Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
Richards S.,Oregon Health And Science University |
Aziz N.,The American College |
Bale S.,GeneDx |
Bick D.,Medical College of Wisconsin |
And 9 more authors.
Genetics in Medicine | Year: 2015
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes, and epigenetic assays for genetic disorders. By virtue of increased complexity, this shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context the ACMG convened a workgroup in 2013 comprising representatives from the ACMG, the Association for Molecular Pathology (AMP), and the College of American Pathologists to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP, and College of American Pathologists stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. This report recommends the use of specific standard terminology-"pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"-to describe variants identified in genes that cause Mendelian disorders. Moreover, this recommendation describes a process for classifying variants into these five categories based on criteria using typical types of variant evidence (e.g., population data, computational data, functional data, segregation data). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a Clinical Laboratory Improvement Amendments-approved laboratory, with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or the equivalent. © American College of Medical Genetics and Genomics.
Knapke S.,GeneDx |
Haidle J.L.,Guardant Health |
Nagy R.,Humphrey Cancer Center |
Pirzadeh-Miller S.,University of Texas at Dallas
Genetics in Medicine | Year: 2016
Purpose:Genetic risk assessment and counseling by a qualified genetics professional are recommended to ensure high-quality care for individuals at risk of hereditary cancer. Timely access to genetic services provided by a genetic counselor (GC) is essential, especially in cases where genetic testing results may affect impending surgical decisions.Methods:A survey of GCs who specialize in cancer genetics was performed to assess service delivery models and ability to accommodate urgent cases.Results:Over half of all respondents indicated that urgent patients can be seen for consultation the same day or within 1-2 business days, and almost all respondents indicated that urgent cases can be seen within 1 week. Most respondents indicated that urgent cases are seen by a GC only with no physician involved.Conclusions:The results of this survey of GCs demonstrate that timely access to cancer genetic counseling by GCs in an urgent setting is available.Genet Med 18 4, 410-412. © American College of Medical Genetics and Genomics.
Sergeev Y.V.,U.S. National Institutes of Health |
Caruso R.C.,University of Pennsylvania |
Meltzer M.R.,U.S. National Institutes of Health |
Smaoui N.,GeneDx |
And 2 more authors.
Human Molecular Genetics | Year: 2010
Gene mutations that encode retinoschisin (RS1) cause X-linked retinoschisis (XLRS), a form of juvenile macular and retinal degeneration that affects males. RS1 is an adhesive protein which is proposed to preserve the structural and functional integrity of the retina, but there is very little evidence of the mechanism by which protein changes are related to XLRS disease. Here, we report molecular modeling of the RS1 protein and consider perturbations caused by mutations found in human XLRS subjects. In 60 XLRS patients who share 27 missense mutations, we then evaluated possible correlations of the molecular modeling with retinal function as determined by the electroretinogram (ERG) a- and b-waves. The b/a-wave ratio reflects visual-signal transfer in retina. We sorted the ERG b/a-ratios by patient age and by the mutation impact on protein structure. The majority of RS1 mutations caused minimal structure perturbation and targeted the protein surface. These patients' b/aratios were similar across younger and older subjects. Maximum structural perturbations from either the removal or insertion of cysteine residues or changes in the hydrophobic core were associated with greater difference in the b/a-ratio with age, with a significantly smaller ratio at younger ages, analogous to the ERG changes with age observed in mice with no RS1-protein expression due to a recombinant RS1-knockout gene. The molecular modeling suggests an association between the predicted structural alteration and/or damage to retinoschisin and the severity of XLRS as measured by the ERG analogous to the RS1-knockout mouse. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: firstname.lastname@example.org.
Rehm H.L.,HealthCare Partners |
Rehm H.L.,Harvard University |
Bale S.J.,GeneDx |
Bayrak-Toydemir P.,University of Utah |
And 8 more authors.
Genetics in Medicine | Year: 2013
Next-generation sequencing technologies have been and continue to be deployed in clinical laboratories, enabling rapid transformations in genomic medicine. These technologies have reduced the cost of large-scale sequencing by several orders of magnitude, and continuous advances are being made. It is now feasible to analyze an individual's near-complete exome or genome to assist in the diagnosis of a wide array of clinical scenarios. Next-generation sequencing technologies are also facilitating further advances in therapeutic decision making and disease prediction for at-risk patients. However, with rapid advances come additional challenges involving the clinical validation and use of these constantly evolving technologies and platforms in clinical laboratories. To assist clinical laboratories with the validation of next-generation sequencing methods and platforms, the ongoing monitoring of next-generation sequencing testing to ensure quality results, and the interpretation and reporting of variants found using these technologies, the American College of Medical Genetics and Genomics has developed the following professional standards and guidelines. © American College of Medical Genetics and Genomics.
Lopez H.U.,Columbia University |
Haverfield E.,GeneDx |
Chung W.K.,Columbia University
Pediatric and Developmental Pathology | Year: 2015
Cases of sudden unexpected infant death (SUID) leave many families devastated, especially in those without an identified cause of death. Here, we describe the case of an apparently healthy 15-day-old infant who died suddenly and unexpectedly. Through whole-exome sequencing, the infant was posthumously found to have 2 mutations in the CLCNKB gene, leading to a molecular diagnosis of Bartter syndrome type III, the likely cause of death. This case illustrates the potential utility of exome sequencing in cases of SUID to suggest a diagnosis, with important implications for families, allowing them to come to closure over the cause of death, informing their future reproductive decisions, and minimizing the risk of recurrence. © 2015 Society for Pediatric Pathology.