Epilepsy Behav. 2022 Oct 7;136:108927. doi: 10.1016/j.yebeh.2022.108927. Online ahead of print.

ABSTRACT

Rare epilepsy centers, also called reference centers in France, have the mission to coordinate care for rare diseases, improve knowledge, and conduct research on rare diseases. Dissemination of knowledge is conducted in collaboration with patient associations. In just a few years, the Internet and social media have become the main source for news and knowledge. We conducted a survey about the use of social media and the expectations of patient associations from a rare epilepsy center. From the 29 associations on our website, 18 (62%) answered the survey, representing about 9000 members. All of the patient associations use social media. Facebook is used by all of them, and most of them also used additional social media channels. 13/18 (72%) associations found that it was easy to get in touch with our center and almost all partner associations were satisfied with the information published on our website (17/18, 94%). Eight patient associations (8/15, 53%) expected more information from us regarding scientific news (10/13) and clinical trials (8/13). Despite the existence of an active website and a monthly newsletter, the family associations interacting with our rare epilepsy center still want to collaborate even more with us. The use of social media by the rare epilepsy centers might help to fill the gap of the knowledge dissemination.

PMID:36215829 | DOI:10.1016/j.yebeh.2022.108927

J Transl Med. 2022 Oct 8;20(1):458. doi: 10.1186/s12967-022-03671-6.

ABSTRACT

BACKGROUND: The low number of patients suffering from any given rare diseases poses a difficult problem for medical research: With the exception of some specialized biobanks and disease registries, potential study participants' information are disjoint and distributed over many medical institutions. Whenever some of those facilities are in close proximity, a significant overlap of patients can reasonably be expected, further complicating statistical study feasibility assessments and data gathering. Due to the sensitive nature of medical records and identifying data, data transfer and joint computations are often forbidden by law or associated with prohibitive amounts of effort. To alleviate this problem and to support rare disease research, we developed the Mainzelliste Secure EpiLinker (MainSEL) record linkage framework, a secure Multi-Party Computation based application using trusted-third-party-less cryptographic protocols to perform privacy-preserving record linkage with high security guarantees. In this work, we extend MainSEL to allow the record linkage based calculation of the number of common patients between institutions. This allows privacy-preserving statistical feasibility estimations for further analyses and data consolidation. Additionally, we created easy to deploy software packages using microservice containerization and continuous deployment/continuous integration. We performed tests with medical researchers using MainSEL in real-world medical IT environments, using synthetic patient data.

RESULTS: We show that MainSEL achieves practical runtimes, performing 10 000 comparisons in approximately 5 minutes. Our approach proved to be feasible in a wide range of network settings and use cases. The "lessons learned" from the real-world testing show the need to explicitly support and document the usage and deployment for both analysis pipeline integration and researcher driven ad-hoc analysis use cases, thus clarifying the wide applicability of our software. MainSEL is freely available under: https://github.com/medicalinformatics/MainSEL CONCLUSIONS: MainSEL performs well in real-world settings and is a useful tool not only for rare disease research, but medical research in general. It achieves practical runtimes, improved security guarantees compared to existing solutions, and is simple to deploy in strict clinical IT environments. Based on the "lessons learned" from the real-word testing, we hope to enable a wide range of medical researchers to meet their needs and requirements using modern privacy-preserving technologies.

PMID:36209221 | PMC:PMC9547637 | DOI:10.1186/s12967-022-03671-6

Orphanet J Rare Dis. 2022 Oct 8;17(1):372. doi: 10.1186/s13023-022-02520-5.

ABSTRACT

BACKGROUND: Phase I of the Korean Undiagnosed Diseases Program (KUDP), performed for 3 years, has been completed. The Phase I program aimed to solve the problem of undiagnosed patients throughout the country and develop infrastructure, including a data management system and functional core laboratory, for long-term translational research. Herein, we share the clinical experiences of the Phase I program and introduce the activities of the functional core laboratory and data management system.

RESULTS: During the program (2018-2020), 458 patients were enrolled and classified into 3 groups according to the following criteria: (I) those with a specific clinical assessment which can be verified by direct testing (32 patients); (II) those with a disease group with genetic and phenotypic heterogeneity (353 patients); and (III) those with atypical presentations or diseases unknown to date (73 patients). All patients underwent individualized diagnostic processes based on the decision of an expert consortium. Confirmative diagnoses were obtained for 242 patients (52.8%). The diagnostic yield was different for each group: 81.3% for Group I, 53.3% for Group II, and 38.4% for Group III. Diagnoses were made by next-generation sequencing for 204 patients (84.3%) and other genetic testing for 35 patients (14.5%). Three patients (1.2%) were diagnosed with nongenetic disorders. The KUDP functional core laboratory, with a group of experts, organized a streamlined research pipeline covering various resources, including animal models, stem cells, structural modeling and metabolic and biochemical approaches. Regular data review was performed to screen for candidate genes among undiagnosed patients, and six different genes were identified for functional research. We also developed a web-based database system that supports clinical cohort management and provides a matchmaker exchange protocol based on a matchbox, likely to reinforce the nationwide clinical network and further international collaboration.

CONCLUSIONS: The KUDP evaluated the unmet needs of undiagnosed patients and established infrastructure for a data-sharing system and future functional research. The advancement of the KUDP may lead to sustainable bench-to-bedside research in Korea and contribute to ongoing international collaboration.

PMID:36209187 | PMC:PMC9548182 | DOI:10.1186/s13023-022-02520-5

Orphanet J Rare Dis. 2022 Oct 8;17(1):371. doi: 10.1186/s13023-022-02534-z.

ABSTRACT

OBJECTIVE: Rare diseases are life-threatening, debilitating, or serious chronic conditions that affect < 50/100,000 people. Canadians can only access approximately 60% of drugs for rare diseases (DRDs), which is partially related to high per-patient costs and payers' affordability concerns. However, limiting access to DRDs can reduce survival and quality of life among patients and caregivers. Therefore, we projected Canadian non-oncology DRD spending relative to total public drug spending to provide perspective for decision makers.

METHODS: Candidate historical (2010-2020) and pipeline (2021-2025) Canadian-marketed non-oncology DRDs were identified using definitions from the European Medicines Agency and the US Food and Drug Administration databases. Inclusion and exclusion criteria were applied to identify eligible DRDs. Public payer claims data, prevalence rates, regulatory, and health technology assessment factors were used to project DRD spending in relation to total Canadian public drug spending.

RESULTS: We included 42 historical DRDs and 122 pipeline DRDs. Public spending on DRDs grew from $14.8 million in 2010 (11 DRDs) to $380.9 million in 2020, then a projected $527.6 million in 2021 (59 potential DRDs) and $1.6 billion in 2025 (164 potential DRDs). Projected DRD spending increased from 3.2% of $16.5 billion public drug spending in 2021 to 8.3% of $19.4 billion in 2025. These projections do not include confidential manufacturer discounts, health outcome-related offsets, or additional safety-related costs.

CONCLUSIONS: Projected DRD spending shows robust growth but remains a fraction of total public drug spending. Limiting DRD access because of this growth is not aligned with Canadian patient or societal values. Given the renewed interest in a Canadian DRD framework, our results may help guide discussions that aim to balance control of public drug spending with the well-being of patients with rare diseases.

PMID:36209128 | PMC:PMC9548177 | DOI:10.1186/s13023-022-02534-z

Orphanet J Rare Dis. 2022 Oct 8;17(1):373. doi: 10.1186/s13023-022-02524-1.

ABSTRACT

BACKGROUND: Rare diseases impose a heavy economic burden on patients' families and society worldwide. This study used the samples from Sichuan Province in China to estimate the curative care expenditure (CCE) of ten rare diseases, for supporting the prioritization of rare disease health policies.

METHODS: Multi-stage cluster sampling method was adopted to investigate 9714 rare disease patients from 1556 medical institutions in Sichuan Province. Based on the System of Health Accounts 2011, this study estimated the total CCE of 10 rare diseases, financing schemes, and their allocation among different medical institutions and groups of people.

RESULTS: In 2018, the total CCE of the ten rare diseases was $19.00 million, the three costliest rare diseases were Hemophilia ($4.38 million), Young-onset Parkinson's disease ($2.96 million), and Systemic Sclerosis ($2.45 million). Household out-of-pocket expenditure (86.00% for outpatients, 41.60% for inpatients) and social health insurance (7.85% for outpatients; 39.58% for inpatients) were the main sources of financing CCE. The out-of-pocket expenditures for patients with Young-onset Parkinson's disease, Congenital Scoliosis, and Autoimmune Encephalitis accounted for more than 60% of the total CCE. More than 80% of the rare disease CCE was incurred in general hospitals. The 40-59 age group accounted for the highest CCE (38.70%) while men spent slightly more (55.37%) than women (44.64%).

CONCLUSIONS: As rare disease treatment is costly and household out-of-pocket expenditure is high, we suggest taking steps to include rare disease drugs in the National Reimbursement Drug List and scientifically re-design insurance coverage. It is also necessary to explore a multi-tiered healthcare security system to pay for the CCE of rare diseases and reduce the economic burden on patients.

PMID:36209113 | PMC:PMC9548194 | DOI:10.1186/s13023-022-02524-1

Vnitr Lek. 2022 Summer;68(E-2):11-21.

ABSTRACT

Langerhans cell histiocytosis (LCH) is a rare condition with incidence in adults 1-2/1 million, wherein Langerhans cells proliferate abnormally, adversely impacting organs including most frequently bones, skin, lungs, pituitary gland, lymph nodes, gums and other organs. The LCH course varies widely among patients from a self-limiting condition, to one that progresses. But LCH only very rarely culminates in death. To aim of this text is to review all possible symptoms and manifestations of this disease.

PMID:36208940

Nat Commun. 2022 Oct 7;13(1):5918. doi: 10.1038/s41467-022-33642-w.

ABSTRACT

Replication errors and various genotoxins cause DNA double-strand breaks (DSBs) where error-prone repair creates genomic mutations, most frequently focal deletions, and defective repair may lead to neurodegeneration. Despite its pathophysiological importance, the extent to which faulty DSB repair alters the genome, and the mechanisms by which mutations arise, have not been systematically examined reflecting ineffective methods. Here, we develop PhaseDel, a computational method to detect focal deletions and characterize underlying mechanisms in single-cell whole genome sequences (scWGS). We analyzed high-coverage scWGS of 107 single neurons from 18 neurotypical individuals of various ages, and found that somatic deletions increased with age and in highly expressed genes in human brain. Our analysis of 50 single neurons from DNA repair-deficient diseases with progressive neurodegeneration (Cockayne syndrome, Xeroderma pigmentosum, and Ataxia telangiectasia) reveals elevated somatic deletions compared to age-matched controls. Distinctive mechanistic signatures and transcriptional associations suggest roles for somatic deletions in neurodegeneration.

PMID:36207339 | DOI:10.1038/s41467-022-33642-w

J Invest Surg. 2022 Nov-Dec;35(11-12):1836-1840. doi: 10.1080/08941939.2022.2130481. Epub 2022 Oct 6.

ABSTRACT

INTRODUCTION: Splenic abscess secondary to endocarditis is a rare complication with high mortality. The treatment modality, splenectomy versus percutaneous drainage, and the best time, before or after valve replacement, are controversial. In the literature, there are only a few small case series about the subject. The objective of this study is to analyze the experience of a referral center in treating such condition.

METHODS: Patients with splenic abscesses due to endocarditis from 2006 to 2020 were retrospectively analyzed.

RESULTS: Thirteen patients (mean age 46 years old, 69% male) were identified. Eight patients (62%) had at least 2 comorbidities and 5 (38%) had a history of cardiac surgery. The diagnosis was incidental in 6 (46%). The mean time of abscess diagnosis after endocarditis definition was 14 days. Six patients (46%) had at least two organ dysfunctions. The median APACHE II score was 12 overall, and 24.5 in patients who died. Six patients (46%) had a valve replacement, and in two the abscess was diagnosed postoperatively. Of the other four patients, splenectomy was performed before the cardiac operation in three and at the same time in one. Splenectomy was performed immediately in 9 (69%) patients while three patients had percutaneous drainage (23%), one of which underwent splenectomy due to drainage failure. Exclusive antibiotic treatment was performed on only one patient. The median length of hospitalization was 24 days and mortality was 46%.

CONCLUSION: Splenic abscess due to endocarditis is a life-threatening condition with controversial treatment that results in a prolonged length of stay and high mortality.

PMID:36202396 | DOI:10.1080/08941939.2022.2130481

J Eur Acad Dermatol Venereol. 2022 Oct 4. doi: 10.1111/jdv.18637. Online ahead of print.

ABSTRACT

BACKGROUND: Epidermolysis bullosa (EB) is a rare genetic disorder manifesting with skin and mucosal membrane blistering in different degrees of severity.

OBJECTIVE: Epidemiological data from different countries have been published, but none are available from Germany.

METHODS: In this population-based cross-sectional study, people living with EB in Germany were identified using the following sources: academic hospitals, diagnostic laboratories, and patient organization.

RESULTS: Our study indicates an overall EB incidence of 45 per million live births in Germany. With 14.23 per million live births for junctional EB, the incidence is higher than in other countries, possibly reflecting the availability of early molecular genetic diagnostics in severely affected neonates. Dystrophic EB was assessed at 15.58 cases per million live births. The relatively low incidence found for EB simplex, 14.93 per million live births, could be explained by late or missed diagnosis, but also by 33% of cases remaining not otherwise specified. Using log-linear models, we estimated a prevalence of 54 per million for all EB types, 2.44 for junctional EB, 12.16 for dystrophic EB, and 28.44 per million for EB simplex. These figures are comparable to previously reported data from other countries.

CONCLUSIONS: Altogether, there are at least 2000 patients with EB in the German population. These results should support national policies and pharmaceutical companies in decision making, allow more precise planning of drug development and clinical trials, and aid patient advocacy groups in their effort to improve quality of life of people with this orphan disease.

PMID:36196047 | DOI:10.1111/jdv.18637

Br J Dermatol. 2022 Oct;187(4):453-454. doi: 10.1111/bjd.21686.

NO ABSTRACT

PMID:36192346 | DOI:10.1111/bjd.21686

Neurology. 2022 Oct 4;99(14):e1511-e1526. doi: 10.1212/WNL.0000000000200927. Epub 2022 Jul 18.

ABSTRACT

BACKGROUND AND OBJECTIVES: ATP1A3 is associated with a broad spectrum of predominantly neurologic disorders, which continues to expand beyond the initially defined phenotypes of alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome. This phenotypic variability makes it challenging to assess the pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurologic disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process.

METHODS: Undiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders study with additional cases contributed by collaborators internationally. Detailed clinical data were collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term "ATP1A3" from 2004 to 2021.

RESULTS: Twenty-four individuals with a previously undiagnosed neurologic phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2-3 different types of paroxysmal events. Permanent neurologic features were common including microcephaly (7; 29%), ataxia (13; 54%), dystonia (10; 42%), and hypotonia (7; 29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied, and most individuals did not fit clinical criteria for previously published phenotypes. On review of the literature, 1,108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study. Combined Annotation-Dependent Depletion (CADD) scores of pathogenic and likely pathogenic variants were significantly higher and variants clustered within 6 regions of constraint.

DISCUSSION: Our study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment and evaluating the CADD score and variant location can help identify an ATP1A3-related condition, rather than applying diagnostic criteria alone.

PMID:36192182 | DOI:10.1212/WNL.0000000000200927

Genome Med. 2022 Sep 30;14(1):113. doi: 10.1186/s13073-022-01113-y.

ABSTRACT

BACKGROUND: In medical genetics, discovery and characterization of disease trait contributory genes and alleles depends on genetic reasoning, study design, and patient ascertainment; we suggest a segmental haploid genetics approach to enhance gene discovery and molecular diagnostics.

METHODS: We constructed a genome-wide map for nonallelic homologous recombination (NAHR)-mediated recurrent genomic deletions and used this map to estimate population frequencies of NAHR deletions based on large-scale population cohorts and region-specific studies. We calculated recessive disease carrier burden using high-quality pathogenic or likely pathogenic variants from ClinVar and gnomAD. We developed a NIRD (NAHR deletion Impact to Recessive Disease) score for recessive disorders by quantifying the contribution of NAHR deletion to the overall allele load that enumerated all pairwise combinations of disease-causing alleles; we used a Punnett square approach based on an assumption of random mating. Literature mining was conducted to identify all reported patients with defects in a gene with a high NIRD score; meta-analysis was performed on these patients to estimate the representation of NAHR deletions in recessive traits from contemporary human genomics studies. Retrospective analyses of extant clinical exome sequencing (cES) were performed for novel rare recessive disease trait gene and allele discovery from individuals with NAHR deletions.

RESULTS: We present novel genomic insights regarding the genome-wide impact of NAHR recurrent segmental variants on recessive disease burden; we demonstrate the utility of NAHR recurrent deletions to enhance discovery in the challenging context of autosomal recessive (AR) traits and biallelic variation. Computational results demonstrate new mutations mediated by NAHR, involving recurrent deletions at 30 genomic regions, likely drive recessive disease burden for over 74% of loci within these segmental deletions or at least 2% of loci genome-wide. Meta-analyses on 170 literature-reported patients implicate that NAHR deletions are depleted from the ascertained pool of AR trait alleles. Exome reanalysis of personal genomes from subjects harboring recurrent deletions uncovered new disease-contributing variants in genes including COX10, ERCC6, PRRT2, and OTUD7A.

CONCLUSIONS: Our results demonstrate that genomic sequencing of personal genomes with NAHR deletions could dramatically improve allele and gene discovery and enhance clinical molecular diagnosis. Moreover, results suggest NAHR events could potentially enable human haploid genetic screens as an approach to experimental inquiry into disease biology.

PMID:36180924 | PMC:PMC9526336 | DOI:10.1186/s13073-022-01113-y

Orphanet J Rare Dis. 2022 Sep 29;17(1):366. doi: 10.1186/s13023-022-02458-8.

ABSTRACT

BACKGROUND: Rare diseases are a new global health priority, requiring evidence-based estimates of the global prevalence of diseases to inform public policymakers and provide a serious challenge to the healthcare system that must not be ignored. The purpose of this study is to investigate Iranian future healthcare professionals' knowledge and opinions about rare diseases.

RESULTS: A total of 6838 students responded to the questionnaire. Nursing and medical students had the highest participation. Almost 85% of participants rated their knowledge about rare diseases as poor or insufficient. While nearly 70 percent of participants took courses about rare diseases at university. Finally, 72.7% of future healthcare professionals did not feel ready to take care of a patient with a rare disease.

CONCLUSION: The present study has indicated a gap in Iranian medical students' knowledge of rare diseases. The researchers believe that health science policymakers should make a joint effort to improve knowledge about rare diseases. Including courses with regard to rare diseases would be of benefit to future healthcare professionals.

PMID:36175905 | PMC:PMC9524105 | DOI:10.1186/s13023-022-02458-8

BMJ Case Rep. 2022 Sep 29;15(9):e249986. doi: 10.1136/bcr-2022-249986.

ABSTRACT

Incarceration of the gravid uterus (IGU) is a rare obstetric disorder that may lead to pregnancy-related complications. Acute urinary retention (AUR) is one of the associated symptoms in IGU and it is mostly observed in the first semester and early second trimester. A case of a woman, in her 30s, is described, who presented AUR and lower abdominal pain in the early second trimester. The diagnosis was confirmed upon pelvic examination, and abdominal and transvaginal ultrasound. Management included long-term bladder catheterisation, manual reduction manoeuvres and passive positioning manoeuvres at home. At 24 weeks of gestation, the uterus returned in its correct polarity, the Foley catheter was removed and the patient was able to void spontaneously. A healthy infant was delivered vaginally at term.No specific guidelines have been published for IGU treatment. However, prompt diagnosis and tight follow-up of these patients are essential to define strategies, reduce complications and prevent recurrences.

PMID:36175041 | DOI:10.1136/bcr-2022-249986

World J Surg Oncol. 2022 Sep 28;20(1):317. doi: 10.1186/s12957-022-02784-y.

ABSTRACT

BACKGROUND: Desmoid-type fibromatosis (DTF) is a rare benign lesion that usually arises from the abdominal wall or extremities and rarely from the mesentery or intrabdominal organs. Malignant peritoneal mesothelioma is also a rare, yet aggressive disease. To our knowledge, this is the first case report of desmoid-type fibromatosis in the setting of malignant peritoneal mesothelioma.

CASE PRESENTATION: An early 30-year-old female was referred to our center for large intra-abdominal mass concerning for recurrent malignant peritoneal mesothelioma after previous cytoreductive surgery with hyperthermic intraperitoneal chemotherapy and adjuvant chemotherapy. Further investigation revealed a large mesenteric mass, which was resected en bloc with the cecum and terminal ileum. Pathologic findings confirmed a surprising diagnosis of desmoid-type fibromatosis.

CONCLUSIONS: No adjuvant therapy was offered to this patient due to negative tumor margins; however, close follow-up will be provided for recurrence of both malignant peritoneal mesothelioma and desmoid-type fibromatosis, which can be differentiated in the future via biopsy in this patient.

PMID:36171577 | DOI:10.1186/s12957-022-02784-y

Arch Pathol Lab Med. 2022 Sep 28. doi: 10.5858/arpa.2021-0612-RA. Online ahead of print.

ABSTRACT

CONTEXT.—: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcome. BPDCN diagnostically overlaps with entities such as acute myeloid leukemia, histiocytic/dendritic cell neoplasms, and natural killer/T-cell lymphomas. Unfortunately, large, patient-centered studies that comprehensively analyze clinical, pathologic, and other diagnostic features are lacking. As such, there is an incomplete understanding of this disease.

OBJECTIVE.—: To better characterize BPDCN, a multicenter working group consisting of hematopathologists and dermatopathologists gathered in person and remotely to review the current understanding of BPDCN, discuss specific issues regarding the diagnosis and differential diagnosis, and perform a retrospective analysis of the literature.

DATA SOURCES.—: The working group curated a database of published BPDCN patient cases (BPDCN Network literature database) following careful discussion and review, 361 articles were identified, comprising a total of 1513 individually annotated patients.

CONCLUSIONS.—: By conducting an in-depth analysis, not only did we confirm known findings such as frequent skin involvement (84% of patients; 861 of 1028) and a male predominance among older patients (>60 years old; male to female ratio of 3.5:1; 617:177), but we also identified a number of underrecognized features, such as significant central nervous system involvement (38% of cases; 24 of 64), and a more equal male to female prevalence among patients younger than 40 years (male to female ratio of 1.25:1; 167:134). Furthermore, we were able to accurately summarize the immunophenotypic, cytogenetic, and molecular features of this disease. BPDCN is a complex disease with distinct morphologic, immunophenotypic, and molecular findings. Continual updates of the literature database generated here and further analysis can allow for prospective refinement of our understanding of this orphan disease.

PMID:36170615 | DOI:10.5858/arpa.2021-0612-RA

J Investig Med High Impact Case Rep. 2022 Jan-Dec;10:23247096221123146. doi: 10.1177/23247096221123146.

ABSTRACT

Central giant cell granuloma (CGCG) is a rare disease characterized by sporadic, benign, intraosseous mandibular lesions of unknown etiology. Histologically, these lesions are indistinguishable from brown tumors of hyperparathyroidism and cherubism, and occasionally have been associated with different syndromes raising a question for genetic etiology. The CGCG has varied presentation ranging from nonaggressive and indolent to aggressive, destructive, and recurrent, often posing diagnostic and therapeutic challenges. Herein, we present the first case of a 10-year-old boy with CGCG and 16p13.11 microdeletion syndrome, highlight the diagnostic challenges inherent to this heterogeneous disorder, and discuss the genetics and treatment approaches of these complex lesions.

PMID:36154495 | DOI:10.1177/23247096221123146

Nat Genet. 2022 Sep 26. doi: 10.1038/s41588-022-01180-2. Online ahead of print.

ABSTRACT

Accurate somatic mutation detection from single-cell DNA sequencing is challenging due to amplification-related artifacts. To reduce this artifact burden, an improved amplification technique, primary template-directed amplification (PTA), was recently introduced. We analyzed whole-genome sequencing data from 52 PTA-amplified single neurons using SCAN2, a new genotyper we developed to leverage mutation signatures and allele balance in identifying somatic single-nucleotide variants (SNVs) and small insertions and deletions (indels) in PTA data. Our analysis confirms an increase in nonclonal somatic mutation in single neurons with age, but revises the estimated rate of this accumulation to 16 SNVs per year. We also identify artifacts in other amplification methods. Most importantly, we show that somatic indels increase by at least three per year per neuron and are enriched in functional regions of the genome such as enhancers and promoters. Our data suggest that indels in gene-regulatory elements have a considerable effect on genome integrity in human neurons.

PMID:36163278 | DOI:10.1038/s41588-022-01180-2

Genes (Basel). 2022 Sep 9;13(9):1619. doi: 10.3390/genes13091619.

ABSTRACT

BACKGROUND: Fabry disease (FD, OMIM #301500) is a rare, progressive, X-linked, inherited genetic disease caused by a functional deficiency of lysosomal α-galactosidase, leading to the accumulation of glycosphingolipids in virtually all of the body's cell types and fluids. Patients with rare genetic diseases and non-specific symptoms often experience substantial diagnostic delays, which can negatively impact the prompt initiation of treatment. If FD is not treated specifically, end organ damage (such as chronic renal failure, hypertrophic cardiomyopathy with arrhythmia, and strokes) impairs quality of life and reduces life expectancy.

PATIENTS AND METHODS: For 83 consecutive patients with FD referred to the Russian reference center for lysosomal storage diseases, family trees were built and genetic testing (cascade genotyping) was offered to family members.

RESULTS: The pathogenic GLA variant associated with FD was identified for all 83 probands. Family testing using cascade genotyping enabled the identification of 165 additional cases of FD among the tested 331 at-risk family members.

DISCUSSION: This is the first study to have described family screening in a large Russian cohort of patients with FD and chronic kidney disease. Raising awareness of FD among clinicians is important for earlier diagnosis and specific treatment.

PMID:36140787 | PMC:PMC9498688 | DOI:10.3390/genes13091619

Am J Med Genet C Semin Med Genet. 2022 Jun;190(2):156-161. doi: 10.1002/ajmg.c.32001. Epub 2022 Sep 22.

ABSTRACT

The National MPS Society, Inc., founded in 1974, is a rare disease advocacy non-profit with a tripartite mission addressing the needs of the mucopolysaccharidosis and mucolipidosis communities through advocacy, research, and family and patient support. The Recommended Uniform Screening Panel (RUSP) of conditions for newborn screening (NBS), legislatively mandated in 2008, was implemented in 2010 by the Secretary of Health and Human Services (HSS), through the adoption of 29 core conditions. Since its inception the RUSP has grown to 35 core conditions. Each addition followed a defined nomination process that has itself undergone further definition over time. Since the adoption of the RUSP, the Society has nominated two conditions that have been approved by the Advisory Committee on Heritable Disorders in Children and Newborns (ACHDNC) and forwarded to the Secretary of HSS for inclusion on the RUSP. This history places the Society in a position to reflect on the process of successfully nominating conditions. Additionally, the Society is well placed by this experience to provide observations on the RUSP process. We will highlight best practices for pending and future nominations and reflect on potential improvements to the process and infrastructure of NBS, the RUSP, and the ACHDNC.

PMID:36135708 | DOI:10.1002/ajmg.c.32001