Decoding Complex Inherited Phenotypes in Rare Disorders: The DECIPHERD initiative for rare undiagnosed diseases in Chile (original) (raw)
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Whole-genome sequencing of patients with rare diseases in a national health system
Nature
Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and mediating genes for more than half such disorders remain to be discovered 1. We implemented whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants, in the coding and non-coding regions of the genome. In a pilot study for the 100,000 Genomes Project, we generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 patients with detailed phenotypic data. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed aetiological. Using WGS of UK Biobank 2 , we showed that rare alleles can explain the presence of some individuals in the tails of a quantitative red blood cell (RBC) trait. Finally, we identified 4 novel non-coding variants which cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare. Rare diseases affect approximately 1 in 20 people, but only a minority of patients receive a genetic diagnosis 3. Approximately 10,000 rare diseases are known, but fewer than half have a resolved genetic aetiology 1. Even when the aetiology is known, the prospects for diagnosis are severely diminished by fragmentary phenotyping and the restriction of testing to disease-specific panels of genes. On average, a molecular cause is determined after three misdiagnoses and 16 physician visits over several years 4. Recent development of WGS technology allows systematic, comprehensive genetic testing in integrated health systems concurrent with aetiological discovery in the coding and non-coding genome.
Solving patients with rare diseases through programmatic reanalysis of genome-phenome data
European Journal of Human Genetics
Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP’s Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an aver...
Exome sequencing of 500 Brazilian patients with rare diseases: what we have learned
Sao Paulo Medical Journal
Dear Editor, Rare diseases comprise a large and diverse group of an estimated 7,000 different conditions that collectively affect millions of people worldwide. We recently studied the genomic findings of 500 Brazilian patients with suspected rare diseases of genetic etiology who have undergone exome sequencing (ES) for diagnostic purposes. 1 We observed an overall diagnostic yield of 31.6% in our cohort. Figure 1-A shows the inheritance patterns of the genetic diseases. These diagnoses were associated with 195 sequence variants, among which 38% were rare variants that have not been previously published in the literature (Figure 1-B). The diagnostic rate varied widely depending on age, and we observed higher diagnostic rates in prenatal samples (67%) and children younger than one year (44%) and lower rates for adults older than 50 years (13%). Undiagnosed patients still comprise the majority of patients in our cohort (68.4%) and remain a challenge in genomics. Even with the advances in genomic technology, for many patients with rare diseases, the diagnostic odyssey has not come to an end. Valuable techniques such as trio exome analysis (testing of samples from a proband and both parents) or genome sequencing may increase the genetic diagnosis of rare diseases. We also found additional genetic alterations that may directly affect the morbidity and mortality of individuals. In 37 patients (7.4%), we found deleterious genetic variants associated with clinically actionable conditions, such as hereditary cancer, arrhythmia, metabolic diseases, and cardiomyopathies. These secondary findings were previously referred to as "incidental findings". (Figure 2). Determining reportable secondary findings remains controversial and challenging. 2-4 Discussions on this subject are prevalent in North American, European, and some Asian countries but have yet to take place in Brazil and other Latin American countries. Indeed, there are no regulatory documents, legislation, or policies from scientific societies in Brazil regarding the protocols for reporting secondary findings in genomic studies. We urge our medical societies to adopt specific policies for reporting these conditions, and more importantly, consider the
SpainUDP: The Spanish Undiagnosed Rare Diseases Program
International journal of environmental research and public health, 2018
One of the IRDiRC goals for 2017⁻2027 is to achieve definitive diagnosis for rare undiagnosed diseases within one year, as delay in diagnosis remains one of the pending issues in the rare diseases field. The Spanish Undiagnosed Rare Diseases Program (SpainUDP) was created in response to this challenging scenario to cover patients' needs and after seeing the success of the Undiagnosed Diseases Program (UDP) in the USA. SpainUDP offers a multidisciplinary approach to those patients who have long sought a diagnosis without any success. During the first phase of the protocol, undiagnosed cases are sent to SpainUDP by individual patients or families, patient organizations or hospitals. After careful analysis of phenotype, data from sequencing experiments (WES) is processed with a standard pipeline and detailed standardized phenotypic information (mapped to the Human Phenotype Ontology, HPO) is connected to genetic data. In addition, the participation of SpainUDP in international init...
100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report
New England Journal of Medicine
BACKGROUND The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection. METHODS We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis. RESULTS 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. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives. CONCLUSIONS Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases.
Genome Medicine, 2021
Background We report the findings from 4437 individuals (3219 patients and 1218 relatives) who have been analyzed by whole genome sequencing (WGS) at the Genomic Medicine Center Karolinska-Rare Diseases (GMCK-RD) since mid-2015. GMCK-RD represents a long-term collaborative initiative between Karolinska University Hospital and Science for Life Laboratory to establish advanced, genomics-based diagnostics in the Stockholm healthcare setting. Methods Our analysis covers detection and interpretation of SNVs, INDELs, uniparental disomy, CNVs, balanced structural variants, and short tandem repeat expansions. Visualization of results for clinical interpretation is carried out in Scout—a custom-developed decision support system. Results from both singleton (84%) and trio/family (16%) analyses are reported. Variant interpretation is done by 15 expert teams at the hospital involving staff from three clinics. For patients with complex phenotypes, data is shared between the teams. Results Overal...