Rare Pediatric Disease Research Articles

Hospital-wide access to genomic data advanced pediatric rare disease research and clinical outcomes

Boston Children’s Hospital has established a genomic sequencing and analysis research initiative to improve clinical care for pediatric rare disease patients. Through the Children’s Rare Disease Collaborative (CRDC), the hospital offers CLIA-grade exome and genome sequencing, along with other sequencing types, to patients enrolled in specialized rare disease research studies. The data, consented for broad research use, are harmonized and analyzed with CRDC-supported variant interpretation tools. Since its launch, 66 investigators representing 26 divisions and 45 phenotype-based cohorts have joined the CRDC. These studies enrolled 4653 families, with 35% of analyzed cases having a finding either confirmed or under further investigation. This accessible and harmonized genomics platform also supports additional institutional data collections, research and clinical, and now encompasses 13,800+ patients and their families. This has fostered new research projects and collaborations, increased genetic diagnoses and accelerated innovative research via integration of genomics research with clinical care.

Implementation of multi-omics in diagnosis of pediatric rare diseases.

The rapid and accurate diagnosis of rare diseases is paramount in directing clinical management. In recent years, the integration of multi-omics approaches has emerged as a potential strategy to overcome diagnostic hurdles. This review examines the application of multi-omics technologies, including genomics, epigenomics, transcriptomics, proteomics, and metabolomics, in relation to the diagnostic journey of rare diseases. We explore how these combined approaches enhance the detection of pathogenic genetic variants and decipher molecular mechanisms. This review highlights the groundbreaking potential of multi-omics in advancing the precision medicine paradigm for rare diseases, offering insights into future directions and clinical applications. IMPACT: This review discusses using current tests and emerging technologies to diagnose pediatric rare diseases. We describe the next steps after inconclusive molecular testing and a structure for using multi-omics in further investigations. The use of multi-omics is expanding, and it is essential to incorporate it into clinical practice to enhance individualized patient care.

Variation Exists in Service Delivery: Similarities and Differences in the Provision of a Whole Genome Sequencing Service for Paediatric Rare Disease Patients in the English National Health Service.

The English National Health Service (NHS) is the first to offer whole genome sequencing (WGS) as part of standard care. As a high-income country with a universal healthcare system, England contributes a valuable perspective to global developments in WGS. We used an implementation science approach with mixed methods to characterise delivery of WGS for paediatric rare diseases. Observations and field notes of consent appointments in clinical genetics and mainstream settings and follow-up qualitative semi-structured interviews with the clinical team. Process maps were developed for each department to identify similarities and variations between sites, and thematic analysis of interview data to understand barriers and facilitators. Data collection occurred in 12 departments (7 genetic, 3 neurology, 1 cardiology and 1 general paediatric) across 7 NHS Trusts. 26 observations of 21 healthcare professionals were conducted, alongside 19 follow-up interviews. Two master maps were developed - one for clinical genetics and one for the mainstream. We identified 11 steps involved in delivering WGS, including 9 variations and 9 similarities. We identified most variation in the processes related to the 'who', 'when', 'how' and 'where' as these were aspects that could be adapted to fit into the specific set-up of the department. Barriers included reluctance to uptake in the mainstream and difficulties tracking samples. Recommendations include developing SOPs and hiring healthcare professionals responsible for facilitating consent alongside administrative aspects. These would reduce the burden on clinical geneticists and improve turnaround times as well as contribute to streamlining and standardisation of the service.

A Novel Human TBCK- Neuronal Cell Model Results in Severe Neurodegeneration and Partial Rescue with Mitochondrial Fission Inhibition.

TBCK syndrome is a rare fatal pediatric neurodegenerative disease caused by biallelic loss-of-function mutations in the TBCK gene. Previous studies by our lab and others have implicated mTOR, autophagy, lysosomes, and intracellular mRNA transport, however the exact primary pathologic mechanism is unknown. This gap has prevented the development of targeted therapies. We employed a human neural progenitor cell line (NPC), ReNcell VM, which can differentiate into neurons and astrocytes, to understand the role of TBCK in mTORC1 activity and neuronal autophagy and cellular mechanisms of pathology. We used shRNA technology to knockdown TBCK in ReNcells. These data showed that loss of TBCK did not inhibit mTORC1 activity in neither NPC nor neurons. Additionally, analysis of eight patient-derived cells and TBCK knock down HeLa cells showed that mTORC1 inhibition is inconsistent across different patients and cell types. We showed that TBCK knockdown in ReNcells affected NPC differentiation to neurons and astrocytes. Specifically, differentiation defects are coupled to cell cycle defects in NPC and increased cell death during differentiation. RNAseq analysis indicated the downregulation of several different neurodevelopmental and differentiation pathways. We observed a higher number of LC3-positive vesicles in the soma and neurites of TBCK knockdown cells. Further, TBCK knockdown altered mitochondrial dynamics and membrane potential in NPC, neurons and astrocytes. We found partial mitochondrial rescue with the mitochondrial fission inhibitor mdivi-1. This work outlines a new Human Cell Model for TBCK-related neurodegeneration and the essential role of mitochondrial health and partial rescue with mitochondrial fission inhibitor. This data, along with human neurons and astrocytes, illuminate mechanisms of neurodegeneration and provide a possible novel therapeutic avenue for affected patients.

Identifying pathogenic variants in rare pediatric neurological diseases using exome sequencing.

Variant annotations are crucial for efficient identification of pathogenic variants. In this study, we retrospectively analyzed the utility of four annotation tools (allele frequency, ClinVar, SpliceAI, and Phenomatcher) in identifying 271 pathogenic single nucleotide and small insertion/deletion variants (SNVs/small indels). Although variant filtering based on allele frequency is essential for narrowing down on candidate variants, we found that 13 de novo pathogenic variants in autosomal dominant or X-linked dominant genes are registered in gnomADv4.0 or 54KJPN, with an allele frequency of less than 0.001%, suggesting that very rare variants in large cohort data can be pathogenic de novo variants. Notably, 38.4% candidate SNVs/small indels are registered in the ClinVar database as pathogenic or likely pathogenic, which highlights the significance of this database. SpliceAI can detect candidate variants affecting RNA splicing, leading to the identification of four variants located 11 to 50bp away from the exon-intron boundary. Prioritization of candidate genes by proband phenotype using the PhenoMatcher module revealed that approximately 95% of the candidate genes had a maximum PhenoMatch score ≥ 0.6, suggesting the utility of phenotype-based variant prioritization. Our results suggest that a combination of multiple annotation tools and appropriate evaluation can improve the diagnosis of rare diseases.

Mechanistic Basis for a Single Amino Acid Residue Mutation Causing Human DNA Ligase 1 Deficiency, A Rare Pediatric Disease

In mammalian cells, DNA ligase 1 (LIG1) functions as the primary DNA ligase in both genomic replication and single-strand break repair. Several reported mutations in human LIG1, including R305Q, R641L, and R771W, cause LIG1 syndrome, a primary immunodeficiency. While the R641L and R771W mutations, respectively located in the nucleotidyl transferase and oligonucleotide binding domains, have been biochemically characterized and shown to reduce catalytic efficiency, the recently reported R305Q mutation within the DNA binding domain (DBD) remains mechanistically unexplored. The R641L and R771W mutations are known to decrease the catalytic activity of LIG1 by affecting both interdomain interactions and DNA binding during catalysis, without significantly impacting overall DNA affinity. To elucidate the molecular basis of the LIG1 syndrome-causing R305Q mutation, we purified this single-residue mutant protein and investigated its secondary structure, protein stability, DNA binding affinity, and catalytic efficiency. Our findings reveal that the R305Q mutation significantly impairs the function of LIG1 by disrupting the DBD-DNA interactions, leading to a 7–21-fold lower DNA binding affinity and a 33–300-fold reduced catalytic efficiency of LIG1. Additionally, the R305Q mutation slightly decreases LIG1’s protein stability by 2 to 3.6 °C, on par with the effect observed previously with either the R641L or R771W mutant. Collectively, our results uncover a new mechanism whereby the R305Q mutation impairs LIG1-catalyzed nicked DNA ligation, resulting in LIG1 syndrome, and highlight the crucial roles of the DBD-DNA interactions in tight DNA binding and efficient LIG1 catalysis.

494P Evaluation of transcriptome forward computational strategies to improve molecular diagnosis in rare pediatric neuromuscular disease

494P Evaluation of transcriptome forward computational strategies to improve molecular diagnosis in rare pediatric neuromuscular disease

Unravel the Enigma of Kawasaki Disease: Groping in the Dark

Kawasaki disease is one of the leading causes of acquired cardiac disease in childhood especially in Asian countries. Research efforts are extensive and focus on finding the molecular origin of Kawasaki disease. Kawasaki disease shows initially typical symptoms followed by coronary artery lesions in a few percentage of cases. Some patients develop coronary artery lesions, some do not. Research focus on finding biomarkers to predict the development of coronary artery lesions in a child with Kawasaki disease. Kawasaki-like features of the disease are known like MIS-C or Kawasaki-like syndrome, not clearly showing the classical clinical picture of Kawasaki disease. From that point, Kawasaki is not Kawasaki. This manuscript attempts to unravel the molecular and immunological enigma of a rare pediatric disease with to date, unknown etiology.

Diagnostic Accuracy of a Custom Large Language Model on Rare Pediatric Disease Case Reports.

Accurately diagnosing rare pediatric diseases frequently represent a clinical challenge due to their complex and unusual clinical presentations. Here, we explore the capabilities of three large language models (LLMs), GPT-4, Gemini Pro, and a custom-built LLM (GPT-4 integrated with the Human Phenotype Ontology [GPT-4 HPO]), by evaluating their diagnostic performance on 61 rare pediatric disease case reports. The performance of the LLMs were assessed for accuracy in identifying specific diagnoses, listing the correct diagnosis among a differential list, and broad disease categories. In addition, GPT-4 HPO was tested on 100 general pediatrics case reports previously assessed on other LLMs to further validate its performance. The results indicated that GPT-4 was able to predict the correct diagnosis with a diagnostic accuracy of 13.1%, whereas both GPT-4 HPO and Gemini Pro had diagnostic accuracies of 8.2%. Further, GPT-4 HPO showed an improved performance compared with the other two LLMs in identifying the correct diagnosis among its differential list and the broad disease category. Although these findings underscore the potential of LLMs for diagnostic support, particularly when enhanced with domain-specific ontologies, they also stress the need for further improvement prior to integration into clinical practice.

Genetic Treatment Approaches in Rare Pediatric Diseases

Gene and cell therapies have been developed and approved for a growing number of pediatric diseases, with ongoing research for additional treatments. Each therapy is tailored to the specific disease and targets a specific genetic alteration or cell population. The development of new therapies is a complex and regulated process, with strict oversight at regional and European levels. Research begins in the laboratory and progresses through clinical trials to ensure safety and efficacy. Scientists are exploring novel therapies using human cells and tissues to model pediatric diseases. Clinical trials are conducted to evaluate the effectiveness of these therapies, and researchers are also investigating repurposing approved treatments for other diseases or aspects of the same disease.

Getting the Dose Right in Drug Development for Rare Diseases: Barriers and Enablers.

In the relentless pursuit of optimizing drug development, the intricate process of determining the ideal dosage unfolds. This involves "dose-finding" studies, crucial for providing insights into subsequent registration trials. However, the challenges intensify when tackling rare diseases. The complexity arises from poorly understood pathophysiologies, scarcity of appropriate animal models, and limited natural history understanding. The inherent heterogeneity, coupled with challenges in defining clinical end points, poses substantial challenges, hindering the utility of available data. The small affected population, low disease awareness, and restricted healthcare access compound the difficulty in conducting dose-finding studies. This white paper delves into critical dose selection aspects, focusing on key therapeutic areas, such as oncology, neurology, hepatology, metabolic rare diseases. It also explores dose selection challenges posed by pediatric rare diseases as well as novel modalities, including enzyme replacement therapies, cell and gene therapies, and oligonucleotides. Several examples emphasize the pivotal role of clinical pharmacology in navigating the complexities associated with these diseases and emerging treatment modalities.

Pediatric Rare Diseases Development in the Pharmaceutical Industry: An International Consortium for Innovation and Quality in Pharmaceutical Development, Clinical Pharmacology Leadership Group-Pediatrics Working Group, Rare Diseases Subteam Whitepaper Examining the Current Landscape and Recommendations for the Future.

Many new opportunities surround rare pediatric disease drug development, thanks to key advances in regulatory thinking and in the scientific community. As rare disease drug development brings challenges to the developers in terms of limited understanding of natural history, heterogeneity in drug response, as well as difficulty recruiting patients in pivotal trials, there has never been a greater need for quantitative integration. To understand how International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) member companies approach pediatric rare disease drug development, the rare pediatric subteam of the Clinical Pharmacology Leadership Group (CPLG) sponsored Pediatrics Working Group conducted a baseline survey to assess the four main pillars of this quantitative innovation, namely, biomarkers and surrogate end points, statistical methodologies, model-informed drug development, as well as public-private partnerships. The survey was administered by IQ and yielded 13 evaluable responders from represented companies. This article presents the key findings from this baseline identifying survey, highlighting the key blind spots, and providing insightful expert opinions to address those gaps. In summary, we call an urgent attention to the community on the opportunities to enhance integration and within-industry learnings from this analysis on aspects related to platform studies, end-to-end quantitative integration, and sharing of trial-level placebo data for better understanding of disease progression and more efficient trial designs. We collectively hope that these findings will stimulate discussion and debate around cross-industry sharing and collaboration to better delineate principles and further enhance the efficiency of rare pediatric disease drug development.

Experience of the first adult-focussed undiagnosed disease program in Australia (AHA-UDP): solving rare and puzzling genetic disorders is ageless

BackgroundSignificant recent efforts have facilitated increased access to clinical genetics assessment and genomic sequencing for children with rare diseases in many centres, but there remains a service gap for adults. The Austin Health Adult Undiagnosed Disease Program (AHA-UDP) was designed to complement existing UDP programs that focus on paediatric rare diseases and address an area of unmet diagnostic need for adults with undiagnosed rare conditions in Victoria, Australia. It was conducted at a large Victorian hospital to demonstrate the benefits of bringing genomic techniques currently used predominantly in a research setting into hospital clinical practice, and identify the benefits of enrolling adults with undiagnosed rare diseases into a UDP program. The main objectives were to identify the causal mutation for a variety of diseases of individuals and families enrolled, and to discover novel disease genes.MethodsUnsolved patients in whom standard genomic diagnostic techniques such as targeted gene panel, exome-wide next generation sequencing, and/or chromosomal microarray, had already been performed were recruited. Genome sequencing and enhanced genomic analysis from the research setting were applied to aid novel gene discovery.ResultsIn total, 16/50 (32%) families/cases were solved. One or more candidate variants of uncertain significance were detected in 18/50 (36%) families. No candidate variants were identified in 16/50 (32%) families. Two novel disease genes (TOP3B, PRKACB) and two novel genotype–phenotype correlations (NARS, and KMT2C genes) were identified. Three out of eight patients with suspected mosaic tuberous sclerosis complex had their diagnosis confirmed which provided reproductive options for two patients. The utility of confirming diagnoses for patients with mosaic conditions (using high read depth sequencing and ddPCR) was not specifically envisaged at the onset of the project, but the flexibility to offer recruitment and analyses on an as-needed basis proved to be a strength of the AHA-UDP.ConclusionAHA-UDP demonstrates the utility of a UDP approach applying genome sequencing approaches in diagnosing adults with rare diseases who have had uninformative conventional genetic analysis, informing clinical management, recurrence risk, and recommendations for relatives.

Clinical Benefit and Revenues of Drugs Affected by Rare Pediatric Disease Priority Review Vouchers, 2017-2023

To determine the clinical benefit of drugs that earned or redeemed rare pediatric disease priority review vouchers (PRVs) from 2017 through 2023, and the revenues generated by such drugs. In this cohort study, Federal Register documents, publicly available health technology agency (HTA) assessments, and financial filings were used to identify drugs that were issued or redeemed using a rare pediatric disease PRV from 2017 through 2023, and to assess their added therapeutic benefit and drug-specific global revenues. Among the 36 drugs whose approval resulted in issuance of a rare pediatric PRV, therapeutic benefit ratings were available for 17 (47%), with 9 (53%) rated as high by at least 1 organization. Mean annual global revenues were $363 million (year 1), $621 million (year 2), and $850 million (year 3). The median annual list price for drugs issued a voucher was $788,705. Vouchers were then redeemed for 15 different drugs; out of 13 drugs with therapeutic benefit ratings, 4 (31%) were high value. Drugs that treat rare pediatric diseases generate similar revenues compared with other brand drugs, and drugs with high therapeutic benefit tend to generate more revenue than those with low therapeutic benefit. Drugs that earned the rare pediatric disease PRV for their manufacturer generate significant revenues and the voucher may not be necessary to incentivize drug development in the rare pediatric disease space.

The Birth Prevalence of Congenital Hyperinsulinism: A Narrative Review of the Epidemiology of a Rare Disease.

Congenital hyperinsulinism (HI) is a rare pediatric disease and the most common cause of severe, persistent hypoglycemia in childhood. It is characterized by the dysregulation of insulin secretion from the pancreas and can lead to irreversible brain damage with lifelong neurodisability. The global birth prevalence of HI is currently unknown. An evidence-based estimate of HI birth prevalence is essential to improve diagnosis and patient management, to drive clinical research and the development of new treatments, and to inform public policy. In order to estimate the birth prevalence of persistent HI, a targeted literature review of studies that report HI epidemiological data was undertaken, and the strengths and limitations of each study were analyzed. Overall, eight global studies were identified that reported independently determined HI epidemiological data. The best estimate for the birth prevalence of persistent HI in European-ancestry populations is 3.5 per 100,000 births. Local consanguinity patterns appear to have a considerable impact on the birth prevalence of persistent HI in each country, precluding the application of this figure to all global populations. More epidemiological studies with robust methodology are needed to enable a reliable approximation of the incidence and prevalence of HI in global populations.

Next generation sequencing identifies WNT signalling as a significant pathway in Autosomal Recessive Polycystic Kidney Disease (ARPKD) manifestation and may be linked to disease severity

IntroductionAutosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare paediatric disease primarily caused by sequence variants in PKHD1. ARPKD presents with considerable clinical variability relating to the type of PKHD1 sequence variant, but not its position. Animal models of Polycystic Kidney Disease (PKD) suggest a complex genetic landscape, with genetic modifiers as a potential cause of disease variability. MethodsTo investigate in an unbiased manner the molecular mechanisms of ARPKD and identify potential indicators of disease severity, Whole Exome Sequencing (WES) and RNA-Sequencing (RNA-Seq) were employed on human ARPKD kidneys and age-matched healthy controls. ResultsWES confirmed the clinical diagnosis of ARPKD in our patient cohort consisting of ten ARPKD kidneys. Sequence variant type, nor position of PKHD1 sequence variants, was linked to disease severity. Sequence variants in genes associated with other ciliopathies were detected in the ARPKD cohort, but only PKD1 could be linked to disease severity. Transcriptomic analysis on a subset of four ARPKD kidneys representing severe and moderate ARPKD, identified a significant number of genes relating to WNT signalling, cellular metabolism and development. Increased expression of WNT signalling-related genes was validated by RT-qPCR in severe and moderate ARPKD kidneys. Two individuals in our cohort with the same PKHD1 sequence variants but different rates of kidney disease progression, with displayed transcriptomic differences in the expression of WNT signalling genes. ConclusionARPKD kidney transcriptomics highlights changes in WNT signalling as potentially significant in ARPKD manifestation and severity, providing indicators for slowing down the progression of ARPKD.

Commentary: Intervention research in pediatric rare diseases.

Commentary: Intervention research in pediatric rare diseases.

Characterizing Families of Pediatric Patients with Rare Diseases and Their Diagnostic Odysseys: A Comprehensive Survey Analysis from a Single Tertiary Center in Korea

Purpose: Rare diseases necessitate consistent access to specialized health services. In Korea, despite the growing socioeconomic burden, insufficient comprehensive research is available on patients with rare diseases and their families, particularly concerning factors influencing the length of time to diagnosis. The aim of this study was to thoroughly characterize rare pediatric diseases and explore factors impacting the diagnostic odyssey. Methods: The study enrolled patients under 15 years old seeking medical care at the Seoul National University Children’s Hospital Rare Disease Center between January 2022 and December 2023. Participating patients were required to have been diagnosed with one of the 1,248 rare diseases recognized in Korea. A 33-question survey was developed to assess clinical features of the patients, characteristics of their primary caregivers, and their perceptions of ongoing medical care. Results: The study included 101 patients and their families. Regarding perceived cognitive and motor functions, most families indicated moderate or severe limitations (cognitive, 62.4%; motor, 57.4%). Over half of the families (53.5%) reported discontinuing employment to provide patient care. Neurological symptoms represented the most common initial chief concern, with dermatologic symptoms and laboratory test abnormalities also noted. Three factors were associated with time to diagnosis: the number of hospitals visited, whether the districts of residence and diagnosis aligned, and the age at symptom onset.Conclusion: The comprehensive characterization of patients with rare diseases and their families in Korea, along with the identification of factors impacting the diagnostic odyssey, provides key insights for the development of a tailored support system.

Pediatric Pulmonology 2023 year in review: Rare and diffuse lung disease.

The field of pediatric rare and diffuse lung disease continues its maturation as research advances the understanding of diagnosis and treatment of children's interstitial lung disease, noncystic fibrosis bronchiectasis, and primary ciliary dyskinesia. The rarity and breadth of these conditions make them challenging to study, yet we continue to make progress in our understanding of pathophysiology, genotype/phenotype relationships, and treatment. Papers published on these topics in Pediatric Pulmonology and other journals in 2023 describe the power of multicenter cooperation and patient registries, enhance our understanding of pathophysiology and genotype/phenotype relationships, and report progress in treatments. In this review, we hope to increase awareness and knowledge of these conditions and to inspire future research.

Current Pathophysiological and Therapeutic Options for Children with Hutchinson Gilford Syndrome

Hutchinson-Gilford-Progeria syndrome (HGPS) cannot, to date, be treated causally. Therapy for affected children focus on alleviating the symptoms, treating secondary diseases and preventing complications such as strokes or heart attacks. Various medications and physiotherapeutic methods are primarily available for this extremely rare pediatric genetic disease. Lonafarnib, a farnesyltransferase inhibitor, has been used for the treatment of progeria in children since 2022, which can extend the life of children with HGPS up to 4 years. Farnesyltransferase inhibitors are able to block an enzyme that is involved in progerin processing. Progerin is the altered protein that occurs in HGPS due to the spelling mistake in the lamin A gene and accumulates within the cell nucleus envelope. As a result, the envelope is weakened and the cell nucleus becomes deformed. The spectrum of therapies includes progerin-targeting strategies on one hand and on therapies to alleviate the tremendous effects by progerin. Research focus on different new targets in the management of HGPS-like the farnesyltransferase inhibitor lonafarnib, Acetyltransferase NAT10-inhibitors, KAT 6a/b and -7 inhibitors, paclitaxel, small molecule ICMT-inhibitors, exportin CRM-1 Inhibitors, progerin-lamin A binding inhibitors (Progerinin), Ghrelin, micro-RNA inhibitors, doxycycline and the regulation of rapamycin complex 1 (mTORC1). This manuscript analyses these new therapeutic targets and pathophysiological aspects in a review manuscript.