International Precision Child Health Partnership (IPCHiP): an initiative to accelerate discovery and improve outcomes in rare pediatric disease

Abstract

Advances in genomic technologies have revolutionized the diagnosis of rare genetic diseases, leading to the emergence of precision therapies. However, there remains significant effort ahead to ensure the promise of precision medicine translates to improved outcomes. Here, we discuss the challenges in advancing precision child health and highlight how international collaborations such as the International Precision Child Health Partnership, which embed research into clinical care, can maximize benefits for children globally.

Fig. 1. Defining rare disease numbers.

Epidemiologic and genetic data highlight the urgent unmet need for improving the diagnosis and treatment of rare disease, with a coordinated and comprehensive approach to advancing discovery and translation in precision child health given the high genetic and phenotypic heterogeneity. In total, 12% of disease-associated genes have established interventions that may modify outcomes, which highlights both the imperative for prompt diagnosis, but also that most rare diseases lack a precision treatment currently^,,,,–. Created with Biorender.com.

Fig. 2. Strategies for increasing diagnostic yield in rare disease.

Strategic advancements and methodological innovations are essential for enhancing diagnostic accuracy and overcoming current bottlenecks. Key priority areas include improved ability to rapidly resolve variants of unknown significance (VUS), identification of novel disease genes, advancing informatic capabilities, and overcoming diagnostic challenges with emerging technologies^,. Created with Biorender.com.

Fig. 3. Current and future opportunities for precision treatment in childhood epilepsies.

Level of intervention, e.g., at a DNA/RNA/protein/pathway or network level, appears on the left of the figure. Examples of methods of novel therapeutic approaches appear on the right. Text in green indicates examples of previous or current clinical trials^–, text in orange indicates evidence from pre-clinical models^,. In early-onset severe SCN2A-related epilepsy, variants result in a GOF and thus seizures are responsive to sodium channel blocking antiseizure medication, as are neonatal and infantile epilepsies due to LOF variants in KCNQ2, likely due to co-localization with sodium channels^,. l-serine acts as an alternate agonist at NMDA receptors to improve both seizure and non-seizure outcomes in LOF GRIN neurodevelopmental disorders. Pathway-focused approaches are possible in metabolic epilepsies such as GLUT1-related epilepsy, disorders of the Vitamin B6 pathway, and biotinidase deficiency, but also as a broad approach in focal epilepsies related to mTOR pathway dysfunction including tuberous sclerosis complex, germline and somatic MTOR variants, and GATOR1 complex (DEPDC5, NPRL2, NPRL3) epilepsies^–. Network-based approaches remain limited, but there is emerging evidence of targeted stimulation strategies in severe epilepsies such as Lennox Gastaut syndrome, and development of activity-based gene therapies which may allow targeted interruption of epileptic networks by targeting overactive neurons^–. Created with Biorender.com. AAV adeno-associated virus, EKC engineered potassium channel, CRISPRa CRISPR activation, CRISPRi CRISPR inhibition, ASO antisense oligonucleotide, siRNA small interfering RNA, ssRNA single strand RNA, GOF gain-of-function, LOF loss-of-function, MTOR mammalian target of rapamycin, DBS deep brain stimulation, RNS responsive neurostimulation.

Fig. 4. Understanding phenotype–genotype correlations is key to advancing precision therapies.

The gene encoding the Na_v1.1 sodium channel, SCN1A, provides an example of one gene causing more than one disease. This gene is associated with both gain- and loss-of-function disease mechanisms, and phenotypes of variable severity, only some of which are associated with poor outcomes^,,. Clinical trials of novel therapies for Dravet syndrome (SCN1A loss-of-function phenotype), including AAV9 gene therapy and an antisense oligonucleotide, are underway^,. Much work has been done to understand phenotypic variability, natural history, and phenotype–disease mechanism correlations, which has been critical for therapeutic development, clinical trial design and candidate selection, and outcome measurements^,,–. The more recently identified gain-of-function SCN1A phenotypes will require different treatments^,. Created with Biorender.com.

Fig. 5. The infrastructure, resources, and expertise required to establish the Gene-STEPS study across multiple health systems.

BCH = Boston Children’s Hospital, GOS ICH = Great Ormond Street Institute for Child Health, MCC = Melbourne Children’s Campus (Murdoch Children’s Research Institute and the Royal Children’s Hospital), SickKids = The Hospital for Sick Children. Color of orange squares denotes the availability of each resource required for the study in clinical practice at each site prior to the commencement of Gene-STEPS. Solid orange = clinically available and routine for this patient group, orange diagonal lines = clinically available but not routine, orange grid lines = was not available clinically and needed to be established, research = white. *Other assessments include measures of adaptive function, quality of life, and clinical impact of genomic testing. **Advanced-omic testing includes RNA sequencing, long-read genome sequencing.