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Feb 2024

The Schinzel-Giedion Syndrome Foundation: Navigating Challenges and Progress in Schinzel-Giedion Syndrome Research, Diagnosis, and Patient Care

Welcome to another blog post!

Every year on the last day of February, Rare Disease Day is observed to raise awareness, improve access to treatments, and support medical advocacy for people living with a rare disease and their families. It is estimated that there are over 7,000 rare diseases – defined by the European Union as a disease affecting fewer than 1 in 2,000 people1. Although rare diseases are individually rare, they are collectively common, amounting to approximately 350 million people living with a rare disease globally2. Rare diseases often have a genetic cause; a recent study reported 72% of analysed rare diseases as having a genetic origin2. The genetic nature of many rare diseases means that they disproportionately affect children, while their rarity, complexity, and heterogeneity make them challenging to diagnose. Clinical research into rare diseases is logistically challenging, and they often lack the visibility and resources needed for significant clinical advances3. Rare disease foundations and patient advocacy groups are central to improving visibility, raising awareness, and driving research towards life-changing treatments for affected patients.

One such organisation is the Schinzel-Giedion Syndrome (SGS) Foundation. Since it was founded in 2019, the SGS Foundation has strived to advocate for its community by raising awareness among medical professionals, scientists, and the general public, empowering parents and caregivers to attain the best standard of care, and driving translational research towards developing life-changing treatments for children living with SGS. 

Ahead of Rare Disease Day, we spoke to Dr Nuala Summerfield, founder and chair of the SGS Foundation, about the SGS Foundation’s work, recent advancements and challenges in the field of SGS, and the impact of collaboration with industry partners, like Nostos Genomics, in progressing rare disease research and clinical practice.

Understanding Schinzel-Giedion Syndrome

SGS is rare among rare diseases: approximately 40 children are currently living with SGS globally, and to date, fewer than 150 children have been diagnosed with SGS, though the true birth frequency is likely higher4. SGS is a severe, life-limiting, autosomal dominant disorder characterised by distinctive facial features and multiple organ malformations5

SGS is caused by de novo mutations in a degron-coding region of the SETBP1 gene that leads to toxic accumulations of SET binding protein 1 (SETBP1)6. The accumulation of SETBP1 disrupts normal embryonic development, which impacts several organs, including the brain. This leads to the characteristic seizures and neurodevelopmental delay present in many SGS patients.

Notwithstanding its rarity, there has been some promising research into the molecular mechanisms of SGS. A recent study reported a human in vitro SGS model – induced pluripotent stem cell (iPSC) lines reprogrammed from patient fibroblasts and isogenic controls – that displays disease-relevant phenotypes7. The authors applied this model to explore the mechanistic basis of neuronal death in SGS, demonstrating that elevated levels of SETBP1 disrupt key protective processes in neurons, leading to cell death in SGS. Notably, they find that certain small molecules can reduce this damage7. Overall, this work enhances our understanding of the mechanistic basis of SGS and provides a disease-relevant in vitro system for testing candidate therapeutic compounds.

The Current Landscape of SGS Treatment

Currently, there are no effective treatments developed specifically for SGS, and patient management is based on symptoms, such as anti-convulsants to control seizures4. However, these treatments are not always effective; for example, many SGS patients have medically refractory epilepsy, which leads to acute, uncontrollable seizures which severely impact patients’ quality and length of life.

The SGS Foundation has been instrumental in establishing a global network for SGS research, achieving significant success in fostering collaborative efforts to develop targeted treatments for SGS. Recently, a substantial research grant was awarded to one such project, known as TREAT-SGS. This collaborative project is led by Prof. Carl Ernst, leader of the Rare Neurodevelopmental Disorders Laboratory at McGill University, in collaboration with academic researchers across Europe and Canada, as well as the SGS Foundation8. The project focuses on the development and preclinical testing of novel SGS treatments in human cell models and transgenic mice. Another grant was awarded to Prof. Alessandro Sessa, professor at Ospedale San Raffaele and collaborator on the TREAT-SGS project, to study the molecular basis and pathophysiology of SGS8. These grants, totalling over €2 million, represent a significant milestone as the first major funding for SGS research and are a testament to the SGS Foundation’s pivotal work.

Nuala explained that this research has resulted in the development of a promising oligonucleotide therapy that could potentially reduce seizure frequency in SGS patients, dramatically improving quality of life and life expectancy. This treatment is currently undergoing pre-clinical testing, and while results are yet to be fully elucidated, it is hoped that this will progress to a Phase I clinical trial within the next year. This is particularly notable for a condition that has fewer than 150 patients diagnosed worldwide, representing a huge milestone towards the development of effective treatments and highlighting the significant impact of patient advocacy groups in driving change.

Though this is extremely promising, identifying a potentially effective therapeutic is not the end of the road: the real challenge will likely lie in clinical testing and bringing the drug to market. This is a common bottleneck within rare disease research, where the disease's natural history is often poorly understood, impeding the detection of clinically meaningful outcomes9. Aiming to improve understanding of natural history in SGS, the SGS Foundation is leading a natural history study in collaboration with COMBINEDBrain and the Across Healthcare Matrix. This represents a crucial endeavour for gathering valuable patient information and enables comprehensive data collection across SGS and related disorders. By incorporating patient and caregiver insights through standardised ClinGen surveys translated into multiple languages, the SGS Foundation hopes to gain meaningful global insights. These surveys are designed for periodic completion to monitor changes over time, and the SGS Foundation is looking to incorporate telehealth methods to enable the inclusion of clinician data for patients around the world. This is a prime example of how patient organisations, like the SGS Foundation, are innovatively addressing the challenge of geographical and linguistic barriers by providing information in multiple languages and leveraging technology to reach their global community. This study will not only facilitate the detection of clinically meaningful outcomes in clinical trials but also remove barriers to research by ensuring that scientists can access a wealth of information, supplemented by the availability of patient biospecimens stored at the SGS Biorepository, in collaboration with COMBINEDBrain. 

Moreover, the small patient population means that standard trial designs are unviable for obtaining sufficient safety and efficacy data10. To overcome this, alternative trial designs, such as enrichment, crossover, adaptive, and N-of-1 studies, must be considered and implemented where possible. New strategies are currently being worked on; for example, a personalised treatment was recently developed and tested through proof-of-concept experiments in patient cell lines from another rare disease followed by an N-of-1 study, providing a template for the development of other patient-customised or rare disease treatments11. Patient registries are also instrumental in identifying affected patients for trial inclusion, particularly given their geographic dispersion. The SGS Foundation has developed a patient registry, which could be invaluable in identifying patients for future clinical trials. 

During our discussion, Nuala explained that the rarity of the disease poses a challenge in attracting pharmaceutical investment. Given the low prevalence of the condition, the potential for return on investment for drug development is minimal, making it unlikely that pharmaceutical companies will commit to manufacturing the treatment. However, identical SETBP1 mutations that, if germline, cause SGS are known to play an important role in certain haematological malignancies if the mutations are somatic. Examples of these SETBP1-driven leukaemias are myelodysplastic syndromes, chronic myelomonocytic leukaemia, and chronic neutrophilic leukaemia9. Finding an oncological use case for this potentially impactful treatment will likely improve funding prospects, and consequently, characterising this crossover in more detail is currently a major goal of the SGS Foundation.

Impact of Patient Advocacy Groups in Effecting Change

Despite the current lack of available impactful treatments for SGS, the SGS Foundation strongly believes that accurate genetic diagnosis is paramount for effective patient care. The distinctive facial features associated with SGS make the condition visually identifiable from birth, allowing for an initial physical diagnosis to be confirmed through genetic testing. The genetic diagnosis process involves genetic sequencing via whole exome sequencing (WES), whole genome sequencing (WGS), or targeted gene testing and gene panels (e.g., panels for infantile epilepsy)12,13.

With recent advances in sequencing technologies and the availability and accessibility of genetic sequencing-based diagnostic tests, the frequency and timeliness of diagnoses are improving. Generally, children are diagnosed very early, often within the first few months of life and frequently in the neonatal intensive care unit12. However, Nuala informed us that barriers to accurate genetic diagnosis remain: firstly, genetic diagnosis is less accessible in some parts of the world due to cost constraints. Other barriers to diagnosis include a lack of awareness of the disease among medical professionals; the extreme rarity of SGS means that most healthcare professionals will have never encountered a patient with SGS and may not know what to look out for. Moreover, the other mutations that can occur on the SETBP1 gene, leading to SETBP1 haploinsufficiency disorder (SETBP1-HD)14, mean that misdiagnosis can occur, which can negatively impact patient care.

The SGS Foundation is actively working to tackle these challenges by enhancing awareness among medical professionals and developing standard-of-care guidelines for publication in medical literature. Given SGS's multifaceted and complex impact on various organ systems, which necessitates collaborative management between medical specialists, these efforts are crucial for improving, coordinating, and streamlining patient care.

Nostos Genomics’ Collaboration with the SGS Foundation

In an effort to tackle some of the considerable challenges associated with SGS research, diagnosis, and patient care, Nostos Genomics is working with the SGS Foundation to establish genotype-phenotype correlations in SGS. This research will leverage Nostos Genomics’ advanced natural language processing (NLP) software to systematically extract and structure genetic and clinical information, in terms of variants and human phenotype ontology (HPO) terms, from patients with SETBP1 mutations. Obtaining this information has the potential to directly impact patient care by empowering clinicians with a more comprehensive understanding of the likelihood of particular clinical features based on genetic screening data. This will facilitate more informed clinical decisions and more precise, personalised treatment of conditions before they manifest and lead to complications.

This work will primarily focus on SGS patients but has the potential for expansion to include other SETBP1-related disorders, which could enable better classification, grouping, and understanding of the best treatment strategies for these distinct but related conditions. Moreover, a better understanding of genotype-phenotype correlations could guide the development of targeted therapies, improving therapeutic efficacy while minimising the risk of off-target adverse effects.


Conclusion and Future Directions

In conclusion, the fight for patients living with rare diseases like SGS requires a comprehensive approach integrating translational research and drug development, accurate diagnostics, and robust care standards. The SGS Foundation has achieved notable progress in raising awareness, driving promising research, and improving the quality of care for affected patients and their families. Through our discussion with Nuala, we learnt that recent research efforts have uncovered promising therapeutic avenues with the potential to improve the quality and length of life for SGS patients. However, barriers remain, especially in clinical research and patient care, which the SGS Foundation is working to overcome in collaboration with partners such as Nostos Genomics. Looking ahead, the continued expansion of rare disease research initiatives alongside innovative collaborations promises not only to advance our understanding of SGS but also to bring hope and improved outcomes to patients and families affected by rare diseases worldwide.

To learn more about Nostos Genomics’ work towards improving outcomes in rare disease diagnosis, check out our resources.

To find out more about the work of the SGS foundation and their pivotal role in advancing research and improving standards of care for those affected by SGS, visit their website at or get in contact here:


1. Rare diseases - European Commission. Accessed February 22, 2024.

2. Nguengang Wakap S, Lambert DM, Olry A, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet. 2020;28(2):165-173. doi:10.1038/s41431-019-0508-0

3. Chung CCY, Hong Kong Genome Project, Chu ATW, Chung BHY. Rare disease emerging as a global public health priority. Front Public Health. 2022;10:1028545. doi:10.3389/fpubh.2022.1028545

4. Schinzel Giedion Syndrome - Symptoms, Causes, Treatment | NORD. Accessed February 23, 2024.

5. Schinzel A, Giedion A. A syndrome of severe midface retraction, multiple skull anomalies, clubfeet, and cardiac and renal malformations in sibs. Am J Med Genet. 1978;1(4):361-375. doi:10.1002/ajmg.1320010402

6. Leone MP, Palumbo P, Palumbo O, et al. The recurrent SETBP1 c.2608G > A, p.(Gly870Ser) variant in a patient with Schinzel-Giedion syndrome: an illustrative case of the utility of whole exome sequencing in a critically ill neonate. Ital J Pediatr. 2020;46(1):74. doi:10.1186/s13052-020-00839-y

7. Banfi F, Rubio A, Zaghi M, et al. SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome. Nat Commun. 2021;12(1):4050. doi:10.1038/s41467-021-24391-3

8. SGS Foundation. Schinzel-Giedion Syndrome Awarded € 2 000 000. Schinzel-Giedion Syndrome Foundation. Published January 27, 2021. Accessed February 23, 2024.

9. Shou LH, Cao D, Dong XH, et al. Prognostic significance of SETBP1 mutations in myelodysplastic syndromes, chronic myelomonocytic leukemia, and chronic neutrophilic leukemia: A meta-analysis. Hills RK, ed. PLOS ONE. 2017;12(2):e0171608. doi:10.1371/journal.pone.0171608

10. Kempf L, Goldsmith JC, Temple R. Challenges of developing and conducting clinical trials in rare disorders. Am J Med Genet A. 2018;176(4):773-783. doi:10.1002/ajmg.a.38413

11. Kim J, Hu C, Moufawad El Achkar C, et al. Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease. N Engl J Med. 2019;381(17):1644-1652. doi:10.1056/NEJMoa1813279

12. Kovačević G, Kravljanac R, Tadić BV, Ostojić S, Ryu SW. Schinzel-Giedion syndrome: a rare cause of psychomotor delay and refractory seizures. Glob Pediatr. 2024;7:100124. doi:10.1016/j.gpeds.2023.100124

13. About SGS. Schinzel-Giedion Syndrome Foundation. Accessed February 23, 2024.

14. Leonardi E, Bettella E, Pelizza MF, et al. Identification of SETBP1 Mutations by Gene Panel Sequencing in Individuals With Intellectual Disability or With “Developmental and Epileptic Encephalopathy.” Front Neurol. 2020;11:593446. doi:10.3389/fneur.2020.593446

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