible and I know from my own professional experience, it is not nice for families that find themselves in this situation. However, the possibility of this needs to be balanced with the unnecessary anxiety this may generate.

Yes, can it also cause unnecessary worry to know of a diagnosis that you would otherwise not have cared about until later? Can this make it harder to access insurance or other similar consequences?

That is a possibility that such testing may reveal unexpected diagnosis causing unnecessary worry for the parents. However, the testing will only report back those genetic changes which are associated with the condition tested for and there is strong association with OI. It may then require further clinical work up in the metabolic bone clinic and follow up to ascertain that the child indeed has clinical features of the condition and if so, decisions need to be made around starting treatments for OI where required.

At the moment, with any genetic testing, there is a moratorium which means there is no obligation to reveal genetic testing results for insurance purposes, so hopefully that will not be an issue unless there is a clinical presentation of the condition.

Why do you think some have called it controversial?

It is a research study to check feasibility and parents would be counselled about the nature of the study and what testing is being undertaken. Of course, with any of these studies there is a potential to uncover diagnoses that may not have come to light until much later and having the diagnosis made when the family are not ready to receive such a news.

Any other messages to our readers?

Thank you for everything you do, I am always amazed by how generous families and adults with OI are with their involvement in research. It is always motivating to see the resilience and the unbreakable spirit which inspires me to do even more within my capacity to improve the lives of children, families, and individuals with OI. I work closely with Brittle Bone Society and always humbled by the overwhelming support I get whenever I have contacted colleagues at BBS be it Patricia or Coreen for support with my research.

This article was first published in OIFE Magazine 1-2024.

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