Precision medicine initiatives are being launched worldwide, each with the capacity to sequence many thousands to millions of human genomes. At the strategic planning level, all are debating the ...extent to which these resources will be directed towards rare diseases (and cancers) versus common diseases. However, these are not mutually exclusive choices. The organizational and governmental infrastructure created for rare diseases is extensible to common diseases. As we will explain, the underlying technology can also be used to identify drug targets for common diseases with a strategy focused on naturally occurring human knockouts. This flips on its head the prevailing modus operandi of studying people with diseases of interest, shifting the onus to defining traits worth emulating by pharmaceuticals, and searching phenotypically for people with these traits. This also shifts the question of what is rare or common from the many underlying causes to the possibility of a common final pathway.
Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and ...BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor’s DNA binding.
Bronchiectasis is the abnormal dilation of the airway which may be caused by various etiologies in children. Beyond the more recognized cause of bacterial and viral infections and primary ...immunodeficiencies, other genetic conditions such as cystic fibrosis and primary ciliary dyskinesia (PCD) can also contribute to the disease. Currently, there is still debate on whether genome sequencing (GS) or exome sequencing reanalysis (rES) would be beneficial if the initial targeted testing results returned negative. This study aims to provide a back-to-back comparison between rES and GS to explore the best integrated approach for the functional and genetics evaluation for patients referred for assessment of bronchiectasis. In phase 1, an initial 60 patients were analyzed by exome sequencing (ES) with one additional individual recruited later as an affected sibling for ES. Functional evaluation of the nasal nitric oxide test, transmission electron microscopy, and high-speed video microscopy were also conducted when possible. In phase 2, GS was performed on 30 selected cases with trio samples available. To provide a back-to-back comparison, two teams of genome analysts were alternatively allocated to GS or rES and were blinded to each other's analysis. The time for bioinformatics, analysis, and diagnostic utility was recorded for evaluation. ES revealed five positive diagnoses (5/60, 8.3%) in phase 1, and four additional diagnoses were made by rES and GS (4/30, 13%) during phase 2. Subsequently, one additional positive diagnosis was identified in a sibling by ES and an overall diagnostic yield of 10/61 (16.4%) was reached. Among those patients with a clinical suspicion of PCD (n = 31/61), the diagnostic yield was 26% (
= 8/31). While GS did not increase the diagnostic yield, we showed that a variant of uncertain significance could only be detected by GS due to improved coverage over ES and hence is a potential benefit for GS in the future. We show that genetic testing is an essential component for the diagnosis of early-onset bronchiectasis and is most effective when used in combination with functional tools such as TEM or HSVM. Our comparison of rES vs. GS suggests that rES and GS are comparable in clinical diagnosis.
Neonatal diabetes mellitus is a rare monogenic condition affecting 1 in 100,000–300,000 live births. Mutations in the subunits of ATP-sensitive potassium (KATP) channels, which are the central ...gatekeepers of electrical activity, are the common cause of this condition, thereby reducing insulin secretion in the pancreatic beta cells. Most cases are diagnosed before 6 mo of age. The development of this condition in the latter half of the first year of life is rare; hence, testing in older infants is not routinely performed. Here, we describe the case of a patient who presented with neonatal diabetes mellitus and diabetic ketoacidosis at 10 mo of age. All the pancreatic autoantibodies were undetectable, prompting us to pursue genetic testing. At 13 yr of age, a heterozygous missense variant, C42R, was identified in the KCNJ11 gene by exome sequencing. Subsequently, sulfonylurea was initiated, and insulin therapy was discontinued that resulted in improved blood glucose control and increased C-peptide levels. Given the potential benefit of switching to oral medication, genetic testing should be extended to all infants diagnosed with antibody-negative diabetes before 1 yr of age.
This study assesses the areas and extent of impact of the Coronavirus Disease of 2019 (COVID-19) pandemic on rare disease (RD) organisations in the Asia Pacific region. There is no existing ...literature that focuses on such impact on RD organisations in any jurisdictions, nor RD populations across multiple jurisdictions in the Asia Pacific region. A cross-sectional survey was distributed to RD organisations between April and May 2020. Quantitative and qualitative data on the impact of COVID-19 on RD organisations and patients were collected from the organisation representative's perspective. Qualitative data was analysed using thematic analysis. A follow-up focus group meeting was conducted in August 2020 to validate the survey findings and to discuss specific needs, support and recommendations for sustainable healthcare systems during the pandemic.
A total of 80 RD organisations from Australia, Hong Kong Special Administrative Region of China, India, Japan, mainland China, Malaysia, New Zealand, the Philippines, Singapore and Taiwan participated in the study. Of all, 89% were concerned about the impact of pandemic on their organisations. Results indicate that 63% of the organisations functioned at a reduced capacity and 42% stated a decrease in funding as their biggest challenge. Overall, 95% believed their patients were impacted, particularly in healthcare access, social lives, physical health, psychological health and financial impact. Specifically, 43% identified the reduced healthcare access as their top impact, followed by 26% about the impact on daily living and social life. Focus group meeting discussed differential impact across jurisdictions and point towards telemedicine and digitalisation as potential solutions.
This serves as the first study to assess the impact of COVID-19 on RD patients and organisations across multiple jurisdictions in the Asia Pacific region, identifying major themes on the impact on both RD patients and organisations. By including 80 organisations from ten jurisdictions, our study presents the most comprehensive assessment of the pandemic's impact to date. It highlights the need for mental health support and sheds light on moving towards telemedicine and digitalisation of organisation operation, which constitutes a sustainable model in times of pandemics and beyond.
A partnership model in interprofessional education (IPE) is important in promoting a sense of global citizenship while preparing students for cross-sector problem-solving. However, the literature ...remains scant in providing useful guidance for the development of an IPE programme co-implemented by external partners. In this pioneering study, we describe the processes of forging global partnerships in co-implementing IPE and evaluate the programme in light of the preliminary data available.
This study is generally quantitative. We collected data from a total of 747 health and social care students from four higher education institutions. We utilized a descriptive narrative format and a quantitative design to present our experiences of running IPE with external partners and performed independent t-tests and analysis of variance to examine pretest and posttest mean differences in students' data.
We identified factors in establishing a cross-institutional IPE programme. These factors include complementarity of expertise, mutual benefits, internet connectivity, interactivity of design, and time difference. We found significant pretest-posttest differences in students' readiness for interprofessional learning (teamwork and collaboration, positive professional identity, roles, and responsibilities). We also found a significant decrease in students' social interaction anxiety after the IPE simulation.
The narrative of our experiences described in this manuscript could be considered by higher education institutions seeking to forge meaningful external partnerships in their effort to establish interprofessional global health education.
The threat and experience of pandemics occur differently for different groups. The rare disease population is at particular risk of being further marginalised during pandemics. In this study, our ...objective was to assess the hospital mortality patterns in the rare disease and the general populations during the coronavirus disease of 2019 (COVID-19) and severe acute respiratory syndrome (SARS) pandemics in Hong Kong. All admission records during the COVID-19 pandemic (January 23-August 23, 2020) and SARS pandemic (March 11-June 30, 2003) were extracted from the local public healthcare database. Patients with rare diseases were identified using one or more of the 1084 10th version International Classification of Diseases and Related Health Problems (ICD-10) codes cross-referenced with 467 ORPHAcodes. Hospital mortality patterns were compared in patients with and without COVID-19/SARS infection. Admission records during the same period in 2019 and 2002 were retrieved for comparison. During the COVID-19 pandemic, 407,219 patients were admitted to one or more of the 43 public hospitals in Hong Kong, of which, 13,894 were patients with rare diseases (3.4%). A total of 4381 and 77 patients from the general and rare disease populations were infected with COVID-19. Rare disease patients had an adjusted 3.4 times odds of COVID-19-related hospital mortality compared with that of the general population (95% C.I. 1.24-9.41). COVID-19-related mortality was almost exclusively seen in patients greater than or equai to 60 years. While age-related increase in mortality was also observed for the general population during the SARS pandemic, the pattern observed in the rare disease population was significantly different, with a 12.5 times higher SARS-related mortality observed in rare disease patients less than or equai to 18 years than those in the general population (12.5% vs 1.0%). Patients admitted during the same pandemic periods without coronavirus infection had a significantly higher hospital mortality compared with those admitted one year before the pandemic (p < 0.001). This population-based study demonstrated the differential impacts of the COVID-19 and SARS pandemics on the rare disease population. In the era of budget and resource scarcity, this study warrants cautious healthcare planning, with consideration of the rare disease population in healthcare prioritisation.
Objective
Previous genome‐wide association studies (GWAS), which were mainly based on single‐variant analysis, have identified many systemic lupus erythematosus (SLE) susceptibility loci. However, ...the genetic architecture of this complex disease is far from being understood. The aim of this study was to investigate whether using a gene‐based analysis may help to identify novel loci, by considering global evidence of association from a gene or a genomic region rather than focusing on evidence for individual variants.
Methods
Based on the results of a meta‐analysis of 2 GWAS of SLE conducted in 2 Asian cohorts, we performed an in‐depth gene‐based analysis followed by replication in a total of 4,626 patients and 7,466 control subjects of Asian ancestry. Differential allelic expression was measured by pyrosequencing.
Results
More than one‐half of the reported SLE susceptibility loci showed evidence of independent effects, and this finding is important for understanding the mechanisms of association and explaining disease heritability. ANXA6 was detected as a novel SLE susceptibility gene, with several single‐nucleotide polymorphisms (SNPs) contributing independently to the association with disease. The risk allele of rs11960458 correlated significantly with increased expression of ANXA6 in peripheral blood mononuclear cells from heterozygous healthy control subjects. Several other associated SNPs may also regulate ANXA6 expression, according to data obtained from public databases. Higher expression of ANXA6 in patients with SLE was also reported previously.
Conclusion
Our study demonstrated the merit of using gene‐based analysis to identify novel susceptibility loci, especially those with independent effects, and also demonstrated the widespread presence of loci with independent effects in SLE susceptibility genes.
BackgroundExpanded carrier screening (ECS) is a genetic test that investigates the genetic composition of a couple and determines whether their offspring has an elevated risk of inherited disorders. ...Comparisons between commercially available ECS has, however, only shown small overlaps in common genes offered for screening.ObjectivesCompiled with the inadequate information surrounding carrier frequencies in the Chinese population, secondary usage of next generation sequencing could be used in the optimization of ECS panels surrounding clinical utility, public health benefits, and reducing unnecessary socio-psychological stress.MethodsIn this study, a total of 1543 Southern Chinese and 366 Northern Chinese genome and exome sequencing were screened for carrier status over 315 genes. The gene list curated for this study was compiled from three ECS panels offered by frequently used commercial companies and literature reporting high carrier frequencies for treatable inherited disorder in South East Asia population genomics.Results180 unique disease-causing variants were identified and 47.8% (n = 738) of Southern Chinese individuals screened in this study harboured at least 1 disease-causing variant. CNV calling determined 4 unique pathogenic or likely pathogenic copy number variants. A total of 285 unique carrier variants were classified as pathogenic or likely pathogenic. Results have also identified 12 genes with a carrier frequency over 1% including GJB2, HBA1/HBA2, SMN1, SLC22A5, SLC25A13, ATP7B, SLC26A4, GALC, POLG, USH2A, and HBB.ConclusionsThis study shows that secondary analysis of NGS data can illustrate the carrier frequencies in the Southern Chinese population. Through the comparison of different commercially available ECS panels, we identified potential for improvement in the optimization of commercially available ECS panels for the future of precision medicine.
Genomic research can lead to discoveries of copy number variations (CNVs) which can be a susceptibility factor for autism spectrum disorder (ASD). The clinical translation is that this can improve ...the care of children with ASD. Chromosome microarray is now the first-tiered genetic investigation for ASD, with a detection rate exceeding conventional cytogenetics and any single gene testing. However, interpretation of the results is challenging and there is no consensus on “what” and “how much” to disclose. In this article, we will review how CNV studies have improved our understanding of ASD, the clinical applications, and related counseling issues. Future direction of autism genetic research is also discussed.
PDF
