Genetics in Medicine

ObjectiveWe sought to evaluate outcomes for clinical management following a genetic diagnosis from the Deciphering Developmental Disorders (DDD) Study. DesignIndividuals in the DDD study who had a pathogenic/likely pathogenic genotype in the DECIPHER database were selected for inclusion (n=5010). Clinical notes from regional clinical genetics services notes were reviewed to assess pre-defined clinical outcomes relating to interventions, prenatal choices, and information provision. ResultsOutco...

BackgroundGenome-wide sequencing and genetic matchmaker services are propelling a new era of genotype-first ascertainment of novel genetic conditions. The degree to which reported phenotype data in discovery-focused studies address informational priorities for clinicians and families is unclear. MethodsWe identified reports published from 2017-2021 in ten genetics journals of novel Mendelian disorders ascertained genotype-first. We adjudicated the quality and detail of the phenotype data via 46...

Payer coverage for Exome Sequencing (ES) is becoming commonplace (albeit in some cases with prior authorization restrictions), coverage for Genome Sequencing (GS) is rare, with most payers considering it as investigational and not medically necessary. Previous studies had identified several concerns and challenges from the payer perspective. The objective of this study is to conduct a targeted literature review of the evidence describing the cost and clinical utility of GS and ES compared to sta...

PurposeTo evaluate the diagnostic yield and clinical utility of clinical genome sequencing (cWGS) as a first genetic test for patients with suspected monogenic disorders. MethodsWe conducted a prospective randomized study with pediatric and adult patients recruited from genetics clinics at Massachusetts General Hospital who were undergoing planned genetic testing. Participants were randomized into two groups: standard-of-care genetic testing (SOC) only or SOC and cWGS. Results204 participants ...

3.0ImportanceRare genetic diseases are one of the leading causes of infant mortality worldwide. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) are relatively new techniques for diagnosing genetic diseases, that classic newborn screening (NBS) fails to detect. ObjectiveTo systematically assess the diagnostic and clinical utility of WGS and WES, compared to standard genetic testing (SGT), in children with suspected genetic diseases, and discuss its impact on the expansion of NBS. ...

Backgroundexome (ES) or genome (GS) sequencing are recommended as first- or second-tier molecular tests for patients with developmental disorders (DD), but the clinical utility of GS continues to be debated. MethodsThis prospective randomized trial involving all Belgian Human Genetics centers compared the standard of care (SoC) - combining ES and chromosomal microarray analysis or shallow GS - with GS for 567 individuals with unexplained DD. ResultsThe diagnostic yield of GS was 39.8% (113/284...

Genetic testing of patients with neurodevelopmental disabilities (NDDs) is critical for diagnosis, medical management, and access to precision therapies. Because genetic testing approaches evolve rapidly, professional society practice guidelines serve an essential role in guiding clinical care; however, several challenges exist regarding the creation and equitable implementation of these guidelines. In this scoping review, we assessed the current state of United States professional societies gui...

BackgroundParent/patient-reported datasets provide ready access to phenotypic data for monogenic neurodevelopmental disorders yet their concordance with clinical data is unclear. MethodsIn the GenROC study 547 children (mean age 7.6y, balanced sex ratio) had parallel parent-reported(PRD) web questionnaires and clinician-reported (CRD) Human Phenotype Ontology(HPO) proformas. We compared the two sources per participant by system, gene and gene group and overall for quantity, detail and similarit...

To determine if a variant identified by diagnostic genetic testing is causal for disease, applied genetics professionals evaluate all available evidence to assign a clinical classification. Experimental assay data can provide strong functional evidence for or against pathogenicity in variant classification, but appears to be underutilised. We surveyed genetic diagnostic professionals in Australasia to assess their application of functional evidence in clinical practice. Results indicated that su...

ObjectivesGenome-wide sequencing (GWS) is now used across the breadth of paediatric research. There is a greater potential to identify unexpected, clinically relevant findings with GWS than with the targeted genetic techniques used in prior decades. Individual research teams may not have the expertise to evaluate and manage these findings. The Hospital for Sick Children (SickKids) Genome Board is a no-cost consultation service for researchers with questions arising from genetic aspects of their ...

BackgroundRare diseases affect over 300 million people worldwide, with more than half of these cases presenting in childhood. Despite advances in genomic technologies, significant diagnostic delays remain, particularly in underrepresented populations. Although whole-genome sequencing is expected to be more effective than whole-exome sequencing, there are currently no direct patient-level comparisons from Albania. MethodsWe conducted a prospective, head-to-head comparison of whole-genome sequenc...

Background and objectivesSingle gene mutations are increasingly recognized as causes of cerebral palsy (CP) phenotypes, yet there is currently no standardized framework for measuring their clinical impact. We evaluated Pathogenic/Likely Pathogenic (P/LP) variants identified in individuals with CP to determine how frequently genetic testing results would prompt changes in care. MethodsWe analyzed published P/LP variants in OMIM genes identified in clinical (n = 1,345 individuals) or research (n ...

IntroductionVariant-level functional data is a core component of clinical variant classification and can aid in reinterpreting variants of uncertain significance (VUS). However, the usage of functional data by genetics professionals is currently unknown. MethodsAn online survey was developed and distributed in spring of 2024 to individuals actively engaged in variant interpretation. Quantitative and qualitative methods were used to assess responses. Results190 eligible individuals responded, w...

BackgroundThe use of in silico pathogenicity predictions as evidence when interpreting genetic variants is widely accepted as part of standard variant classification guidelines. Although numerous algorithms have been developed and evaluated for classifying missense variants, in-frame insertions/deletions (indels) have been much less well studied. MethodsWe created a dataset of 3964 small (<100bp) indels predicted to result in in-frame amino acid insertions or deletions using data from gnomAD v3...

PurposeGenomic medicine has transformed the diagnosis of neurodevelopmental disorders. Evidence of increased psychiatric comorbidity associated with genomic copy number and single nucleotide variants (CNV and SNV) may not be fully considered when providing genetic counselling. We explored parents experiences of genetics services and how they obtained information concerning psychiatric manifestations. MethodsParents of children diagnosed with genomic variants completed an online survey exploring...

PurposeSouthSeq, a translational research study to perform genome sequencing (GS) for infants with symptoms suggestive of a genetic disorder, was conducted in NICUs in the Southeastern US. Recruitment targeted racial/ethnic minorities and rural, medically underserved areas that are historically under-represented in genomic medicine research. MethodsGS and analysis were performed for 367 newborns to detect disease-causal genetic variation concurrent with standard of care evaluation and testing. ...

IntroductionRapid genome sequencing (rGS) provides high diagnostic yield for critically ill infants with suspected genetic disorders, but has high upfront costs and insufficient insurance coverage. Assessing the downstream costs and health outcomes associated with rGS is important for guiding coverage decisions. This study compares 1-year healthcare costs and quality-adjusted life years (QALYs) for: 1) early rGS (within 7 days of admission) for all infants, and 2) early targeted neonatal gene se...

PurposeIt has been hypothesized that diagnostic yield (DY) from Exome Sequencing (ES) may be lower among patients with non-European ancestries than those with European ancestry. We examined the association of DY with estimated continental genetic ancestry in a racially/ethnically diverse pediatric and prenatal clinical cohort. MethodsCases (N=845) with suspected genetic disorders underwent ES for diagnosis. Continental genetic ancestry proportions were estimated from the ES data. We compared th...

Around 2000 children are born in the UK per year with a neurodevelopmental genetic syndrome with significantly increased morbidity and mortality(1). Often little is known about expected growth and phenotypes in these children. Parents have responded by setting up social media groups to generate data themselves. Given the significant clinical evidence gaps, this research will attempt to identify growth patterns, developmental profiles and phenotypes, providing data on long-term medical and educat...

PurposeTo estimate the proportion of molecular genetic diagnoses in a real-world, phenotypically heterogeneous patient cohort that are amenable to antisense oligonucleotide (ASO) treatment. MethodsWe retrospectively applied the N=1 Collaboratives VARIANT (Variant Assessments towards Eligibility for Antisense Oligonucleotide Treatment) guidelines to all diagnostic variants found by clinical genome-wide sequencing at a single pediatric hospital in 532 patients over a 6-year period. Variants were ...