Metabolism. 2024 Jan;150:155738. doi: 10.1016/j.metabol.2023.155738. Epub 2023 Nov 18.

ABSTRACT

Inborn errors of metabolism (IEMs) are a group of more than 1000 inherited diseases that are individually rare but have a cumulative global prevalence of 50 per 100,000 births. Recently, it has been recognized that like common diseases, patients with rare diseases can greatly vary in the manifestation and severity of symptoms. Here, we review omics-driven approaches that enable an integrated, holistic view of metabolic phenotypes in IEM patients. We focus on applications of Constraint-based Reconstruction and Analysis (COBRA), a widely used mechanistic systems biology approach, to model the effects of inherited diseases. Moreover, we review evidence that the gut microbiome is also altered in rare diseases. Finally, we outline an approach using personalized metabolic models of IEM patients for the prediction of biomarkers and tailored therapeutic or dietary interventions. Such applications could pave the way towards personalized medicine not just for common, but also for rare diseases.

PMID:37981189 | DOI:10.1016/j.metabol.2023.155738

Orphanet J Rare Dis. 2023 Nov 17;18(1):362. doi: 10.1186/s13023-023-02944-7.

ABSTRACT

BACKGROUND: Rare diseases (RD) are a heterogeneous group of diseases, sharing aspects of complexity. Prognosis is variable, even in individuals with the same disease. Real-world data on RD as a whole are scarce. The aim of this study is to provide data on mortality and survival for a substantial group of RD deriving from a population-based registry, which covers the Veneto region in Italy (4.9 million inhabitants).

RESULTS: During the study period, 3367 deaths occurred, mainly in males (53.9%), elderly patients (63.5%) and patients with diseases having a reported prevalence of 1-9/100000 (65.6%). When standardizing by age, the mortality ratio was higher in RD patients than in the general population, SMR = 1.93 (95% CI 1.84-2.11), with an observed gender difference, 2.01 (95% CI 1.88-2.29) in females and 1.86 (95% CI 1.73-2.10) in males. The lowest survival rates are experienced by patients with rare neurologic diseases, rare skin diseases and rare systemic or rheumatologic diseases, 58%, 68% and 81%, respectively, after a 15-year observation period. It should be noted that only 18% of patients diagnosed with motor neuron diseases were alive after 15 years from diagnosis.

CONCLUSIONS: Despite progress in diagnosis, treatment and care in recent years, RD patients globally have higher mortality rates and reduced survival compared to the general population, with specific variations according to gender, age and disease group.

PMID:37978388 | PMC:PMC10655462 | DOI:10.1186/s13023-023-02944-7

Med Sci (Paris). 2023 Nov;39 Hors série n° 1:67-71. doi: 10.1051/medsci/2023138. Epub 2023 Nov 17.

NO ABSTRACT

PMID:37975776 | DOI:10.1051/medsci/2023138

Lancet Neurol. 2023 Dec;22(12):1125-1139. doi: 10.1016/S1474-4422(23)00313-7.

ABSTRACT

BACKGROUND: X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1.

METHODS: ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 1014 vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 1014 vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated.

FINDINGS: Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0-30·9; range 9·5-49·7) in the lower dose cohort, 31·1 months (16·0-64·7; 6·8-72·7) in the higher dose cohort, and 18·7 months (10·1-31·5; 5·9-39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0-49·5; range 2·1-54·7) for lower dose participants, 27·6 months (24·6-29·1; 3·4-41·0) for higher dose participants, and 28·3 months (9·7-46·9; 5·7-32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure).

INTERPRETATION: Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing.

FUNDING: Astellas Gene Therapies.

PMID:37977713 | DOI:10.1016/S1474-4422(23)00313-7

Indian J Otolaryngol Head Neck Surg. 2023 Dec;75(4):3798-3814. doi: 10.1007/s12070-023-03998-6. Epub 2023 Jul 10.

ABSTRACT

Tracheobronchopathia osteochondroplastica (TO) is an orphan disease of the tracheobronchial tree without any known etiological attributes. There are several case reports published on this condition, yet the available information about the TO is discrete and of little clinical value. This scoping review is the first large-scale review on TO that collates individual patient data from the published case reports and descriptively analyses the clinicopathological features of this unique condition along with its management approaches and therapeutic outcomes. The objective was to synthesize comprehensive literature review on TO that can aid clinical practice and further research. An electronic search conducted in five large databases, including PubMed, EMBASE, CINAHL, CENTRAL, and Web of Science, for the published articles of TO yielded 1072 items. After screening, the individual patient data of 371 TO cases from 228 eligible articles were included and analysed in this scoping review.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12070-023-03998-6.

PMID:37974722 | PMC:PMC10646011 | DOI:10.1007/s12070-023-03998-6

Semin Liver Dis. 2023 Nov;43(4):446-459. doi: 10.1055/s-0043-1776760. Epub 2023 Nov 16.

ABSTRACT

The porphyrias are a group of metabolic disorders that are caused by defects in heme biosynthesis pathway enzymes. The result is accumulation of heme precursors, which can cause neurovisceral and/or cutaneous photosensitivity. Liver is commonly either a source or target of excess porphyrins, and porphyria-associated hepatic dysfunction ranges from minor abnormalities to liver failure. In this review, the first of a three-part series, we describe the defects commonly found in each of the eight enzymes involved in heme biosynthesis. We also discuss the pathophysiology of the hepatic porphyrias in detail, covering epidemiology, histopathology, diagnosis, and complications. Cellular consequences of porphyrin accumulation are discussed, with an emphasis on oxidative stress, protein aggregation, hepatocellular cancer, and endothelial dysfunction. Finally, we review current therapies to treat and manage symptoms of hepatic porphyria.

PMID:37973028 | DOI:10.1055/s-0043-1776760

J Comp Eff Res. 2023 Nov 16:e230054. doi: 10.57264/cer-2023-0054. Online ahead of print.

ABSTRACT

Aim: Patients with Rett syndrome (RTT) experience gastrointestinal (GI) manifestations. This study aimed to describe the prevalence of GI manifestations and the associated medical costs in patients with RTT in the USA. Patients & Methods: The study combined an insurance claims database analysis with a survey of 100 physicians experienced in RTT management. Results: GI manifestations affected 43.0% of 5940 patients, with increased prevalence in pediatric patients (45.6%) relative to adult patients (40.2%). Annualized mean medical cost of managing GI manifestations was $4473. Only 5.9-8.2% of neurologists and pediatricians ranked GI symptom management among the five most important treatment goals. Conclusion: Patients with RTT experience a high burden of GI manifestations, which translate to considerable medical costs. Importantly, the prevalence of GI manifestations was likely underestimated in this study, as only those symptoms which resulted in a healthcare encounter were captured.

PMID:37971297 | DOI:10.57264/cer-2023-0054

Med. 2023 Dec 8;4(12):913-927.e3. doi: 10.1016/j.medj.2023.10.003. Epub 2023 Nov 13.

ABSTRACT

BACKGROUND: Navigating the clinical literature to determine the optimal clinical management for rare diseases presents significant challenges. We introduce the Medical Action Ontology (MAxO), an ontology specifically designed to organize medical procedures, therapies, and interventions.

METHODS: MAxO incorporates logical structures that link MAxO terms to numerous other ontologies within the OBO Foundry. Term development involves a blend of manual and semi-automated processes. Additionally, we have generated annotations detailing diagnostic modalities for specific phenotypic abnormalities defined by the Human Phenotype Ontology (HPO). We introduce a web application, POET, that facilitates MAxO annotations for specific medical actions for diseases using the Mondo Disease Ontology.

FINDINGS: MAxO encompasses 1,757 terms spanning a wide range of biomedical domains, from human anatomy and investigations to the chemical and protein entities involved in biological processes. These terms annotate phenotypic features associated with specific disease (using HPO and Mondo). Presently, there are over 16,000 MAxO diagnostic annotations that target HPO terms. Through POET, we have created 413 MAxO annotations specifying treatments for 189 rare diseases.

CONCLUSIONS: MAxO offers a computational representation of treatments and other actions taken for the clinical management of patients. Its development is closely coupled to Mondo and HPO, broadening the scope of our computational modeling of diseases and phenotypic features. We invite the community to contribute disease annotations using POET (https://poet.jax.org/). MAxO is available under the open-source CC-BY 4.0 license (https://github.com/monarch-initiative/MAxO).

FUNDING: NHGRI 1U24HG011449-01A1 and NHGRI 5RM1HG010860-04.

PMID:37963467 | DOI:10.1016/j.medj.2023.10.003

BMC Med Res Methodol. 2023 Nov 13;23(1):269. doi: 10.1186/s12874-023-02080-7.

ABSTRACT

BACKGROUND: The design of clinical trials in rare diseases is often complicated by a lack of real-world translational knowledge. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by skeletal malformations and progressive heterotopic ossification (HO). Palovarotene is a selective retinoic acid receptor gamma agonist. Here, we describe the methodology of three studies in the palovarotene clinical development program in FOP and discuss insights that could inform future research, including endpoint suitability and the impact of trial design.

METHODS: PVO-1A-001 (NCT02322255) was a prospective, protocol-specified, longitudinal FOP natural history study (NHS). PVO-1A-201 (NCT02190747) was a randomized, double-blind, placebo-controlled phase II trial; PVO-1A-202 (NCT02279095) was its open-label extension. Trial designs, including treatment regimens and imaging assessments, were refined between PVO-1A-201 and PVO-‍1A-202, and within PVO-1A-202, based on emerging data as the studies progressed. Palovarotene doses were administered using a flare-up treatment regimen (higher dose for 2/4 weeks, followed by lower dose for 4/≥8 weeks; from flare-up onset), with or without accompanying chronic (daily) treatment. Flare-up and disease progression outcomes were assessed, including incidence and volume of new HO during flare-ups and/or annually, as well as other clinical, patient-reported, and exploratory outcomes. Safety was monitored throughout all studies.

RESULTS: Overall, 114 and 58 individuals with FOP were enrolled in the NHS and phase II trials, respectively. Results of the NHS and PVO-1A-201 were published in 2022; complete results of PVO-1A-202 will be publicly available in due course. Together the studies yielded important information on endpoint suitability, including that low-dose whole-body computed tomography was the optimum imaging modality for assessing HO progression annually and that long study durations are needed to detect substantial changes in functional and patient-reported outcomes.

CONCLUSIONS: A flexible clinical development program is necessary for underexplored rare diseases to overcome the many challenges faced. Here, the NHS provided a longitudinal evaluation of FOP progression and interventional trials were based on emerging data. The studies described informed the design and endpoints implemented in the phase III MOVE trial (NCT03312634) and provide a foundation for future clinical trial development.

TRIAL REGISTRATION: NCT02322255 (registered 23/12/2014); NCT02190747 (registered 15/07/2014); NCT02279095 (registered 30/10/2014).

PMID:37957586 | DOI:10.1186/s12874-023-02080-7

Int J Mol Sci. 2023 Nov 6;24(21):15999. doi: 10.3390/ijms242115999.

ABSTRACT

Inborn error of metabolism disorders (IEMs) are a family of diseases resulting from single-gene mutations that lead to the accumulation of metabolites that are usually toxic or interfere with normal cell function. The etiological link between metabolic alteration and the symptoms of IEMs is still elusive. Several metabolites, which accumulate in IEMs, were shown to self-assemble to form ordered structures. These structures display the same biophysical, biochemical, and biological characteristics as proteinaceous amyloid fibrils. Here, we have demonstrated, for the first time, the ability of each of the branched-chain amino acids (BCAAs) that accumulate in maple syrup urine disease (MSUD) to self-assemble into amyloid-like fibrils depicted by characteristic morphology, binding to indicative amyloid-specific dyes and dose-dependent cytotoxicity by a late apoptosis mechanism. We could also detect the presence of the assemblies in living cells. In addition, by employing several in vitro techniques, we demonstrated the ability of known polyphenols to inhibit the formation of the BCAA fibrils. Our study implies that BCAAs possess a pathological role in MSUD, extends the paradigm-shifting concept regarding the toxicity of metabolite amyloid-like structures, and suggests new pathological targets that may lead to highly needed novel therapeutic opportunities for this orphan disease.

PMID:37958982 | DOI:10.3390/ijms242115999

Rev Med Liege. 2023 Nov;78(11):626-633.

ABSTRACT

The Ehlers Danlos syndromes (EDS) are a heterogenous group of inherited connective tissue disorders characterized by generalized joint hypermobility and instability, tissue fragility and multiple functional disorders. The EDS hypermobility type (hEDS) is the most common but the mildest subtype of EDS and is defined by joint involvement. hSED diagnosis is based on clinical criteria because no genetic factors nor molecular basis have yet been identified. Since chronic pain constitutes one of hESD main symptoms, the diagnosis is frequently suspected although the syndrome is rare, with a prevalence estimated to be 1/10.000. An expert clinical evaluation is therefore necessary in order to establish an accurate diagnosis. This allows the implementation of physical therapy which is the only treatment that has proven efficacious in reducing joint instability, generalized pain and secondary osteoarthritis.

PMID:37955292

Med Clin North Am. 2024 Jan;108(1):xv-xvi. doi: 10.1016/j.mcna.2023.09.001. Epub 2023 Sep 19.

NO ABSTRACT

PMID:37951659 | DOI:10.1016/j.mcna.2023.09.001

Med Clin North Am. 2024 Jan;108(1):xvii-xviii. doi: 10.1016/j.mcna.2023.06.019. Epub 2023 Jul 19.

NO ABSTRACT

PMID:37951660 | DOI:10.1016/j.mcna.2023.06.019

Med Clin North Am. 2024 Jan;108(1):1-14. doi: 10.1016/j.mcna.2023.06.013. Epub 2023 Jul 26.

ABSTRACT

Patients with rare or otherwise undiagnosed disorders frequently find themselves on a diagnostic odyssey, the often-prolonged journey toward diagnosis that can be characterized by significant physical, emotional, and financial hardship, as well as by diagnostic errors and delays. The wider availability of clinical exome sequencing has helped end many diagnostic odysseys, though diagnostic success rates of around 35% for exome sequencing leave many patients undiagnosed. Diagnostic yields can be improved via the implementation of advanced genetic testing modalities, though both these modalities and exome sequencing perform significantly better when paired with high-quality phenotypic data. Diagnostic centers of excellence can improve outcomes for patients on a diagnostic odyssey by providing a process and environment that address shortfalls in diagnostic access while providing high-quality phenotyping. Features of successful undiagnosed and rare disease evaluation teams are discussed and an illustrative case is provided.

PMID:37951644 | DOI:10.1016/j.mcna.2023.06.013

Orphanet J Rare Dis. 2023 Nov 10;18(1):352. doi: 10.1186/s13023-023-02964-3.

ABSTRACT

BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv) is a rare genetic disease that negatively affects patients' quality of life through the involvement of various organs and tissues. Despite a large amount of research on medical and psychosocial interventions, the impact of occupational therapy (OT) on patients with ATTRv is not well understood.

OBJECTIVE: The aim of this study was to develop an OT programme to improve the daily functioning and quality of life of patients with ATTRv.

METHODS: Fourteen patients with ATTRv were interviewed. Together they developed short- and medium-term occupational goals. Patients received the OT intervention for six months. Outcomes were measured using scores for activities of daily living and psychological well-being.

RESULTS: The study found that OT can have a positive impact as a complementary intervention to medical and other psychosocial treatments. Of the 14 patients, 12 maintained the same scores in activities of daily living. Two deteriorated and eight improved their psychological scores.

CONCLUSION: This study highlights the need for further research in this area and the importance of OT in the management of patients with ATTRv. Early intervention is of paramount importance and further research is needed to evaluate the long-term effects of OT interventions in patients with ATTRv.

PMID:37950297 | PMC:PMC10636990 | DOI:10.1186/s13023-023-02964-3

Comput Methods Programs Biomed. 2024 Jan;243:107917. doi: 10.1016/j.cmpb.2023.107917. Epub 2023 Nov 7.

ABSTRACT

BACKGROUND: Rare disease diagnoses are often delayed by years, including multiple doctor visits, and potential imprecise or incorrect diagnoses before receiving the correct one. Machine learning could solve this problem by flagging potential patients that doctors should examine more closely.

METHODS: Making the prediction situation as close as possible to real situation, we tested different masking sizes. In the masking phase, data was removed, and it was applied to all data points following the first rare disease diagnosis, including the day when the diagnosis was received, and in addition applied to selected number of days before initial diagnosis. Performance of machine learning models were compared with positive predictive value (PPV), negative predictive value (NPV), prevalence PPV (pPPV), prevalence NPV (pNPV), accuracy (ACC) and area under the receiver operation characteristics curve (AUC).

RESULTS: XGBoost had PPVs over 90 % in all masking settings, and InceptionVasGloMyotides had most of the PPVs over 90 %, but not as consistently. When the prevalence of the diseases was considered XGBoost achieved highest value of 8.8 % in binary classification with 30 days masking and InceptionVasGloMyotides achieved the best value of 6 % in the binary classification as well, but with 2160 days and 4320 days masking. ACC were varying between 89 % and 98 % with XGBoost and InceptionVasGloMyotides having variation between 79 % and 94 %. AUC on the other hand varied between 72.6 % and 94.5 % with InceptionVasGloMyotides and for XGBoost it varied between 69.9 % and 96.4 %.

CONCLUSIONS: XGBoost and InceptionVasGloMyotides could successfully predict rare diseases for patients at least 30 days prior to initial rare disease diagnose. In addition, we managed to build performative custom deep learning model.

PMID:37948909 | DOI:10.1016/j.cmpb.2023.107917

Anaesthesiologie. 2023 Dec;72(12):907-918. doi: 10.1007/s00101-023-01353-6. Epub 2023 Nov 10.

ABSTRACT

Due to refined and new diagnostic possibilities and improved medical care, in the future anesthesiologists will be more frequently confronted with patients suffering from rare diseases. As the physicians providing perioperative care often have little or no experience with the diseases of such patients, the access to high-quality specific literature is essential. In this respect they must be able to assess and classify the quality of the information which is predominantly available online, especially as when evidence-based knowledge is available, it is only available to a very limited extent. Patients with rare diseases mostly present with recurring problem constellations. A systematic assignment to the most important problem areas (airway, circulation, metabolism, etc.) as well as a structured and interdisciplinary approach are decisive for a successful perioperative treatment of these patients. Due to low prevalence, lack of personal experience and lack of evidence-based data, anesthesia in patients with SE is an absolute challenge, especially in time-critical situations.

PMID:37947803 | DOI:10.1007/s00101-023-01353-6

Genome Med. 2023 Nov 9;15(1):94. doi: 10.1186/s13073-023-01240-0.

ABSTRACT

BACKGROUND: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25-30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome.

METHODS: We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants.

RESULTS: Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving.

CONCLUSIONS: Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.

PMID:37946251 | PMC:PMC10636885 | DOI:10.1186/s13073-023-01240-0

Orphanet J Rare Dis. 2023 Nov 9;18(1):348. doi: 10.1186/s13023-023-02966-1.

ABSTRACT

Over the last 15 years, Undiagnosed Diseases Programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases, integrating research and clinical care to optimize diagnostic outcomes. This narrative review summarizes the published literature surrounding Undiagnosed Diseases Programs worldwide, including thirteen studies that evaluate outcomes and two commentary papers. Commonalities in the diagnostic and research process of Undiagnosed Diseases Programs are explored through an appraisal of available literature. This exploration allowed for an assessment of the strengths and limitations of each of the six common steps, namely enrollment, comprehensive clinical phenotyping, research diagnostics, data sharing and matchmaking, results, and follow-up. Current literature highlights the potential utility of Undiagnosed Diseases Programs in research diagnostics. Since participants have often had extensive previous genetic studies, research pipelines allow for diagnostic approaches beyond exome or whole genome sequencing, through reanalysis using research-grade bioinformatics tools and multi-omics technologies. The overall diagnostic yield is presented by study, since different selection criteria at enrollment and reporting processes make comparisons challenging and not particularly informative. Nonetheless, diagnostic yield in an undiagnosed cohort reflects the potential of an Undiagnosed Diseases Program. Further comparisons and exploration of the outcomes of Undiagnosed Diseases Programs worldwide will allow for the development and improvement of the diagnostic and research process and in turn improve the value and utility of an Undiagnosed Diseases Program.

PMID:37946247 | PMC:PMC10633944 | DOI:10.1186/s13023-023-02966-1

Science. 2023 Nov 10;382(6671):657. doi: 10.1126/science.adk8633. Epub 2023 Nov 9.

ABSTRACT

Mathematical models hold the key to equitable patient care.

PMID:37943923 | DOI:10.1126/science.adk8633