Genetics. 2023 Aug 9;224(4):iyad121. doi: 10.1093/genetics/iyad121.

NO ABSTRACT

PMID:37556311 | PMC:PMC10411596 | DOI:10.1093/genetics/iyad121

Hematology. 2023 Dec;28(1):2241226. doi: 10.1080/16078454.2023.2241226.

ABSTRACT

BACKGROUND: In China, conventional genetic testing methods can only detect common thalassemia variants. Accurate detection of rare thalassemia is crucial for clinical diagnosis, especially for children that need long-term blood transfusion. This study aims to explore the application value of third-generation sequencing (TGS) in the diagnosis of rare thalassemia in children with anemia.

METHODS: We enrolled 20 children with anemia, excluding from iron deficiency anemia (IDA). TGS was employed to identify both known and novel thalassemia genotypes, while sanger sequencing was used to confirm the novel mutation detected.

RESULTS: Among the 20 samples, we identified 5 cases of rare thalassemia. These included β-4.9 (hg38,Chr11:5226187-5231089) at HBB gene, α-91(HBA2:c.*91delT), αCD30(HBA2:c.91-93delGAG), Chinese Gγ+(Aγδβ)0(NG_000007.3: g .48795-127698 del 78904) and delta - 77(T > C)(HBD:c.-127T>C). Notably, the -SEA/α-91α genotype associated with severe non-deletional hemoglobin H disease (HbH disease) has not been previously reported. Patients with genotypes β654/β-4.9 and -SEA/α-91α necessitate long-term blood transfusions, and those with the -SEA/αCD30α, Chinese Gγ+(Aγδβ)0 and delta thalassemia demonstrate mild anemia.

CONCLUSIONS: TGS demonstrates promising potential as a diagnostic tool for suspected cases of rare thalassemia in children, especially those suspected to have transfusion-dependent thalassemia (TDT).

PMID:37548329 | DOI:10.1080/16078454.2023.2241226

Front Endocrinol (Lausanne). 2023 Jul 20;14:1211426. doi: 10.3389/fendo.2023.1211426. eCollection 2023.

ABSTRACT

X-linked hypophosphatemia (XLH) is a rare, progressive, genetic disease with multisystem impact that typically begins to manifest in early childhood. Two treatment options exist: oral phosphate in combination with active vitamin D ("conventional therapy") and a fully human monoclonal anti-FGF23 antibody, burosumab. The clinical benefit of conventional therapy in adults is limited, and poor tolerance and complications are common. Burosumab was first approved as a treatment for XLH in 2018 and its disease-modifying benefits in clinical trials in children suggest burosumab treatment could also alter the disease course in adults. Without long-term clinical data on multiple XLH-related sequelae available, the results of an elicitation exercise are reported, in which eight global experts in XLH posited how long-term treatment with burosumab is anticipated to impact the life course of clinical sequelae in adults with XLH. Based on their clinical experiences, the available evidence and their disease understanding, the experts agreed that some long-term benefits of using burosumab are likely in adults with XLH even if they have a misaligned skeleton from childhood. Burosumab treatment is anticipated to reduce the incidence of fractures and halt the progression of clinical sequelae associated with conventional therapy. While the trajectories for established dental abscesses are not expected to improve with burosumab treatment, dental abscess development may be prevented. Starting treatment with burosumab in childhood to increase the likelihood of an aligned skeleton and continuation into and throughout adulthood to maintain euphosphatemia may optimize patient outcomes, although future real-world investigation is required to support this hypothesis.

PMID:37547321 | PMC:PMC10400326 | DOI:10.3389/fendo.2023.1211426

J Allergy Clin Immunol Pract. 2023 Aug 4:S2213-2198(23)00815-2. doi: 10.1016/j.jaip.2023.07.042. Online ahead of print.

ABSTRACT

BACKGROUND: Debates on the allocation of medical resources during the COVID-19 pandemic revealed the need for a better understanding of immunologic risk. Studies highlighted variable clinical outcomes of SARS-CoV-2 infections in individuals with defects in both adaptive and innate immunity, suggesting additional contributions from other factors. Notably, none of these studies controlled for variables linked with social determinants of health.

OBJECTIVE: To determine the contributions of determinants of health to risk of hospitalization for SARS-CoV-2 infection among individuals with inborn errors of immunodeficiencies.

METHODS: This is a retrospective, single-center cohort study of 166 individuals with inborn errors of immunity, aged two months through 69 years, who developed SARS-CoV-2 infections from March 1, 2020 through March 31, 2022. Risks of hospitalization was assessed using a multivariable logistic regression analysis.

RESULTS: The risk of SARS-CoV-2-related hospitalization was associated with underrepresented racial and ethnic populations (odds ratio [OR] 4.50; confidence interval [CI], 1.57 - 13.4), a diagnosis of any genetically-defined immunodeficiency (OR 3.32; CI, 1.24 - 9.43), obesity (OR 4.24; CI, 1.38 - 13.3), and neurologic disease (OR 4.47; CI, 1.44 - 14.3. COVID-19 vaccination was associated with reduced hospitalization risk (OR 0.52; CI, 0.31 - 0.81). Defects in T cell and innate immune function, immune-mediated organ dysfunction, and social vulnerability were not associated with increased risk of hospitalization after controlling for covariates.

CONCLUSIONS: The associations between race, ethnicity, and obesity with increased risk of hospitalization for SARS-CoV-2 infection indicate the importance of variables linked with social determinants of health as immunologic risk factors for individuals with inborn errors of immunity.

PMID:37544429 | DOI:10.1016/j.jaip.2023.07.042

Am J Hum Genet. 2023 Aug 3;110(8):1229-1248. doi: 10.1016/j.ajhg.2023.06.009.

ABSTRACT

Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. Newer tests, such as short-read genome or RNA sequencing, can be challenging to order, and emerging technologies, such as optical genome mapping and long-read DNA sequencing, are not available clinically. Furthermore, there is no clear guidance on the next best steps after inconclusive evaluation. Here, we review why a clinical genetic evaluation may be negative, discuss questions to be asked in this setting, and provide a framework for further investigation, including the advantages and disadvantages of new approaches that are nascent in the clinical sphere. We present a guide for the next best steps after inconclusive molecular testing based upon phenotype and prior evaluation, including when to consider referral to research consortia focused on elucidating the underlying cause of rare unsolved genetic disorders.

PMID:37541186 | DOI:10.1016/j.ajhg.2023.06.009

J Glob Health. 2023 Aug 4;13:04030. doi: 10.7189/jogh.13.04030.

ABSTRACT

BACKGROUND: Individuals with rare diseases (RD) have been historically understudied. Previous publications reported that existing primary health care (PHC) workforces and associated infrastructure had been shown to improve their access and health-related outcomes in low- and middle-income countries (LMICs). As current evidence about the impact of PHC on patients diagnosed with RD is yet highly dispersed, this scoping review aimed to collate available evidence of the impact of PHC on patients with RD and summarize published information from multiple stakeholders about the perceived usefulness and barriers to effective use of the PHC system.

METHODS: We searched Embase, Health System Evidence, PubMed, LILACS / BVS, and The Cochrane Library, from inception to September 1, 2022, for publications providing clear expert- or experience-based insights or data from patients living with RD at the PHC level of care. We included publications highlighting barriers to integrated care of patients with RD, reported by multiple social actors involved in caring for patients with RD. Two investigators screened publications, extracted data, and clustered information among records deemed eligible for inclusion. Data synthesis was performed using narrative and thematic-based analysis. Major findings identified and coded through a semantic-driven analysis were processed in vosViewer software and reported using descriptive statistics.

FINDINGS: Eighty publications were included in this review. Quali-quantitative analyses evidenced that the PHC level is essential for approaching patients with RD, mainly due to its longitudinal, multidisciplinary, and coordinated care delivery. In addition, several publications highlighted that the medical curriculum is inappropriate for preparing health care providers to deal with patients presenting unusual signs and symptoms and being diagnosed with RD. PHC teams are essential in orienting patients and families on emergency events. Technology-related concepts were reported in 19 publications, emphasizing their effectiveness on early diagnosis, optimal treatment definition, improvement of quality of life, and long-lasting follow-up.

CONCLUSIONS: We provided valuable information on the effectiveness of the PHC in fostering a creative, integrative, and supportive environment for patients living with RD. Our results can be helpful to several stakeholders in deciding what actions are still pending to achieve a solid and positive experience for patients with RD in the PHC.

REGISTRATION: PROSPERO (CRD42022332347).

PMID:37539555 | PMC:PMC10401310 | DOI:10.7189/jogh.13.04030

Orphanet J Rare Dis. 2023 Aug 3;18(1):229. doi: 10.1186/s13023-023-02845-9.

ABSTRACT

Drug development is a complex, resource intensive and long process in any disease area, and developing medicines to treat rare diseases presents even more challenges due to the small patient populations, often limited disease knowledge, heterogeneous clinical manifestations, and disease progression. However, common to all drug development programs is the need to gather as much information as possible on both the disease and the patients' needs ahead of the development path definition. Here, we propose a checklist named START, a tool that provides an overview of the key pillars to be considered when starting an orphan drug development: STakeholder mapping, Available information on the disease, Resources, and Target patient value profile. This tool helps to build solid foundations of a successful patient-centered medicines development program and guides different types of developers through a set of questions to ask for guidance through the starting phase of a rare disease therapeutic pathway.

PMID:37537670 | PMC:PMC10398909 | DOI:10.1186/s13023-023-02845-9

Seizure. 2023 Jul 30;111:56-57. doi: 10.1016/j.seizure.2023.07.023. Online ahead of print.

NO ABSTRACT

PMID:37536151 | DOI:10.1016/j.seizure.2023.07.023

Orphanet J Rare Dis. 2023 Aug 2;18(1):224. doi: 10.1186/s13023-023-02813-3.

ABSTRACT

Developing drugs for rare diseases is challenging, and the precision and objectivity of outcome measures is critical to this process. In recent years, a number of technologies have increasingly been used for remote monitoring of patient health. We report a systematic literature review that aims to summarize the current state of progress with regard to the use of digital outcome measures for real-life motor function assessment of patients with rare neurological diseases. Our search of published literature identified 3826 records, of which 139 were included across 27 different diseases. This review shows that use of digital outcome measures for motor function outside a clinical setting is feasible and employed in a broad range of diseases, although we found few outcome measures that have been robustly validated and adopted as endpoints in clinical trials. Future research should focus on validation of devices, variables, and algorithms to allow for regulatory qualification and widespread adoption.

PMID:37533072 | PMC:PMC10398976 | DOI:10.1186/s13023-023-02813-3

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2023 Aug 10;40(8):915-921. doi: 10.3760/cma.j.cn511374-20221017-00692.

ABSTRACT

ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020, a supplementary practical guidelines, is based on the Standards and Guidelines for the Interpretation of Sequence Variations issued by the American Society for Medical Genetics and Genomics (ACMG) and the Association of Molecular Pathology (AMP) in 2015 by the British Medical Genetics Society under the Clinical Genomics Society (ACGS), and has integrated the detailed rules of standards developed by the ClinGen Sequence Variant Interpretation (SVI) Working Group by 2020. The further development of the ACMG/AMP guidelines is currently undertaken by the ClinGen SVI working group in the United States, which focuses on the classification of high penetrance and protein coding variants. ClinGen has established many expert panels on variants for specific diseases which required various evidence thresholds and is currently developing disease/gene specific guidelines. The British Medical Genetics Society has collected and integrated information on the guidelines for sequence variation classification and their extended rules, forming its own "2020 ACGS Best Practice Guidelines for Rare Disease Variation Classification" and is regularly updating it. The author has translated and summarized it for the reference of Chinese Medical Genetics Practitioners.

PMID:37532488 | DOI:10.3760/cma.j.cn511374-20221017-00692

Recenti Prog Med. 2023 Sep;114(9):534-535. doi: 10.1701/4088.40801.

NO ABSTRACT

PMID:37530008 | DOI:10.1701/4088.40801

Recenti Prog Med. 2023 Sep;114(9):508-513. doi: 10.1701/4088.40789.

ABSTRACT

Miller-Fisher syndrome is a rare acquired nerve disease related to Guillain-Barré syndrome. Clinical features include asthenia, ocular muscle weakness with ophthalmoplegia, impaired limb coordination with instability, and absence of tendon reflexes. Swallowing disorders and rarely respiratory failure may be associated. The article aims to summarize, starting from the presentation of a clinical case, the latest updates which, in clinical practice, can be useful for a correct diagnosis and treatment of this condition which concerns both adult and pediatric patients.

PMID:37529996 | DOI:10.1701/4088.40789

Zhongguo Dang Dai Er Ke Za Zhi. 2023 Jul 15;25(7):759-766. doi: 10.7499/j.issn.1008-8830.2302048.

ABSTRACT

There are more than 7 000 rare diseases and approximately 475 million individuals with rare diseases globally, with children accounting for two-thirds of this population. Due to a relatively small patient population and limited financial resources allocated for drug research and development in pharmaceutical enterprises, there are still no drugs approved for the treatment of several thousands of these rare diseases. At present, there are no drugs for 95% of the patients with rare diseases, and consequently, the therapeutic drugs for rare diseases have been designated as orphan drugs. In order to guide pharmaceutical enterprises to strengthen the research and development of orphan drugs, various nations have enacted the acts for rare disease drugs, promoted and simplified the patent application process for orphan drugs, and provided scientific recommendations and guidance for the research and development of orphan drugs. Since there is a relatively high incidence rate of rare diseases in children, this article reviews the latest research on pharmacotherapy for children with rare diseases.

PMID:37529960 | DOI:10.7499/j.issn.1008-8830.2302048

Zhongguo Dang Dai Er Ke Za Zhi. 2023 Jul 15;25(7):663-671. doi: 10.7499/j.issn.1008-8830.2304036.

ABSTRACT

Rare diseases in children are characterized by low prevalence, complex pathogenesis, variety, and difficulty in the diagnosis and treatment. With the development of medical services, progress has been made in the diagnosis and treatment of rare diseases. However, due to asymmetric allocation of medical resources at different levels, there are still many shortcomings in the establishment and promotion of the homogenized management system of rare disease diagnosis and treatment. In order to further standardize the homogenized management of rare diseases in children, achieve early and accurate diagnosis and treatment, and improve the quality of life of the children, the Rare Disease Diagnosis and Treatment Center of Tianjin Children's Hospital (Tianjin University Children's Hospital) invited relevant experts in the field to develop recommendations for the management model of homogenized diagnosis and treatment of rare diseases in children from the aspects of information construction, hierarchical diagnosis and treatment, personnel training, scientific popularization, and multi-participation. The recommendations provide reference for the regional homogenization of clinical diagnosis and treatment management system for children with rare diseases.

PMID:37529946 | DOI:10.7499/j.issn.1008-8830.2304036

Hum Mol Genet. 2023 Aug 2:ddad124. doi: 10.1093/hmg/ddad124. Online ahead of print.

ABSTRACT

PPP1R3F (R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures, and other neurological findings including tone, gait, and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization, and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function.

PMID:37531237 | DOI:10.1093/hmg/ddad124

Clin Ther. 2023 Aug;45(8):710-718. doi: 10.1016/j.clinthera.2023.07.004. Epub 2023 Jul 29.

ABSTRACT

PURPOSE: Economic evaluations of health technologies traditionally aim to maximize population health outcomes measured by using quality-adjusted life-years (QALYs). Non-health outcomes, however, may have high social value, and their exclusion has the potential to bias decisions regarding allocation of health care resources. This research positions Australian participants as societal decision-makers to explore their willingness to trade-off health gains in adults for non-health benefits in families with a child affected by a rare disease.

METHODS: To estimate the social value of the different health care interventions, a person trade-off (PTO) method was used. PTOs present participants with groups of beneficiaries that vary in terms of the number of individuals who will benefit, the individuals' characteristics, their expected benefits, or a combination, and ask which group should be prioritized. Each trade-off presented health gains from the treatment of moderate physical and mental health conditions described by the 3-level version of the EuroQol 5-Dimension (EQ-5D-3L) health states. The health gains in these groups were traded-off against non-health gains in families accessing diagnostic genomic testing, and equivalence values were calculated, using median and ratio of means methods, based on the ratio of the group sizes at the point of equivalence. Participants were recruited through Prolific and were stratified according to age, sex, and education. The impact of participant characteristics on equivalence values was assessed using Kruskal-Wallis H tests and ordinary least-squares log-linear regressions.

FINDINGS: Participants (N = 434) positioned as societal decision-makers were generally willing to trade-off adult health gains with the familial non-health benefits of genomic testing, showing a preference for valuing both types of outcomes within public health policy. The aggregation of preferences generated 2 weightings for genomic testing against each health treatment, an unadjusted value and a reweighted value to match target demographic characteristics. Converted into QALY value per test, it was found that participants valued the non-health benefits of genomic testing between 0.730 and 0.756 QALY. A minority of participants always prioritized diagnostic genomic testing over the physical (6.0%) or mental (4.6%) health treatments, with a larger minority always prioritizing the physical (15.4%) or mental (14.8%) health treatments.

IMPLICATIONS: The findings indicate that participants perceived the non-health parental benefits in children experiencing rare disease to have comparable value to health gains in adults experiencing the moderate physical or mental health conditions described using EQ-5D-3L. These findings suggest that the benefits of genomic tests would be underestimated if only health benefits are included in economic evaluations.

PMID:37524571 | DOI:10.1016/j.clinthera.2023.07.004

Ital J Pediatr. 2023 Jul 29;49(1):94. doi: 10.1186/s13052-023-01502-y.

ABSTRACT

BACKGROUND: Primary adrenal insufficiency (PAI) in childhood is a life-threatening disease most commonly due to impaired steroidogenesis. Differently from adulthood, autoimmune adrenalitis is a rare condition amongst PAI's main aetiologies and could present as an isolated disorder or as a component of polyglandular syndromes, particularly type 2. As a matter of fact, autoimmune polyglandular syndrome (APS) type 2 consists of the association between autoimmune Addison's disease, type 1 diabetes mellitus and/or Hashimoto's disease.

CASE PRESENTATION: We report the case of an 8-year-old girl who presented Addison's disease and autoimmune thyroiditis at an early stage of life. The initial course of the disease was characterized by numerous crises of adrenal insufficiency, subsequently the treatment was adjusted in a tertiary hospital with improvement of disease control.

CONCLUSIONS: APS type 2 is a rare condition during childhood, probably because it may remain latent for long periods before resulting in the overt disease. We recommend an early detection of APS type 2 and an adequate treatment of adrenal insufficiency in a tertiary hospital. Moreover, we underline the importance of a regular follow-up in patients with autoimmune diseases, since unrevealed and incomplete forms are frequent, especially in childhood.

PMID:37516895 | DOI:10.1186/s13052-023-01502-y

Genes (Basel). 2023 Jul 21;14(7):1490. doi: 10.3390/genes14071490.

ABSTRACT

Whole-Exome Sequencing (WES) has proven valuable in the characterization of underlying genetic defects in most rare diseases (RDs). Copy Number Variants (CNVs) were initially thought to escape detection. Recent technological advances enabled CNV calling from WES data with the use of accurate and highly sensitive bioinformatic tools. Amongst 920 patients referred for WES, 454 unresolved cases were further analysed using the ExomeDepth algorithm. CNVs were called, evaluated and categorized according to ACMG/ClinGen recommendations. Causative CNVs were identified in 40 patients, increasing the diagnostic yield of WES from 50.7% (466/920) to 55% (506/920). Twenty-two CNVs were available for validation and were all confirmed; of these, five were novel. Implementation of the ExomeDepth tool promoted effective identification of phenotype-relevant and/or novel CNVs. Among the advantages of calling CNVs from WES data, characterization of complex genotypes comprising both CNVs and SNVs minimizes cost and time to final diagnosis, while allowing differentiation between true or false homozygosity, as well as compound heterozygosity of variants in AR genes. The use of a specific algorithm for calling CNVs from WES data enables ancillary detection of different types of causative genetic variants, making WES a critical first-tier diagnostic test for patients with RDs.

PMID:37510394 | PMC:PMC10379589 | DOI:10.3390/genes14071490

Genes (Basel). 2023 Jul 19;14(7):1469. doi: 10.3390/genes14071469.

ABSTRACT

Rare Genetic Disorders (RGDs) are defined as disorders that affect less than 1 in 2000 people, and collectively affect more than 300 million people worldwide [...].

PMID:37510373 | PMC:PMC10379732 | DOI:10.3390/genes14071469

Am J Obstet Gynecol. 2023 Jul 27:S0002-9378(23)00514-8. doi: 10.1016/j.ajog.2023.07.042. Online ahead of print.

ABSTRACT

Preterm birth (PTB) remains one of the most urgent unmet medical problems in obstetrics, yet only two therapeutics to prevent PTB have ever been approved by the U.S. Food and Drug Administration (FDA) and neither remain on the market. The recent withdrawal of 17-hydroxyprogesterone caproate (17-OHPC, Makena) marks a new, but familiar era for obstetrics with no FDA-approved pharmaceuticals to address PTB. The lack of pharmaceuticals reflects a broad and ineffective pipeline hindered by extensive regulatory hurdles, soaring costs to perform drug research, and concerns regarding adverse side effects among a particularly vulnerable population. The pharmaceutical industry has historically limited investments in research for diseases with similarly small markets, such as cystic fibrosis, given their rarity and diminished projected financial return. The Orphan Drug Act, however, incentivizes drug development for "orphan diseases", defined as affecting fewer than 200,000 people in the U.S. annually. Although the total number of PTB in the U.S. exceeds this threshold annually, the early subset of PTB (<34 weeks gestation) would qualify, which is predominantly caused by inflammation and infection. The scientific rationale for classifying PTB into an early and late subset is strong, as their etiologies differ and therapeutics that may be efficacious for one subset may not work for the other subset. For example, anti-inflammatory therapeutics would be expected to be highly effective for early, but not late, PTB. A robust therapeutic pipeline of anti-inflammatory drugs already exists, which could be used to target spontaneous early PTB, in combination with antibiotics shown to sterilize the amniotic cavity. New applications for therapeutics targeting spontaneous early PTB could categorize as orphan disease drugs, which could revitalize the PTB therapeutic pipeline. Here, we describe why drugs targeting early PTB should qualify for orphan status, which may increase pharmaceutical interest for this vitally important obstetrical condition.

PMID:37516401 | DOI:10.1016/j.ajog.2023.07.042