Mitochondrial DNA (mtDNA) variant pathogenicity interpretation has special considerations given unique features of the mtDNA genome, including maternal inheritance, variant heteroplasmy, threshold ...effect, absence of splicing, and contextual effects of haplogroups. Currently, there are insufficient standardized criteria for mtDNA variant assessment, which leads to inconsistencies in clinical variant pathogenicity reporting. An international working group of mtDNA experts was assembled within the Mitochondrial Disease Sequence Data Resource Consortium and obtained Expert Panel status from ClinGen. This group reviewed the 2015 American College of Medical Genetics and Association of Molecular Pathology standards and guidelines that are widely used for clinical interpretation of DNA sequence variants and provided further specifications for additional and specific guidance related to mtDNA variant classification. These Expert Panel consensus specifications allow for consistent consideration of the unique aspects of the mtDNA genome that directly influence variant assessment, including addressing mtDNA genome composition and structure, haplogroups and phylogeny, maternal inheritance, heteroplasmy, and functional analyses unique to mtDNA, as well as specifications for utilization of mtDNA genomic databases and computational algorithms.
Since the discovery of the first gene causing holoprosencephaly (HPE), over 500 patients with mutations in genes associated with non‐chromosomal, non‐syndromic HPE have been described, with detailed ...descriptions available in over 300. Comprehensive clinical analysis of these individuals allows examination for the presence of genotype–phenotype correlations. These correlations allow a degree of differentiation between patients with mutations in different HPE‐associated genes and for the application of functional studies to determine intragenic correlations. These early correlations are an important advance in the understanding of the clinical aspects of this disease, and in general argue for continued analysis of the genetic and clinical findings of large cohorts of patients with rare diseases in order to better inform both basic biological insight and care and counseling for affected patients and families. Published 2010 Wiley‐Liss, Inc.
Germ-line testing for panels of cancer genes using next-generation sequencing is becoming more common in clinical care. We report our experience as a clinical laboratory testing both ...well-established, high-risk cancer genes (e.g., BRCA1/2, MLH1, MSH2) as well as more recently identified cancer genes (e.g., PALB2, BRIP1), many of which have increased but less well-defined penetrance.
Clinical genetic testing was performed on over 10,000 consecutive cases referred for evaluation of germ-line cancer genes, and results were analyzed for frequency of pathogenic or likely pathogenic variants, and were stratified by testing panel, gene, and clinical history.
Overall, a molecular diagnosis was made in 9.0% of patients tested, with the highest yield in the Lynch syndrome/colorectal cancer panel. In patients with breast, ovarian, or colon/stomach cancer, positive yields were 9.7, 13.4, and 14.8%, respectively. Approximately half of the pathogenic variants identified in patients with breast or ovarian cancer were in genes other than BRCA1/2.
The high frequency of positive results in a wide range of cancer genes, including those of high penetrance and with clinical care guidelines, underscores both the genetic heterogeneity of hereditary cancer and the usefulness of multigene panels over genetic tests of one or two genes.
SMAD2 is a downstream effector in the TGF‐β signaling pathway, which is important for pattern formation and tissue differentiation. Pathogenic variants in SMAD2 have been reported in association with ...arterial aneurysms and dissections and in large cohorts of subjects with complex congenital heart disease (CHD). We used whole exome sequencing (WES) to investigate the molecular cause of CHD and other congenital anomalies in three probands and of an arterial aneurysm in an additional patient. Patients 1 and 2 presented with complex CHD, developmental delay, seizures, dysmorphic features, short stature, and poor weight gain. Patient 3 was a fetus with complex CHD and heterotaxy. The fourth patient is an adult female with aortic root aneurysm and physical features suggestive of a connective tissue disorder. WES identified pathogenic truncating variants, a splice variant, and a predicted deleterious missense variant in SMAD2. We compare the phenotypes and genotypes in our patients with previously reported cases. Our data suggest two distinct phenotypes associated with pathogenic variants in SMAD2: complex CHD with or without laterality defects and other congenital anomalies, and a late‐onset vascular phenotype characterized by arterial aneurysms with connective tissue abnormalities.
The manuscript presents detailed clinical and molecular findings of four patients with novel SMAD2 predicted pathogenic variants detected through exome sequencing. The data show that pathogenic variants in SMAD2 are associated with two distinct phenotypes: complex congenital heart malformations with or without laterality defects and other congenital anomalies, and a late‐onset vascular phenotype characterized by arterial aneurysms with connective tissue abnormalities.
Copy-number analysis to detect disease-causing losses and gains across the genome is recommended for the evaluation of individuals with neurodevelopmental disorders and/or multiple congenital ...anomalies, as well as for fetuses with ultrasound abnormalities. In the decade that this analysis has been in widespread clinical use, tremendous strides have been made in understanding the effects of copy-number variants (CNVs) in both affected individuals and the general population. However, continued broad implementation of array and next-generation sequencing-based technologies will expand the types of CNVs encountered in the clinical setting, as well as our understanding of their impact on human health.
To assist clinical laboratories in the classification and reporting of CNVs, irrespective of the technology used to identify them, the American College of Medical Genetics and Genomics has developed the following professional standards in collaboration with the National Institutes of Health (NIH)-funded Clinical Genome Resource (ClinGen) project.
This update introduces a quantitative, evidence-based scoring framework; encourages the implementation of the five-tier classification system widely used in sequence variant classification; and recommends "uncoupling" the evidence-based classification of a variant from its potential implications for a particular individual.
These professional standards will guide the evaluation of constitutional CNVs and encourage consistency and transparency across clinical laboratories.
The broad use of next-generation sequencing and microarray platforms in research and clinical laboratories has led to an increasing appreciation of the role of germline mutations in genes involved in ...hematopoiesis and lineage differentiation that contribute to myeloid neoplasms. Despite implementation of the American College of Medical Genetics and Genomics and Association for Molecular Pathology 2015 guidelines for sequence variant interpretation, the number of variants deposited in ClinVar, a genomic repository of genotype and phenotype data, and classified as having uncertain significance or being discordantly classified among clinical laboratories remains elevated and contributes to indeterminate or inconsistent patient care. In 2018, the American Society of Hematology and the Clinical Genome Resource co-sponsored the Myeloid Malignancy Variant Curation Expert Panel to develop rules for classifying gene variants associated with germline predisposition to myeloid neoplasia. Herein, we demonstrate application of our rules developed for the
gene to variants in six examples to show how we would classify them within the proposed framework.
Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain in humans and is typically characterized by different degrees of hemispheric separation that are often ...accompanied by similarly variable degrees of craniofacial and midline anomalies. HPE is a classic example of a complex genetic trait with “pseudo”‐autosomal dominant transmission showing incomplete penetrance and variable expressivity. Clinical suspicion of HPE is typically based upon compatible craniofacial findings, the presence of developmental delay or seizures, or specific endocrinological abnormalities, and is then followed up by confirmation with brain imaging. Once a clinical diagnosis is made, a thorough genetic evaluation is necessary. This usually includes analysis of chromosomes by high‐resolution karyotyping, clinical assessment to rule‐out well recognized syndromes that are associated with HPE (e.g., Pallister‐Hall syndrome, Smith‐Lemli‐Opitz syndrome and others), and molecular studies of the most common HPE associated genes (e.g., SHH, ZIC2 and SIX3). In this review, we provide current step‐by‐step recommendations that are medically indicated for the genetic evaluation of patients with newly diagnosed HPE. Moreover, we provide a brief review of several available methods used in molecular diagnostics of HPE and describe the advantages and limitations of both currently available and future tests as they relate to high throughput screening, cost, and the results that they may provide. Published 2010 Wiley‐Liss, Inc.
We report the diagnostic yield of whole-exome sequencing (WES) in 3,040 consecutive cases at a single clinical laboratory.
WES was performed for many different clinical indications and included the ...proband plus two or more family members in 76% of cases.
The overall diagnostic yield of WES was 28.8%. The diagnostic yield was 23.6% in proband-only cases and 31.0% when three family members were analyzed. The highest yield was for patients who had disorders involving hearing (55%, N = 11), vision (47%, N = 60), the skeletal muscle system (40%, N = 43), the skeletal system (39%, N = 54), multiple congenital anomalies (36%, N = 729), skin (32%, N = 31), the central nervous system (31%, N = 1,082), and the cardiovascular system (28%, N = 54). Of 2,091 cases in which secondary findings were analyzed for 56 American College of Medical Genetics and Genomics–recommended genes, 6.2% (N = 129) had reportable pathogenic variants. In addition to cases with a definitive diagnosis, in 24.2% of cases a candidate gene was reported that may later be reclassified as being associated with a definitive diagnosis.
Our experience with our first 3,040 WES cases suggests that analysis of trios significantly improves the diagnostic yield compared with proband-only testing for genetically heterogeneous disorders and facilitates identification of novel candidate genes.
Assessing the Immunogenicity of Biopharmaceuticals Pineda, Carlos; Castañeda Hernández, Gilberto; Jacobs, Ira A. ...
BioDrugs : clinical immunotherapeutics, biopharmaceuticals, and gene therapy,
06/2016, Letnik:
30, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Biopharmaceuticals have the potential to raise an immunogenic response in treated individuals, which may impact the efficacy and safety profile of these drugs. As a result, it is essential to ...evaluate immunogenicity throughout the different phases of the clinical development of a biopharmaceutical, including post-marketing surveillance. Although rigorous evaluation of biopharmaceutical immunogenicity is required by regulatory authorities, there is a lack of uniform standards for the type, quantity, and quality of evidence, and for guidance on experimental design for immunogenicity assays or criteria to compare immunogenicity of biopharmaceuticals. Moreover, substantial technological advances in methods to assess immune responses have yielded higher immunogenicity rates with modern assays, and limit comparison of immunogenicity of biopharmaceuticals outside of head-to-head clinical trials. Accordingly, research programs, regulatory agencies, and clinicians need to keep pace with continuously evolving analyses of immunogenicity. Here, we review factors associated with immunogenicity of biopharmaceuticals, potential clinical ramifications, and current regulatory guidance for evaluating immunogenicity, and discuss methods to assess immunogenicity in non-clinical and clinical studies. We also describe special considerations for evaluating the immunogenicity of biosimilar candidates.
Current guidelines recommend single variant testing in relatives of patients with known pathogenic or likely pathogenic germline variants in cancer predisposition genes. This approach may preclude ...the use of risk-reducing strategies in family members who have pathogenic or likely pathogenic germline variants in other cancer predisposition genes. Cascade testing using multigene panels was performed in 3696 relatives of 7433 probands. Unexpected pathogenic or likely pathogenic germline variants were identified in 230 (6.2%) relatives, including 144 who were negative for the familial pathogenic or likely pathogenic variant but positive for a pathogenic or likely pathogenic variant in a different gene than the proband and 74 who tested positive for the familial pathogenic or likely pathogenic variant and had an additional pathogenic or likely pathogenic variant in a different gene than the proband. Of the relatives with unexpected pathogenic or likely pathogenic germline variants, 36.3% would have qualified for different or additional cancer screening recommendations. Limiting cascade testing to only the familial pathogenic or likely pathogenic variant would have resulted in missed, actionable findings for a subset of relatives.
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