Mosaic variegated aneuploidy (MVA) is thought to affect fewer than 50 people worldwide. At that scale, ultra-rare disease research runs into a problem that funding alone does not solve. There is no cohort large enough to randomise. There is often no natural history dataset. There may be no clinician who has seen a second case.
On Thursday 17 September, clinicians and researchers from the UK, North America, Europe and Japan meet at Great Ormond Street Hospital in London. The inaugural MVA Research Conference is hosted by the MVA Society, which describes itself as the only organisation in the world dedicated to the condition.
A failure at the point of cell division
Mosaic variegated aneuploidy is an autosomal recessive disorder of chromosome segregation. Biallelic variants in BUB1B, CEP57 and TRIP13 have each been linked to it, with biallelic BUB1 mutations reported since. These genes govern the mitotic spindle checkpoint, which verifies that chromosomes are correctly attached before a cell is allowed to divide.
When it fails, cells across multiple tissues end up carrying the wrong number of chromosomes. Reported features include intrauterine growth restriction, microcephaly, developmental delay and seizures. The BUB1B subtype, caused by loss of the checkpoint protein BubR1, carries a marked cancer predisposition, with rhabdomyosarcoma, Wilms tumour and leukaemia the malignancies most often described. The CEP57 subtype, by contrast, has not been associated with childhood cancer.
Nobody can say how many patients there are
There is no patient registry for mosaic variegated aneuploidy. The Society knows of around 50 people with the condition worldwide, a figure it describes as anecdotal, drawn from information that is fragmented across different countries rather than held in any central record. It has been told there are nine in the UK, one of them George, the son of the Society’s founder. It cannot confirm whether all nine are still living.
A similar number of cases appears in the published literature, but the two counts are not the same thing. The literature figure includes patients described decades ago, some of whom have died, and excludes anyone diagnosed but never written up. Neither number is authoritative, and the gap between them is itself the problem.
The Society says establishing a formal registry is a priority, with development expected to begin during 2027. In the meantime it is making contact with families directly, including two in Spain and two in Italy.
Why the numbers change the method
At this scale the usual sequence of drug development inverts. Registries come before trials rather than after them. Laboratory disease models stand in for patient cohorts, because the cohort does not exist. Drug repurposing is favoured over novel discovery, since an approved compound arrives with a safety package already assembled.
The conference agenda tracks that logic closely. Sessions cover disease modelling, drug repurposing, patient registries and cohorts, and clinical management, alongside the UK MVA National Audit and international clinical experience.
The speaker list draws from the small group of laboratories that have worked on the underlying biology. It includes Jan van Deursen, Marcos Malumbres, Will Foulkes, Brian North, Andre Brown and Shinya Matsuura, whose work on premature chromatid separation syndrome two decades ago helped define the clinical picture. Harry Leitch, associate professor and honorary consultant in clinical genetics and genomic medicine at UCL Great Ormond Street Institute of Child Health and the North East Thames Regional Genetics Service, is among the UK contingent.
Leitch is clear that the tools themselves are not what makes mosaic variegated aneuploidy difficult to study. Cell and animal models are standard across modern research, he says, including for conditions affecting thousands or millions of patients.
“The difference with MVA is not the scientific tools being used, but the starting point,” he says. “There is no large patient cohort, established research pathway or extensive body of previous work to build on, so researchers are having to create that evidence base from the ground up.”
Nor will any one model be sufficient.
“Cell and animal models can help us understand mechanisms and test ideas, but they can never fully replicate the complexity of a person living with MVA,” he says. “Progress will therefore come from combining these approaches with patient data, clinical observation and other emerging research technologies.”
A charity acting as a research funder
What distinguishes the Society from most patient organisations of its size is that it is funding the work rather than only convening it. It describes four strands currently supported.
At the UCL Great Ormond Street Institute of Child Health, it is funding a stem cell biologist on a two-year placement with Leitch’s group, which specialises in developmental genetics and stem cell biology, to build cellular models of mosaic variegated aneuploidy. At Creighton University School of Medicine in Omaha, it has funded a two-year postdoctoral position supporting work led by Brian North, associate professor in biomedical sciences, on a drug screen intended to identify an approved compound that could be repurposed, using bespoke mouse models. North’s laboratory works on BubR1. At the Vall d’Hebron Institute of Oncology in Barcelona, Marcos Malumbres, who leads the cancer cell cycle group there and co-authored a 2024 Nature Reviews Genetics review of the condition, is running an RNA sequencing project. The Society is also working with Sage Bionetworks on an MVA hackathon, bringing researchers together to interrogate existing data for new directions.
Each of those is a recognisable early-stage research programme. The unusual part is who is paying for them.
What would count as progress
There is currently no established clinical pathway for mosaic variegated aneuploidy and no dedicated treatment centre. The Society says it is in early discussions with the Manchester Rare Conditions Centre, a coordinating platform established in 2021 by Manchester University NHS Foundation Trust and partners, about the beginnings of a more coordinated route. It stresses that the work is at an exploratory stage. The longer-term ambition is a dedicated clinic model that patients could access remotely as well as in person.
For a family receiving a diagnosis, that is the difference between assembling a set of specialists themselves and being pointed towards one. A pathway of that kind is the practical output, more so than any single therapeutic candidate.
Families as research infrastructure
Mel Dixon, who founded the charity Cure DHDDS with her husband Charles in 2023 and now leads it, will describe how the same problem was approached for a different condition. Two of their three children carry an ultra-rare variant in DHDDS, a metabolic disorder producing neurological symptoms that are often progressive, with around 70 cases recorded worldwide. The charity has since funded research across several countries, and Dixon sits on the Genomics England Participant Panel.
The MVA Society itself was founded in 2024 by Jonathan Bracey after his son George was diagnosed. Bracey has worked in pharmaceuticals for two decades and is an executive vice president at Tanner Pharma Group. That combination is increasingly common in ultra-rare disease, where the convening role falls to families rather than institutions.
That model is not a substitute for research infrastructure. It is what fills the gap while one does not exist.
The wider read across matters for anyone working in rare disease. Regulators have grown more willing to accept external controls and natural history data where randomisation is not feasible, and therapies are now reaching approval in conditions once considered too rare to study, among them the FDA’s clearance of Genglycos for glycogen storage disease type Ia. Mosaic variegated aneuploidy sits further along the same spectrum, at the point where the natural history dataset itself has to be built before anything else can follow.
Additional information for this article was provided by the MVA Society. Further detail on the condition and the conference is at mvasociety.org.
