6727 hot topic(s) found with the query "Rare diseases"
Genomic Answers for Kids: Toward more equitable access to genomic testing for rare diseases in rural populations
(Posted: Apr 18, 2024 8AM)
From the abstract: "Next-generation sequencing has revolutionized the speed of rare disease (RD) diagnoses. While clinical exome and genome sequencing represent an effective tool for many RD diagnoses, there is room to further improve the diagnostic odyssey of many RD patients. One recognizable intervention lies in increasing equitable access to genomic testing. Rural communities represent a significant portion of underserved and underrepresented individuals facing additional barriers to diagnosis and treatment."
Lethal phenotypes in Mendelian disorder
P Cacheiro et al, GIM, April 15, 2024
(Posted: Apr 15, 2024 2PM)
From the abstract: "We queried Online Mendelian Inheritance in Man for terms related to lethality and classified all Mendelian genes according to the earliest age of death recorded for the associated disorders, from prenatal death to no reports of premature death. We characterised the genes across these lethality categories, examined the evidence on viability from mouse models and explored how this information could be used for novel gene discovery. "
Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease.
Gabrielle Lemire et al. Am J Hum Genet 2024 4
(Posted: Apr 09, 2024 8AM)
From the abstract: "Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing The addition of CNV detection to exome analysis identified causal CNVs for 171 families (2.6%). "
Consensus reporting guidelines to address gaps in descriptions of ultra-rare genetic conditions.
Ali AlMail et al. NPJ Genom Med 2024 4 (1) 27
(Posted: Apr 08, 2024 9AM)
From the abstract: "Genome-wide sequencing and genetic matchmaker services are propelling a new era of genotype-driven ascertainment of novel genetic conditions. The degree to which reported phenotype data in discovery-focused studies address informational priorities for clinicians and families is unclear. We identified reports published from 2017 to 2021 in 10 genetics journals of novel Mendelian disorders. We adjudicated the quality and detail of the phenotype data via 46 questions pertaining to six priority domains. "
mRNA drug offers hope for treating a devastating childhood disease.
Elie Dolgin et al. Nature 2024 4
(Posted: Apr 04, 2024 9AM)
From the article: " Propionic acidemia is a rare genetic disorder, which affects about one in 100,000 individuals worldwide, arises from mutations in either of two genes that together encode an enzyme necessary for the efficient breakdown of certain protein components. Without this enzyme, cells can’t process some nutrients properly. Results from a small trial of mRNA-3927 indicate that the restoration of enzymatic activity is beneficial. Eight of the 16 participants had experienced life-threatening episodes connected to their impaired metabolism in the year before starting treatment. For those eight, the likelihood of experiencing another such event decreased by an average of 70–80% while taking the therapy. "
Advancing access to genome sequencing for rare genetic disorders: recent progress and call to action.
Vaidehi Jobanputra et al. NPJ Genom Med 2024 3 (1) 23
(Posted: Apr 01, 2024 9AM)
From the article: "GS has ushered in a new era in the diagnosis of genetic diseases, offering the potential for improved patient care. Now is the time for collective action to overcome challenges, implement best practices, and ensure that the benefits of GS are realized for all individuals affected by genetic diseases. Indeed, widespread and appropriate utilization of GS is critical for directing the emerging gene editing, gene therapy, and cell-based therapies for rare genetic disorders. Concerted policy, education, guideline, and care pathway efforts will drive significant advancements in precision medicine and improve health outcomes for patients with genetic conditions. "
Determining priority indicators of utility for genomic testing in rare disease: a Delphi study
Z Fehlberg et al, Genetics in Medicine, March 6, 2024
(Posted: Mar 07, 2024 8AM)
From the abstract: "This study obtained expert consensus on different utility indicators that are considered a priority in determining the value of genomic testing in rare disease. Twenty indicators reached consensus as a priority in value assessment, including those relating to prognostic information, timeliness of results, practical and health care outcomes, clinical accreditation, and diagnostic yield. Indicators may inform a standardized approach to evidence generation and assessment to guide future research, decision-making, and implementation efforts. "
Improving access to exome sequencing in a medically underserved population through the Texome Project
B Vucuolo et al, Genetics in Medicine, February 29, 2024
(Posted: Mar 03, 2024 10AM)
From the abstract: "The Texome Project is a 4-year study that reduces barriers to genomic testing for individuals from underserved and underrepresented populations. Participants with undiagnosed, rare diseases who have financial barriers to obtaining exome sequencing (ES) clinically are enrolled in the Texome Project. We highlight the Texome Project process and describe the outcomes of the first 60 ES results for study participants. Participants received a genetic evaluation, ES, and return of results at no cost. We summarize the psychosocial or medical implications of these genetic diagnoses. "
Exome and genome sequencing in a heterogeneous population of patients with rare disease: Identifying predictors of a diagnosis
J Pucel et al, Genetics in Medicine, March 1, 2024
(Posted: Mar 01, 2024 0PM)
From the abstract: "In this case control study, we reviewed data from 400 diagnosed and 400 undiagnosed randomly selected participants in the Undiagnosed Diseases Network (UDN), all of whom had undergone ES and/or GS. We analyzed factors associated with receiving a diagnosis by ES and/or GS.
Factors associated with a decreased odds of being diagnosed included adult symptom onset, singleton sequencing, and having undergone ES and/or GS prior to acceptance to the UDN (48%, 51%, and 32% lower odds, respectively). Factors that increased the odds of being diagnosed by ES and/or GS included having primarily neurological symptoms and having undergone prior chromosomal microarray testing. "
Overcoming barriers to equitable genomic healthcare
KM Girisha, EJHG, February 13, 2024
(Posted: Feb 13, 2024 9AM)
From the article: "We all recognize the pivotal role of next-generation sequencing in the diagnosis and discovery of rare diseases that are majorly genetic in origin. While limited access might be the result of economic constraints in the three-fourths of the global population, it might also be due to infrastructure (genetic testing laboratories) or trained manpower (genome analysts) in other situations. "
The cost of proband and trio exome and genome analysis in rare disease: a micro-costing study.
Dylan A Mordaunt et al. Genet Med 2024 1 101058
(Posted: Jan 03, 2024 8AM)
From the abstract: "Rare disease genomic testing is a complex process involving various resources. Accurate resource estimation is required for informed prioritization and reimbursement decisions. This study aims to analyze the costs and cost drivers of clinical genomic testing. The most expensive cost component of genomic testing was sequencing (36.9% - 69.4% of total cost), with labor accounting for 27.1% - 63.2% of total cost. "
A medical multimodal large language model for future pandemics
Liu et al, NPJ Digital Medicine, December 2, 2023
(Posted: Dec 02, 2023 8AM)
From the paper: "With the goal of quick deployment of tools for rapid response to rare diseases, we present the medical multimodal large language model (Med-MLLM) framework. We evaluate the effectiveness of Med-MLLM using the COVID-19 pandemic “in replay”, showing that Med-MLLM is able to accomplish accurate COVID-19 decision-support tasks with limited labelled data. In contrast, existing efforts usually require thousands, or even more, labelled data to achieve similar performance. "
Public Health Genetics, Gene Therapy, and Duchenne Muscular Dystrophy
CDC Webinar, December 18, 2023
(Posted: Nov 27, 2023 10AM)
From the website: "This webinar will review the population health impact of rare diseases such as DMD. Presenters will cover the genetics and clinical impact of DMD, the evolution of gene therapy, the development of FDA-approved gene therapy to treat the underlying protein deficiency that causes DMD, and the health equity challenges. "
Evaluation of the diagnostic accuracy of exome sequencing and its impact on diagnostic thinking for rare disease patients in a publicly-funded healthcare system: a prospective cohort study
T Hartley et al, Genetics in Medicine, November 2023
(Posted: Nov 02, 2023 9AM)
From the abstract: "The purpose of this is study it to evaluate the diagnostic utility of publicly-funded clinical exome sequencing (ES) for patients with suspected rare genetic diseases (RGDs). We prospectively enrolled 297 probands who met eligibility criteria and received ES across five sites. We demonstrate robustness in eligibility criteria and high clinical validity of laboratory results from ES testing. The importance of ES was highlighted by the potential 40% of patients that would have gone undiagnosed without this test."
Mobile element insertions in rare diseases: a comparative benchmark and reanalysis of 60,000 exome samples
R Wyngaard et al, EJHG, October 19, 2023
(Posted: Oct 19, 2023 2PM)
From the abstract: "Mobile element insertions (MEIs) are a known cause of genetic disease but have been underexplored due to technical limitations of genetic testing methods. Various bioinformatic tools have been developed to identify MEIs in Next Generation Sequencing data. However, most tools have been developed specifically for genome sequencing (GS) data rather than exome sequencing (ES) data, which remains more widely used for routine diagnostic testing. "
A feasible molecular diagnostic strategy for rare genetic disorders within resource-constrained environments
MM Mudau et al, J Comm Genetics, October 10, 2023
(Posted: Oct 10, 2023 1PM)
From the abstract: " Next-generation sequencing (NGS) has transformed testing approaches for many Mendelian disorders, but this technology is still relatively new in our setting and requires cost-effective ways to implement. As a proof of concept, we describe a feasible diagnostic strategy for genetic disorders frequently seen in our genetics clinics (RASopathies, Cornelia de Lange syndrome, Treacher Collins syndrome, and CHARGE syndrome). The custom-designed targeted NGS gene panel enabled concurrent variant screening for these disorders. Samples were batched during sequencing and analyzed selectively based on the clinical phenotype. The strategy employed in the current study was cost-effective, with sequencing and analysis done at USD849.68 per sample and achieving an overall detection rate of 54.5%"
Gene therapies for rare diseases are under threat. Scientists hope to save them- As industry steps aside, scientists seek innovative ways to make sure expensive treatments can reach people who need them.
H Ledford, Nature, October 6, 2023
(Posted: Oct 06, 2023 7AM)
From the article: "In the past two years, two gene therapies have been withdrawn from the European market for business reasons after earning regulators’ approval. Concern is mounting that other gene therapies for rare diseases will meet a similar fate, as might upcoming treatments that rely on the related technique of genome editing, which makes targeted DNA changes. "
Genome Sequencing for Newborn Screening—An Effective Approach for Tackling Rare Diseases
S Jiang et al. JAMA Network Open, September 2023
(Posted: Sep 05, 2023 1PM)
From the paper: "Newborn screening is a crucial global public health initiative, with a primary aim to identify congenital disorders that could lead to significant morbidity and mortality if left untreated. However, the scope of traditional newborn screening methods is limited, detecting only a finite number of conditions. With the advent of next-generation genome sequencing technologies, gene panel sequencing as a first-tier newborn screening test is a promising strategy, potentially enabling comprehensive and accurate diagnosis of a broad spectrum of genetic conditions at birth."
Realising the potential of gene therapies for rare and ultra-rare inherited diseases.
Claire Booth et al. Hum Gene Ther 2023 8
(Posted: Aug 30, 2023 9AM)
From the abstract: "Rare and ultra-rare diseases have been central to the field of gene therapy since its earliest stage, and we are now witnessing more and more effective treatments entering the clinical realm for patients in need. However, despite promising results across a range of rare diseases, transformative gene therapies may not be available and accessible to patients for non-medical reasons. Traditional regulatory and commercialisation pathways to licensed products seem to be prohibitive for ultra-small patient populations. Here we highlight some of the challenges of delivering gene therapies in rare diseases and discuss innovative solutions being proposed by the gene therapy community."
From target discovery to clinical drug development with human genetics.
Katerina Trajanoska et al. Nature 2023 8 (7975) 737-745
(Posted: Aug 28, 2023 9AM)
From the abstract: "We identified 40 germline genetic observations that led directly to new targets and subsequently to novel approved therapies for 36 rare and 4 common conditions. The median time between genetic target discovery and drug approval was 25 years. Most of the genetically driven therapies for rare diseases compensate for disease-causing loss-of-function mutations. The therapies approved for common conditions are all inhibitors designed to pharmacologically mimic the natural, disease-protective effects of rare loss-of-function variants."
A Test of Automated Use of Electronic Health Records to Aid in Diagnosis of Genetic Disease
T Cassini et al, Genetics in Medicine, August 22, 2023
(Posted: Aug 22, 2023 9AM)
Automated use of electronic health records may aid in decreasing the diagnostic delay for rare diseases. The phenotype risk score (PheRS) is a weighted aggregate of syndromically related phenotypes that measures the similarity between an individual’s conditions and features of a disease. For some diseases, there are individuals without a diagnosis of that disease who have scores similar to diagnosed patients. These individuals may have that disease but not yet be diagnosed.
PhenoScore quantifies phenotypic variation for rare genetic diseases by combining facial analysis with other clinical features using a machine-learning framework.
Alexander J M Dingemans et al. Nat Genet 2023 8
(Posted: Aug 08, 2023 8PM)
We developed PhenoScore: an open-source, artificial intelligence-based phenomics framework, combining facial recognition technology with Human Phenotype Ontology data analysis to quantify phenotypic similarity. Here we show PhenoScore’s ability to recognize distinct phenotypic entities by establishing recognizable phenotypes for 37 of 40 investigated syndromes against clinical features observed in individuals with other neurodevelopmental disorders and show it is an improvement on existing approaches.
Exome and genome sequencing for rare genetic disease diagnosis: A scoping review and critical appraisal of clinical guidance documents produced by genetics professional organizations
T Hartley et al, GIM, Augiut 5, 2023
(Posted: Aug 07, 2023 9AM)
Exome and genome sequencing have rapidly transitioned from research methods to widely used clinical tests for diagnosing rare genetic diseases. We sought to synthesize the topics covered and appraise the development processes of clinical guidance documents generated by genetics professional organizations.
Guidance documents included a broad range of recommendations, but were of low quality, particularly in their rigour of development.
A Revolution Is Coming to Medicine. Who Will It Leave Out?
J Tabery, NY Times, August 5, 2023
(Posted: Aug 07, 2023 9AM)
There are some diseases for which genetics is truly saving lives; in particular, patients with rare diseases like spinal muscular atrophy and certain cancers such as chronic myelogenous leukemia may now be prescribed personalized medicine treatments that simply didn’t exist a couple of decades ago. For most patients with most diseases, though, the lofty promises have failed to materialize.
Genomic testing for rare disease diagnosis—where are we now, and where should we be heading? The reflections of a behavioural scientist
C Lewis, EJHG, August 1, 2023
(Posted: Aug 01, 2023 9AM)
Much work has been done by behavioral scientists over recent years to understand patients’ and parents’ motivations for undergoing genomic testing. Findings highlight patients’ and parents’ desire: for a diagnosis to access treatments, for access to clinical trials and/or disease-specific screening; to receive a clear prognosis and information about recurrence risk; to understand the etiology of the condition and receive a reason “why” it occurred; to gain relief from guilt, for example, that it was not caused by something the mother did during her pregnancy (a concern I frequently come across); to gain legitimacy for the patient’s behavior and/or appearance; and to enable them the opportunity to connect with others through support groups and social media.
Too many treatable diseases go unnoticed. This could change that.
B Venkataraman, Washington Post, July 26, 2023
(Posted: Jul 27, 2023 7AM)
Hundreds of treatable genetic diseases go unnoticed for years — not because they cannot be diagnosed, but because newborn screening for them is not routine in the United States. If biomedical breakthroughs are to benefit the millions of children afflicted with rare diseases, genetic testing of babies needs to expand. This is an urgent problem for families now, but its solution could also pave the way for a future in which doctors can treat many more rare, intractable diseases. By screening newborn genomes for currently known genetic diseases, patients and scientists could gain insights that lead to the treatment and prevention of thousands of illnesses that currently lack cures.
Genomic newborn screening: current concerns and challenges.
The Lancet et al. Lancet 2023 7 (10398) 265
(Posted: Jul 23, 2023 9AM)
The development of genomic sequencing technologies now offers an unprecedented opportunity to expand screening programs. More than 4000 genes have been associated with recognizable monogenic diseases affecting an estimated 400–700 million people worldwide. In the US, health-care costs and utilisation of services by patients with these rare diseases accounted for an estimated US$768 billion in inpatient costs alone in 2016. Why then do we not screen the whole genome of all newborns, given the wealth of information and potential benefits it could provide?
Genomic newborn screening for rare diseases.
Zornitza Stark et al. Nat Rev Genet 2023 6
(Posted: Jun 30, 2023 10AM)
Incorporating genomic sequencing into newborn screening programs at the population scale holds the promise of substantially expanding the early detection of treatable rare diseases, with stored genomic data potentially benefitting health over a lifetime and supporting further research. As several large-scale newborn genomic screening projects launch internationally, we review the challenges and opportunities presented, particularly the need to generate evidence of benefit and to address the ethical, legal and psychosocial issues that genomic newborn screening raises.
Disease screening for newborns varies by state. For some, that means diagnoses come too late.
A Bendix, NBC News, June 16, 2023
(Posted: Jun 23, 2023 9AM)
Many parents have experienced the horror of learning that their children have rare diseases for which earlier intervention might have made a difference, say screening babies for more conditions could save lives. The Department of Health and Human Services recommends that newborns get screened for 37 disorders, including cystic fibrosis and Pompe disease, as well as 26 other related disorders. Krabbe disease isn’t on the list.
What matters to parents? A scoping review of parents’ service experiences and needs regarding genetic testing for rare diseases
E Crellin et al, EJHG, June 12, 2023
(Posted: Jun 12, 2023 9AM)
To understand parents’ service experiences and needs regarding testing of their child for rare diseases, we conducted a scoping review. Five databases were searched (2000–2022), with 29 studies meeting the inclusion criteria. Parents especially valued and emphasised the importance of feeling ‘cared for’, continuous relationships with clinicians, empathic communication, being kept informed while awaiting genetic test results, linkage with informational and psychosocial resources following results disclosure, and follow-up.
Integrated multi-omics for rapid rare disease diagnosis on a national scale.
Sebastian Lunke et al. Nat Med 2023 6
(Posted: Jun 09, 2023 8AM)
Critically ill infants and children with rare diseases need equitable access to rapid and accurate diagnosis to direct clinical management. Over 2 years, the Acute Care Genomics program provided whole-genome sequencing to 290 families whose critically ill infants and children were admitted to hospitals throughout Australia with suspected genetic conditions. The average time to result was 2.9?d and diagnostic yield was 47%.
We Screen Newborns Don’t We? Progress in DNA-based Population Screening
Video presentations, CDC and Precision Public Health Network webinar, May 18, 2023
(Posted: Jun 06, 2023 8AM)
As part of 2023 Public Health Genetics and Genomics week, presenters in this webinar review the concept of population genomic screening for rare diseases beyond the newborn period, share research progress made in the last decade, and discuss the path forward to prepare the medical and public health communities for population-based genomic screening.
The complex genomics of single gene disorders
A McNeill, EJHG, June 5, 2023
(Posted: Jun 05, 2023 8AM)
Meta-analysis of the diagnostic and clinical utility of exome and genome sequencing in pediatric and adult patients with rare diseases across diverse populations
C Ching et al, Genetics in Medicine, May 13, 2023
(Posted: May 14, 2023 9AM)
This meta-analysis aims to compare the diagnostic and clinical utility of whole-exome sequencing (WES) versus whole-genome sequencing (WGS) in pediatric and adult patients with rare diseases across diverse populations. One-hundred-and-sixty-one studies across 31 countries/regions were eligible, featuring 50,417 probands of diverse populations. Diagnostic rates of WES (0.38, 95% CI 0.36-0.40) and WGS (0.34, 95% CI 0.30-0.38) were similar.
Rare-disease researchers pioneer a unique approach to clinical trials.
Mike May et al. Nat Med 2023 5
(Posted: May 10, 2023 6AM)
In the development of new treatments for rare diseases, a crucial challenge lies in the name: rare. Despite their being rare, there are many of these diseases, with more than 7,000 diseases that each affect fewer than 200,000 Americans, according to the US Food and Drug Administration (FDA). Researchers are continually trying to develop safe and effective new treatments for thousands of rare diseases, but it is difficult. Some of the most promising approaches lie in modified clinical trials and making use of real-world data.
Rare disease gene mining.
Kyle Vogan et al. Nat Genet 2023 4 (4) 524
(Posted: Apr 17, 2023 11AM)
Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland.
Caroline F Wright et al. N Engl J Med 2023 4
(Posted: Apr 13, 2023 6AM)
A total of 13,449 probands were included in the analyses. On average, we reported 1.0 candidate variant per parent–offspring trio and 2.5 variants per singleton proband. With the use of clinical and computational approaches to variant classification, a diagnosis was made in approximately 41% of probands (5502 of 13,449), of whom 76% had a pathogenic de novo variant.
Why genetic testing should always be offered to children with neurodevelopmental differences
D Ondrasick, Stat News, April 10., 2023
(Posted: Apr 11, 2023 0PM)
As a board-certified pediatrician and the mother of a child with a rare disease, I believe the medical system is failing the rare disease community by vastly underdiagnosing genetic disorders. Most families are offered either no genetic testing at all or only limited panels that cannot find most genetic mutations. Given the benefits I have seen for my family and my patients, I urge the AAP to develop new guidelines that are aligned with the 2021 American College of Medical Genetics and Genomics practice guidelines. These recommend whole exome/genome sequencing as a first or second-tier test for pediatric patients with congenital anomalies, developmental delay, or intellectual disability.
Newborn genome screening in the USA: early steps on a challenging path
B Furlough, Lancet Child & Adol Health, , April 2023
(Posted: Mar 22, 2023 7AM)
As of March, 2023, the Genomic Uniform-screening Against Rare Diseases In All Newborns (GUARDIAN) study at Columbia University and New York-Presbyterian hospitals in New York, NY, USA, has enrolled more than 1000 of a planned 100?000 babies who will undergo whole-genome sequencing over the next 4 years to detect gene variants associated with 158 rare diseases. It will be the largest US study to date of genome sequencing at birth to detect rare genetic diseases.
Individualized Interventions for Rare Genetic Conditions and the Research-Treatment Spectrum: Stakeholder Perspectives
SSJ Lee et al, Genetics in Medicine, March 22, 2023
(Posted: Mar 22, 2023 7AM)
Advances in the study of ultra-rare genetic conditions are leading to the development of targeted interventions developed for single or very small numbers of patients. Due to the experimental but also highly individualized nature of these interventions, they are difficult to classify cleanly as either research or clinical care.
As a hybrid set of activities, individualized interventions suggest the need for flexibility and new frameworks that acknowledge these activities across the spectrum of research and clinical care.
Genetic association analysis of 77,539 genomes reveals rare disease etiologies.
Daniel Greene et al. Nature medicine 2023 3
(Posted: Mar 18, 2023 7PM)
We provide evidence that (1) loss-of-function variants in the Erythroblast Transformation Specific (ETS)-family transcription factor encoding gene ERG lead to primary lymphoedema, (2) truncating variants in the last exon of transforming growth factor-ß regulator PMEPA1 result in Loeys–Dietz syndrome and (3) loss-of-function variants in GPR156 give rise to recessive congenital hearing impairment. The Rareservoir provides a lightweight, flexible and portable system for synthesizing the genetic and phenotypic data required to study rare disease cohorts with tens of thousands of participants.
Discovering the genetic etiologies of rare diseases in large patient collections.
et al. Nature medicine 2023 3
(Posted: Mar 18, 2023 3PM)
We developed a compact database, called a ‘Rareservoir’, that contains the rare variant genotypes and phenotypes of 34,523 patients with a rare disease and 43,016 unaffected relatives. We inferred 260 genetic associations with rare disease classes, of which 19 were previously unidentified, and validated etiological roles for ERG, PMEPA1 and GPR156.
Individualized ASO therapy for rare diseases
Q's and A's with AA Rus, comm Medicine, February 28, 2023
(Posted: Feb 28, 2023 7AM)
What are the most exciting advances pushing the boundaries of rare disease therapeutics? The development of individualized exon skipping therapies. This is pioneering work as it has not been done in Europe and was done only for a few cases in the USA. The work is done in a very collaborative fashion, where we share successes and failures, and produce processes and procedures to streamline all efforts, as part of the N1C. The challenges of developing individualized therapy are many, as the regular drug development path is not fit for purpose for N?=?1 or N?=?few trials (i.e. the majority of rare diseases). Additionally, not only the therapy itself is individualized, but other aspects of the development are individualized, including outcome measures to test safety and efficacy.
Diagnostics for rare diseases
Q's and A's with S Kingsmore, Comm Medicine, February 28, 2023
(Posted: Feb 28, 2023 7AM)
What are the best approaches currently for diagnosis of rare diseases? Whole genome sequencing is, in the immortal words of JRR Tolkein, the “One ring to rule them all, one ring to find them, One ring to bring them all”. By decoding the entire genome it’s possible to examine it for variants responsible for almost all 7300 genetic diseases (and often to rule them out as causes of a child’s illness).
Rare Disease Day 2023
US Genomics Education Program, February 28, 2023
(Posted: Feb 28, 2023 6AM)
Today is Rare Disease Day, a global campaign that shines a spotlight on rare disease and on the patients, families and carers worldwide whose lives are affected by rare conditions. This Rare Disease Day, the GEP will officially launch its online course. The course takes learners on a journey that begins with the reality of living with a rare disease, then moves on to the practicalities of identifying and testing for rare conditions, before returning to patient stories and examining the wider implications that results may have for families.
Orphan Drugs in Neurology—A Narrative Review
CA Sirbu et al, J per Med, February 20, 2023
(Posted: Feb 26, 2023 9AM)
Orphan diseases, or rare diseases, are defined in Europe as diseases that affect less than 5 out of every 10,000 citizens. Given the small number of cases and the lack of profit potential, pharmaceutical companies have not invested much in the development of possible treatments. However, over the last few years, new therapies for rare diseases have emerged, giving physicians a chance to offer personalized treatment. With this paper, we aim to present some of the orphan neurological diseases for which new drugs have been developed lately.
Access to gene therapy for rare diseases when commercialization is not fit for purpose.
Thomas Fox et al. Nature medicine 2023 2
(Posted: Feb 15, 2023 7AM)
Despite promising preclinical and clinical efficacy data, hematopoietic stem-cell gene therapies for inherited diseases have not been widely adopted into clinical practice. Ultra-rare diseases such as inborn errors of metabolism and inborn errors of immunity are, as their names suggest, individually rare diseases, affecting <1 in 50,000 people. However, such diseases have a profound impact on the lives of many individuals because of reduced life expectancy or chronic progressive morbidity.
Comparing 2D and 3D representations for face-based genetic syndrome diagnosis
JJ Banisterr et al, EJHG, February 7, 2023
(Posted: Feb 07, 2023 8AM)
An automatic facial landmarking for children with rare diseases.
Quentin Hennocq et al. American journal of medical genetics. Part A 2023 1
(Posted: Jan 31, 2023 8AM)
Here, we developed a method for building an automatic landmarking pipeline for frontal and lateral facial photographs as well as photographs of external ears. We evaluated the algorithm on patients diagnosed with Treacher Collins (TC) syndrome as it is the most frequent mandibulofacial dysostosis in humans and is clinically recognizable although highly variable in severity.
As it turns 40, the Orphan Drug Act for rare diseases needs a refresh
ED Kakkis, Stat News, January 30, 2023
(Posted: Jan 30, 2023 6AM)
his month marks the 40th anniversary of the Orphan Drug Act. Since it was signed into law in 1983, the FDA has approved more than 1,100 treatments for rare diseases. The act also created an industry that didn’t exist in the United States before its enactment, enabling the formation of companies to develop and commercialize therapies for rare diseases.
We Screen Newborns Don’t We? Progress in DNA-based Population Screening
CDC Public Health Genomics Webinar, May 18, 2023,
(Posted: Jan 28, 2023 11AM)
As part of 2023 Public Health Genetics and Genomics week, we review in this webinar the concept of population genomic screening for rare diseases beyond the newborn period, share research progress made in the last decade, and discuss the path forward to prepare the medical and public health communities for population-based genomic screening.
Public meeting: FDA Rare Disease Day 2023
FDA, January 2023
(Posted: Jan 24, 2023 8AM)
FDA will host Rare Disease Day, a virtual public meeting, on February 27, 2023, 9:00 am – 4:45 pm ET, in global observance of Rare Disease Week. This year’s theme is “Intersections with Rare Diseases – A patient focused event."
Rare Disease Day at NIH 2023
NIH, December 2022
(Posted: Dec 30, 2022 1PM)
Rare Disease Day takes place worldwide, typically on or near the last day of February each year, to raise awareness among policymakers and the public about rare diseases and their impact on patients’ lives. Since 2011, NCATS and the NIH Clinical Center have sponsored Rare Disease Day at NIH as part of this global observance. Rare Disease Day at NIH aims to raise awareness about rare diseases, the people they affect, and NIH collaborations that address scientific challenges and advance research for new treatments.
In a first, children with rare genetic diseases get mitochondrial transplants from their mothers
M Molteni, Stat News, December 21, 2022
(Posted: Dec 22, 2022 0PM)
Mitochondrial deletion disorders, known as SLSMDs, usually manifest during the second decade of a child’s life as progressive, multisystem failures including hearing and vision loss, muscle weakness, gastrointestinal and cardiac issues, dementia, and early death. Currently, no cure exists. But in the last seven years, a group of researchers has been working on a potential treatment that takes advantage of mitochondria’s enduring capacity to slip between cellular life forms. It involves augmenting patients’ hematopoietic stem cells with healthy mitochondria donated by their mothers.
They Created a Drug for Susannah. What About Millions of Other Patients?
EC Hayden et al, NY Times, December 19, 2022
(Posted: Dec 19, 2022 11AM)
Scientists have made rapid progress in customizing drugs for ultrarare diseases. The hard part now is making such treatments on a large scale. Susannah was the first person to receive a drug designed to treat KIF1A-associated neurological disorder, or KAND, a progressive disease caused by genetic mutations that affect just 400 people in the world. In doing so, the young girl and her parents have found themselves on the edge of personalized medicine.
Rare disease therapeutics: The future of medical genetics in a changing landscape
CD Connolly et al, Genetics in Medicine, December 7, 2022
(Posted: Dec 07, 2022 9AM)
Many therapeutic modalities are currently being investigated as potential avenues to provide disease-modifying treatments for patients affected by genetic disorders. Some of these modalities include small molecule, enzyme replacement, gene, messenger RNA, and gene editing therapies. Although it is impossible to determine how many therapeutics will become available for patients affected by genetic disorders, historical data on the probability of orphan drug approval by the FDA and the current gene therapy trials noted above provide an estimate of the number of gene therapies that may become FDA-approved therapies.
Genome sequencing with gene panel-based analysis for rare inherited conditions in a publicly funded healthcare system: implications for future testing
LJ Hocking et al, EJHG, December 6, 2022
(Posted: Dec 06, 2022 0PM)
We sought to investigate the Genomics England 100,000 Genomes Project diagnostic utility to evaluate genome sequencing for in rare, inherited conditions. Four regional services recruited 999 individuals from 394 families in 200 rare phenotype categories, with negative historic genetic testing. New diagnoses were made in 23% cases – 19% in genes implicated in disease at the time of variant prioritisation, and 4% from later review of additional genes.
The Disease Took Zara, Then Sara. Could Ayla Be Saved?
G Kolata, NY Times, November 9, 2022
(Posted: Nov 10, 2022 6AM)
For the first time, doctors have successfully treated a fetus by infusing a crucial enzyme into its minuscule umbilical cord, halting an otherwise fatal inherited disorder known as severe infantile Pompe disease. The baby, Ayla Bashir, now 16 months old, is developing normally, giggling and babbling and toddling in her home in Ottawa.
Co-design, implementation, and evaluation of plain language genomic test reports
GR Brett et al, NPJ Genomic Medicine, October 22, 2022
(Posted: Oct 22, 2022 0PM)
Through co-design involving patient groups, plain language experts, educators, and genetic health professionals, plain language genomic test report templates were produced for common test outcomes in rare diseases. Eight plain language genomic test report templates were developed. These reports were piloted and evaluated as part of a national pediatric ultra-rapid genomic testing program. Family and genetic health professional experiences with report layout, content, and use were explored using surveys.
Correspondence on “Cost-effectiveness of exome and genome sequencing for children with rare and undiagnosed conditions”
SD Grosse et al, Genetics in Medicine, September 21, 2022
(Posted: Sep 22, 2022 6AM)
The relative cost-effectiveness of rES and rGS should be informed by up-to-date evidence on costs and diagnostic performance and reflect specific clinical settings, meeting the needs of decision-makers in those settings. Published economic evaluations of GS should distinguish between the price and cost (value of resources used) of sequencing and suggested that the use of microcosting data could improve the accuracy of cost-effectiveness analyses from either the societal or health care perspectives.
From Guthrie to Genomes: The Continued Evolution of Newborn Screening
A Gaviglio et al, CDC Blog Post, August 15, 2022
(Posted: Aug 15, 2022 7PM)
Two recent articles discuss the future of newborn screening and identified considerations and needs for the evolution of the newborn screening system as it tries to meet the growing demands to screen for more rare diseases and incorporate genomic technologies. As newborn screening (NBS) moves past 60 years of existence, there is great interest in how this successful public health program will continue to progress. Our understanding of the over 7000 known rare diseases has grown and the potential for use of genomic technologies at the population level has become more feasible leading to a heightened call for a newborn screening evolution.
Enhanced rare disease mapping for phenome-wide genetic association in the UK Biobank.
Patrick Matthew T et al. Genome medicine 2022 8 (1) 85
(Posted: Aug 11, 2022 7AM)
Using our mapping approach, we identified and characterized 420 rare diseases affecting 23,575 individuals in the UK Biobank. Significant genetic associations included JAK2 V617F for immune thrombocytopenic purpura (p?=?1.24?×?10-13) and a novel CALR loss of function variant for essential thrombocythemia (p?=?1.59?×?10-13). We constructed an interactive resource highlighting demographic information and demonstrate transferability by applying our mapping to a medical claims database.
Exome sequencing—one test to rule them all?
A McNeill, EJHG, July 22, 2022
(Posted: Jul 22, 2022 8AM)
Advances in genomic testing have vastly improved clinicians’ ability to identify a molecular genetic cause for both common and rare diseases. But could such testing replace more conventional diagnostic modalities entirely? Exome sequencing is a valuable diagnostic tool—but it does have limitations in the types of variant it can detect. A classic limitation of exome sequencing is limited coverage of deep intronic variants.
The Progress and Future of US Newborn Screening
MS Watson et al, IJNS, July 20, 2022
(Posted: Jul 21, 2022 7AM)
Progress in newborn screening (NBS) has been driven for 60 years by developments in science and technology, growing consumer advocacy, the actions of providers involved in the care of rare disease patients, and by federal and State government funding and policies. With the current explosion of clinical trials of treatments for rare diseases, the pressure for expansion has grown, and concerns about the capacity for improvement and growth are being expressed. Genome and exome sequencing (GS/ES) have now opened more opportunities for early identification and disease prevention at all points in the lifespan.
Convergence and Divergence of Rare Genetic Disorders on Brain Phenotypes: A Review.
Raznahan Armin et al. JAMA psychiatry 2022 6
(Posted: Jul 01, 2022 8AM)
Rare genetic disorders modulating gene expression—as exemplified by gene dosage disorders (GDDs)—represent a collectively common set of high-risk factors for neuropsychiatric illness. Research on GDDs is rapidly expanding because these variants have high effect sizes and a known genetic basis. Moreover, the prevalence of recurrent GDDs (encompassing aneuploidies and certain copy number variations) enables genetic-first phenotypic characterization of the same GDD across multiple individuals, thereby offering a unique window into genetic influences on the human brain and behavior.
Recommendations for whole genome sequencing in diagnostics for rare diseases
E Souche et al, EJHG, May 16, 2022
(Posted: May 16, 2022 8AM)
EuroGentest is a European initiative, aiming to promoting accurate, reliable and high-quality genetic diagnostics across Europe. The aim of these recommendations is primarily to list the points to consider for clinical (laboratory) geneticists, bioinformaticians, and (non-)geneticists, to provide technical advice, aid clinical decision-making and the reporting of the results.
Towards Achieving Equity and Innovation in Newborn Screening across Europe
J Sikonja et al, IJNS,May 2022
(Posted: May 08, 2022 1PM)
Although individual rare disorders are uncommon, it is estimated that, together, 6000+ known rare diseases affect more than 30 million people in Europe, and present a substantial public health burden. Together with the psychosocial burden on affected families, rare disorders frequently, if untreated, result in a low quality of life, disability and even premature death. Newborn screening (NBS) has the potential to detect a number of rare conditions in asymptomatic children, providing the possibility of early treatment and a significantly improved long-term outcome. Despite these clear benefits, the availability and conduct of NBS programs varies considerably across Europe and, with the increasing potential of genomic testing, it is likely that these differences may become even more pronounced.
The complexity of diagnosing rare disease: An organizing framework for outcomes research and health economics based on real-world evidence.
Hayeems Robin Z et al. Genetics in medicine : official journal of the American College of Medical Genetics 2021 12 (3) 694-702
(Posted: Apr 22, 2022 0PM)
Clinical implementation of RNA sequencing for Mendelian disease diagnostics
VA Yepez et al, Genome Medicine, April 5, 2022
(Posted: Apr 06, 2022 10AM)
Lack of functional evidence hampers variant interpretation, leaving a large proportion of individuals with a suspected Mendelian disorder without genetic diagnosis after whole genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects. We implemented an automated RNA-seq protocol and a computational workflow with which we analyzed skin fibroblasts of 303 individuals with a suspected mitochondrial disease that previously underwent WES.
From Guthrie to Genomes: Expanding Bioinformatic Capabilities in Newborn Screening Programs
A Gaviglio et al, CDC Blog Post, March 21, 2022
(Posted: Mar 22, 2022 7AM)
It has been over 50 years since Dr. Robert Guthrie developed the first test that led to population-based newborn screening in the United States. Since that time, testing has become more complex and dozens of diseases have been added to newborn screening panels across the country. In addition, new treatments such as gene-targeted therapies for many rare diseases are expanding the need for newborn screening so that affected babies can have access to these important new treatments as soon as possible.
Genomic answers for children: Dynamic analyses of >1000 pediatric rare disease genomes
ASA Cohen et al, Genetics in Medicine, March 16, 2022
(Posted: Mar 16, 2022 8AM)
This study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program. Diagnostic rates ranged from 11% in patients with prior negative genetic testing to 34.5% in naive patients. Incorporating SVs from genome sequencing added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs compared with srGS. Variants and genes of unknown significance remain the most common finding (58% of nondiagnostic cases).
Rare diseases, common challenges
Editorial, Nature Genetics, March 14, 2022
(Posted: Mar 15, 2022 7AM)
The genetics community has a particularly important part to play in accelerating rare disease research and contributing to improving diagnosis and treatment. Innovations in sequencing technology and machine learning approaches have positively affected diagnostic success, but more coordinated efforts are needed to move towards effective therapies or even cures for these important, and sometimes overlooked, class of diseases.
Why Do Some People Never Get Covid?
DJ Lamas, NY Times, March 8, 2022
(Posted: Mar 09, 2022 3PM)
The host response to infectious agents has not nearly gotten the attention from genetics that rare diseases, common chronic diseases and cancer have. The knowledge gained here, the understanding of both susceptibility and severity, has opened my eyes to how much more genetics can teach us about infectious disease biology. If there was ever a time to move a field forward through worldwide collaboration and tens of thousands of people willing to offer their genetic information to help spur research, this is it. Just as a Covid vaccine was developed on a time scale many felt impossible, so, too, might genetic research into disease be advancing in huge bounds that in normal times might seem implausible.
Participant experiences of genome sequencing for rare diseases in the 100,000 Genomes Project: a mixed methods study
M Peter et al, EJHG, March 9, 2022
(Posted: Mar 09, 2022 9AM)
Both survey and interview findings indicated that decision regret was low. DRS scores revealed no differences in levels of regret between parents and patients, or between those with a diagnosis and those without. Though MICRA scores indicated minimal evidence of negative psychological impacts of receiving GS results, subscale analysis revealed greater distress and uncertainty for parents compared to patients. Receiving a diagnosis was found not to influence MICRA scores, supporting interview findings of both positive and negative emotional and psychological impacts irrespective of a genetic diagnosis. Our findings have implications for policy and practice as GS is integrated into the UK and worldwide; notably, that expectation-setting is critical when offering GS, and that post-test counselling is important
A call for an integrated approach to improve efficiency, equity and sustainability in rare disease research in the United States
MC Halley et al, Nature Genetics, March 7, 2022
(Posted: Mar 08, 2022 8AM)
The cumulative burden of rare diseases is immense, with the over 7,000 identified rare diseases together affecting an estimated 25–30 million Americans1. Most have serious impacts on individuals’ physical and/or cognitive functioning, and many are life-threatening or fatal. To build a more efficient, equitable and sustainable approach to rare disease research in the United States, we must prioritize integrated research infrastructure and approaches that focus on understanding connections across rare diseases.
Good genotype-phenotype relationships in rare disease are hard to find
A McNeill, EJHG, March 4, 2022
(Posted: Mar 04, 2022 8AM)
Time to make rare disease diagnosis accessible to all
HL Rehm, Nature Medicine, February 7, 2022
(Posted: Feb 07, 2022 0PM)
Studies have demonstrated the value of genomic analysis for the diagnosis of rare diseases, but accessibility is still in its infancy; global data sharing is needed to further advance our knowledge of all causes of rare disease.
Man whose genetic condition went undiagnosed for 36 years is awarded £2.5m.
Thornton Jacqui et al. BMJ (Clinical research ed.) 2022 1 o238
(Posted: Jan 29, 2022 11AM)
A man with a rare, progressive, genetic condition who was only diagnosed aged 36 once his sister was found to have a milder form of the disease has been awarded £2.5m in a High Court settlement. The brother, who cannot be identified, was finally diagnosed with the disorder methylmalonic acidemia type CblA after his sister fought as an adult for a diagnosis herself and then paid for private tests which showed he had the same condition. If spotted early enough, the metabolic condition can be treated with a lifetime regime of intramuscular vitamin B12 injections, which can avoid the development of clinical symptoms
Researchers shatter the speed record for diagnosing rare genetic diseases with DNA sequencing
J Wozen, StatNews, January 12, 2022
(Posted: Jan 13, 2022 8AM)
Rare Genetic Diseases: Genomics is ending diagnostic odysseys for patients with rare diseases.
NHGRI, 2022
(Posted: Jan 07, 2022 6AM)
Did you know that there are truly rare people born all the time? Around 350 million people on earth are living with rare disorders - this is a disorder or condition with fewer than 200,000 people diagnosed. About 80 percent of these rare disorders are genetic in origin, and 95 percent of them do not have even one treatment approved by the FDA.
Genomics elucidates both common and rare disease aetiology
A McNeil, EJHG, November 26, 2021
(Posted: Nov 28, 2021 10AM)
We close the year with a range of interesting and informative papers. Birth defects (congenital anomalies) affect many thousands of neonates every year; yet the aetiology of many of them remains unresolved. A new paper reviews what is known about the genomic basis of congenital diaphragmatic hernia (CDH). Around 10% of cases of CDH are associated with a copy number variant. Implicated pathways include NRF2 and vitamin A homeostasis. In contrast to common malformations, the genetic basis of rare disease continues to be elucidated with more and more causal genes identified annually
New Clinical Trial Grants for Rare Diseases
R Rubin, JAMA, November 23, 2021
(Posted: Nov 27, 2021 10AM)
A painful, potentially life-threatening skin disease, an inherited disease that can cause long-term brain development issues, and pediatric brain cancer are among the rare diseases for which the US Food and Drug Administration has awarded 11 new clinical trial research grants. Many of the studies involve children, some as young as newborns. One trial is evaluating the treatment of recessive dystrophic epidermolysis bullosa, the inherited skin disorder that can lead to painful, life-threatening blisters and wounds. Another study is evaluating early treatment of tuberous sclerosis complex before the onset of seizures in infants.
Changing the Course of an Orphan Disease.
Schmidinger Manuela et al. The New England journal of medicine 2021 11 (22) 2090-2091
(Posted: Nov 25, 2021 9AM)
Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.
Jonasch Eric et al. The New England journal of medicine 2021 11 (22) 2036-2046
(Posted: Nov 25, 2021 9AM)
A rare autosomal dominant hereditary disorder, von Hippel–Lindau (VHL) disease is caused by germline pathogenic variants in the VHL gene. VHL disease occurs in approximately 1 in every 27,300 to 39,000 live births. The condition is associated with benign and malignant neoplasms. Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non–renal cell carcinoma neoplasms associated with VHL disease.
100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.
et al. The New England journal of medicine 2021 11 (20) 1868-1880
(Posted: Nov 11, 2021 0PM)
This pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing.
Bespoke Gene Therapy Consortium
NIH, October 2021
(Posted: Oct 27, 2021 0PM)
The AMP Bespoke Gene Therapy Consortium (BGTC) aims to develop platforms and standards that will speed the development and delivery of customized or ‘bespoke’ gene therapies that could treat the millions of people affected by rare diseases.
NIH, FDA and 15 private organizations join forces to increase effective gene therapies for rare diseases
NIH press release, October 27, 2021
(Posted: Oct 27, 2021 0PM)
The National Institutes of Health, U.S. Food and Drug Administration, 10 pharmaceutical companies and five non-profit organizations have partnered to accelerate development of gene therapies for the 30 million Americans who suffer from a rare disease. While there are approximately 7,000 rare diseases, only two heritable diseases currently have FDA-approved gene therapies.
Artificial intelligence enables comprehensive genome interpretation and nomination of candidate diagnoses for rare genetic diseases.
De La Vega Francisco M et al. Genome medicine 2021 10 (1) 153
(Posted: Oct 15, 2021 6AM)
Clinical interpretation of genetic variants in the context of the patient's phenotype is becoming the largest component of cost and time expenditure for genome-based diagnosis of rare genetic diseases. Artificial intelligence (AI) holds promise to greatly simplify and speed genome interpretation by integrating predictive methods with the growing knowledge of genetic disease. Here we assess the diagnostic performance of Fabric GEM, a new, AI-based, clinical decision support tool for expediting genome interpretation.
Application of full-genome analysis to diagnose rare monogenic disorders
AT Shieh et al, NPJ Genomic Medicine, September 23, 2021
(Posted: Sep 24, 2021 6AM)
We built a variant prioritization pipeline and tested FGA’s utility for diagnosis of rare diseases in a clinical setting. FGA identified structural variants and small variants with an overall diagnostic yield of 40% (20 of 50 cases) and 35% in exome-negative cases (8 of 23 cases), 4 of these were structural variants. FGA detected and mapped structural variants that are missed by short reads, including non-coding duplication, and phased variants across long distances of more than 180?kb. With the prioritization algorithm, longer DNA technologies could replace multiple tests for monogenic disorders and expand the range of variants detected.
Muscular Dystrophy
CDC, 2021
(Posted: Sep 15, 2021 9AM)
Muscular dystrophies are a group of genetic disorders that result in muscle weakness over time. Each type of muscular dystrophy is different from the others. It is important to get help as early as possible. Muscular dystrophy has no cure, but acting early may help an individual with muscular dystrophy get the services and treatments he or she needs to lead a full life.
Myotonic Dystrophy at a Glance
Myotonic Dystrophy Foundation, September 15,2021
(Posted: Sep 15, 2021 9AM)
Myotonic dystrophy is a rare, multi-systemic, inherited disease that affects an estimated 1 in 2,100 people, or over 3.6 million individuals across the world. International Myotonic Dystrophy Awareness Day aims to garner the attention of the wider general public, policy makers, regulators, biopharmaceutical representatives, researchers, health care professionals, and anyone with an interest in changing the future of myotonic dystrophy.
Finding a genomic cause: The clinician's role
Genomics Education Program, UK, 2021
(Posted: Sep 06, 2021 6AM)
It’s vital that you provide as much detailed information about the phenotype as possible – even if you’re not sure whether it’s relevant. Even a small omission of relevant information could alter the filtering process and mean the variant of interest is filtered out during one of the filtering stages outlined above. In addition, the handful of variants left for the clinical scientists to analyze at the end of the machine filtering process may be interpreted differently in light of the phenotypic information provided, so it’s vital that it is detailed and precise.
Evaluating the performance of a clinical genome sequencing program for diagnosis of rare genetic disease, seen through the lens of craniosynostosis
Z Hyder et al, Genet Med, August 25, 2021
(Posted: Aug 26, 2021 7AM)
Genome sequencing (GS) for diagnosis of rare genetic disease is being introduced into the clinic, but the complexity of the data poses challenges for developing pipelines with high diagnostic sensitivity. We evaluated the performance of the Genomics England 100,000 Genomes Project (100kGP) panel-based pipelines, using craniosynostosis as a test disease. GS identified likely pathogenic/pathogenic variants in 29.8% of previously undiagnosed patients with craniosynostosis.
Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study
R Savariyan et al GIM, August 2, 2021
(Posted: Aug 03, 2021 2PM)
Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls.
Darras Basil T et al. The New England journal of medicine 2021 7 (5) 427-435
(Posted: Jul 29, 2021 8AM)
In this study involving infants with type 1 SMA, risdiplam resulted in higher percentages of infants who met motor milestones and who showed improvements in motor function than the percentages observed in historical cohorts. Longer and larger trials are required to determine the long-term safety and efficacy of risdiplam in infants with type 1 SMA.
Opportunities and pitfalls of social media research in rare genetic diseases: a systematic review.
Miller Emily G et al. Genetics in medicine : official journal of the American College of Medical Genetics 2021 7
(Posted: Jul 21, 2021 8AM)
Most studies were observational (n = 114, 95.0%) and cross-sectional (n = 107, 89.2%), and more than half (n = 69, 57.5%) utilized only surveys. Only 101 rare diseases were included across all studies. Participant demographics, when reported, were predominantly female (70.1% ± 22.5%) and white (85.0% ± 11.0%) adult patients and caregivers. Despite its potential benefits in rare disease research, the use of social media is still methodologically limited and the participants reached may not be representative of the rare disease population by gender, race, age, or rare disease type.
Establishing a second-generation artificial intelligence-based system for improving diagnosis, treatment, and monitoring of patients with rare diseases
N Hurvitz et al, EJHG, July 19, 2021
(Posted: Jul 19, 2021 8AM)
Patients with rare diseases are a major challenge for healthcare systems. These patients face three major obstacles: late diagnosis and misdiagnosis, lack of proper response to therapies, and absence of valid monitoring tools. We reviewed the relevant literature on first-generation artificial intelligence (AI) algorithms which were designed to improve the management of chronic diseases. The shortage of big data resources and the inability to provide patients with clinical value limit the use of these AI platforms by patients and physicians.
Effective variant filtering and expected candidate variant yield in studies of rare human disease
BS Pedersen et al, NPJ Genomic Medicine, July 15, 2021
(Posted: Jul 16, 2021 7AM)
In studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance.
Rare Diseases Registry Program (RaDaR)
NIH, July 2021
(Posted: Jul 15, 2021 11AM)
There Is Power in Numbers. Each person’s story matters. Registries turn each patient’s experience into quality data that can lead to new discoveries and research advances. RaDaR provides step-by-step guidance and tools for building registries based on good data practices.
Increased risk for dementia in neurofibromatosis type 1
RA Kalionpaa et al, Genetics in Medicine, July 13, 2021
(Posted: Jul 14, 2021 7AM)
Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons
TS Pearson et al, Nat Comms, July 12, 2021
(Posted: Jul 12, 2021 11AM)
Aromatic L-amino acid decarboxylase deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency.
