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The Utility Of Adding Key Phenotypic Criteria Refinement To ACMG Guidelines
No full textIn 2015, ACMG published guidelines for variant interpretation with the intent of creating a common standard that could be utilized by all genetic testing laboratories. However, many studies have shown that the ACMG guidelines do not offer clear or objective grounds for practice, leading to frequent discordance between laboratories in how a given variant is called. To address the limitations of ACMG’s guidelines, the genetic testing laboratory Invitae developed a variant interpretation semi- quantitative framework called Sherloc. Sherloc’s algorithm includes two categories of phenotypic evidence that can be utilized toward establishing pathogenicity for variants found in a patient: case reports and pathognomonics. Applicable case report evidence includes case reports where phenotypic symptoms are present and indicate that an individual would be expected to receive a molecular diagnosis from genetic testing 25% to 75% of the time, for the set of genes that the patient was tested. Pathognomonic evidence can be applied if the presence of the symptom or feature defined as pathognomonic has been proven to result in a molecular diagnostic yield of \u3e75% using the relevant gene or panel test. In this study, concordance and discordance were assessed between classifications made using three systems: the ACMG guidelines, Sherloc with case report criteria only (Case Only), and Sherloc with case report and pathognomonic criteria (Computed). When these three systems were compared, Case Only and Computed criteria lowered the percentage of variants classified as a VUS (from 54% to 20%) or likely pathogenic (from 20% to 13%) while increasing the percentage of pathogenic classifications (from 26% to 67%) when compared to classifications by the ACMG guidelines alone. Moreover, 34% of the unique variants in 2 genes where pathognomonic criteria had been established had a clinically significant upgrade with the potential to impact patient care. Overall, efforts should be made to expand the number of genes across specialties that incorporate pathognomonic criteria to assist the variant interpretation process
The Efficacy of Whole-Genome Sequencing in the Diagnosis Of Complex Neurological Phenotypes
Get PDFWhole-genome sequencing (WGS) is being increasingly utilized for the diagnosis of neurological disease. The advent of next-generation sequencing (NGS) has replaced Sanger sequencing due to its ability to sequence millions of fragments in parallel, in real-time. It’s application in targeted gene panels and whole-exome sequencing (WES) has revolutionized standard investigation practices of neurodevelopmental diseases (NDDs). WGS utilizes NGS technology in order to sequence beyond the exome and into the remaining 98-99% of the genetic code comprising the genome. In addition to increased coverage, WGS allows for the detection of novel gene variants, copy number variants (CNVs) and single nucleotide variants (SNVs) that are not traditionally picked up by WES. Furthermore, RNA sequencing (RNA-Seq) of the blood used in conjunction with WGS may have the ability to validate WGS findings by analyzing gene expression in addition to identifying novel RNA species within the transcriptome. The objective of this retrospective study was to measure the diagnostic yield of trio-based WGS and RNA-Seq against that of negative or inconclusive WES in a patient cohort comprised of complex neurological phenotypes. Whole genome sequencing was performed by Medical Neurogenetics LLC, a CLIA-certified laboratory in Atlanta, Georgia. This laboratory utilized the Illumina NovaSeq 6000 Sequencing System, with a goal of 30x coverage of 99% of mapped genome regions. Alignment and variant interpretation was performed by Dragen v2.2 and CNV analysis by Dragen v2.5. Variants were assessed in accordance with current ACMG criteria. WGS with complementary RNA-Seq resulted in 7 solved patient cases, providing a 31.8% yield. This phenotypically complex cohort was comprised of a spectrum of neurological conditions with suspected underlying genetic mechanisms. The use of WGS in conjunction with RNA-Seq resulted in a markedly increased diagnostic yield over that of preceding WES and conventional first-tier tests which included chromosomal microarray, targeted gene panels, and metabolic testing. Thus, proving its efficacy in the clinical setting
Safety and Feasibility of Early Prenatal Diagnosis Via Celocentesis
No full textObjective Celocentesis, a method of prenatal diagnosis, accesses coelomic fluid, which is comprised of maternal cells and proteins produced by the embryonic cells surrounding the amniotic sac and available as early as 5 weeks of gestation via needle aspiration. The technique can potentially provide unique clinical value for religious sects with restrictive, sometimes time- sensitive termination laws, such as Orthodox Judaism where the statement from the Talmud: “a fetus less than 40 days from conception is considered mere water” is seen by many scholars as permitting termination prior to 40 days from conception.
Methods A meta-analysis was conducted of all relevant celocentesis studies published prior to January 1, 2020 to assess loss rates, collection of samples, accuracy of results, maternal cell contamination (MCC), return of results, and potential limb deformities. Results Loss rates significantly decreased over time, from 25% in 1997 to 2.8% in 2018. Sample collection was successful in 100% of evaluated studies and accuracy of results were confirmed in \u3e96% of samples using Chorionic Villi Sampling, Amniocentesis, Products of Conception or Live Birth testing, with a 100% concordance rate in confirmed samples. Samples displayed a wide range of MCC yet allowed return of results in \u3e96% of cases. To date, there have been no reports of limb deformities in the literature.
Conclusion Celocentesis offers a method of early prenatal diagnosis that may provide clinical value for a population where there are religious and cultural obstacles to the use of existing prenatal testing
Early Interventions and Special Education Services for Children with Autism
Get PDFAutism spectrum disorder (ASD) is a life-long developmental disorder that impairs a child’s ability to communicate and interact with others. The core features of ASD are deficits in communication/social interaction and the presence of restricted, repetitive behaviors. These symptoms appear in early childhood and range in severity. Therefore, no two children are likely to express ASD in the exact same way. There is no cure for the disorder, but early recognition and interventions are highly beneficial in mitigating its effects. It is now widely known that behavioral interventions, cognitive interventions, and various therapies promote positive long- term outcomes in children on the spectrum. Parents play an integral role in deciding which interventions are best for their children and reporting effectiveness in research. This work explores the process of how a child receives a diagnosis and considers the many interventions and special education services available to children with ASD. It also examines the relationship between parent conceptions of ASD and the interventions they choose, identifying the factors that compel parents to select certain interventions over others. Culminating in a case study of a child receiving interventions in a school environment, this work demonstrates how crucial it is that ASD be detected early and that services are accessible to all children with ASD
