Genetics in Medicine最新文献

Purpose: Genetic testing is required to confirm a diagnosis of familial chylomicronemia syndrome (FCS). We assessed the pathogenicity of variants identified in the FCS canonical genes to diagnose FCS cases.

Methods: 245 patients with severe hypertriglyceridemia underwent next-generation sequencing. Preliminary variant pathogenicity criteria and classification, based on the American College of Medical Genetics and Genomics (ACMG) guidelines, were obtained online and verified. Phenotype evaluation was based on lipoprotein lipase activity deficiency, a clinical score, and/or type I hyperlipoproteinemia determined in 25 patients.

Results: Twenty-four biallelic variants were analysed. Evidence-based criteria allowed the reclassification of eight likely pathogenic (LP) variants in the LPL, APOA5, and LMF1 genes into pathogenic (P) and the change of two variants of uncertain significance (VUS) to LP. Conversely, two variations in LMF1 remained as VUS. Additionally, one variant in LPL and two in GPIHBP1 were likely benign (LB). Twenty FCS cases had biallelic P/LP variants and one patient, with an FCS phenotype, harboured biallelic VUS. FCS was excluded from four patients with P/LB combinations.

Conclusion: The analysis of the clinical and biochemical features of patients with variants in the FCS canonical genes allowed a confident variant classification that helped in the diagnosis of novel FCS cases.

Purpose: Universal newborn hearing screening (UNHS) programs using audiometric techniques alone are limited in ability to detect non-congenital childhood permanent hearing loss (PHL). In 2019, Ontario launched universal newborn screening (NBS) for PHL risk factors: congenital cytomegalovirus (cCMV) and 22 common variants in GJB2 and SLC26A4. Here we describe our experience with genetic risk factor screening.

Methods: Ontario newborns who participated in UNHS were offered risk factor screening on dried blood spots collected for conventional newborn screening. Screening was conducted by custom MassArray assay and positives confirmed by Sanger sequencing or PCR. Diagnostic audiology assessment was performed for all screen positive infants.

Results: 412,424 infants were screened, 93 had two variants in GJB2 or SLC26A4. Of these, 72 had confirmed PHL, 20 had normal hearing and 1 declined follow-up. Thirteen infants with PHL (1 in 31,724; 11.8% of screen positives) were not identified through audiometric testing as they passed (3) or missed (10) screening. Importantly, among infants who ultimately received cochlear implants, detection of the genetic etiology through NBS led to accelerated time to diagnosis, assessment, and intervention.

Conclusion: Genetic screening has strengthened UNHS and care for infants with or at risk for PHL in Ontario. This study is a step towards the broader inclusion of genomic testing in NBS.

Purpose: Limited evidence evaluates parents' perceptions of their child's clinical genomic sequencing (GS) results, particularly among individuals from medically underserved groups. Five Clinical Sequencing Evidence-Generating Research (CSER) consortium studies performed GS in children with suspected genetic conditions with high proportions of individuals from underserved groups to address this evidence gap.

Methods: Parents completed surveys of perceived understanding, personal utility, and test-related distress after GS result disclosure. We assessed outcomes' associations with child- and parent-related factors: child age; type of GS finding; and parent health literacy, numeracy, and education.

Results: 1763 parents completed surveys; 83% met "underserved" criteria based on race, ethnicity, and risk factors for barriers to access. We observed high perceived understanding and personal utility and low test-related distress. Outcomes were associated with the type of GS finding; parents of children with a pathogenic or likely pathogenic finding endorsed higher personal utility and more test-related distress than those whose child had a variant of uncertain significance (VUS) or normal finding. Personal utility was higher in parents who met criteria for "underserved."

Conclusions: Our findings shed light on correlates of parents' cognitive and emotional responses to their child's GS findings and emphasize the need for tailored support in disclosure discussions.

Purpose: Noonan syndrome and related disorders (NS) are multisystemic conditions affecting approximately 1:1000 individuals. Previous natural history studies were conducted prior to widespread comprehensive genetic testing. This study provides updated longitudinal natural history data in participants with molecularly confirmed NS.

Methods: Comprehensive medical, developmental, and healthcare utilization (HCU) data were abstracted from the medical record of participants with molecularly confirmed NS. Primary outcomes included developmental outcomes, classroom setting, and HCU.

Results: 172 patients with molecularly confirmed NS were followed for 1,142.2 patient-years total. An average of 3.7 affected organ systems on initial evaluation. Sitting, walking, and talking in two-word phrases all occurred earlier than in previous cohorts (p=0.003, p=0.001, p<0.0001 respectively). Genotype influenced age at milestones and classroom setting; feeding difficulties also influenced age at milestones. HCU was significantly higher in patients with NS compared to peers (p<0.0001) and highest in infancy and adolescence.

Conclusion: Developmental outcomes have improved compared to previous cohorts. Predictors of outcome may identify those at highest risk for developmental delay allowing for appropriate intervention. Children and adolescents with NS have an increased burden of HCU compared to their peers. Multidisciplinary care coordination is needed to decrease medical burden and improve health for patients and families.

Purpose: The increasing complexity of genetic technologies paired with more genetic tests being ordered by nongenetic healthcare providers, has resulted in an increase in the number of inappropriately ordered tests. Genetic counselors (GCs) are ideally suited to assess the appropriateness of a genetic test.

Methods: We performed a scoping review of GC involvement in utilization management initiatives in order to describe the impact of having GCs involved in this process. Five databases (MEDLINE, EMBASE, CINHAL, EBM reviews and Web of Science Core Collection) and grey literature were searched. We considered literature published in English since 2010.

Results: A total of 51 studies were included. Most commonly evaluated outcomes included cancellation rate, economic efficiencies, impact on medical management, diagnostic rate and time or triage efficiencies. Several studies also described GC impact on nongenetic healthcare providers.

Conclusion: Employment of GCs in the laboratory has been implemented widely as a solution to test misordering. These studies describe ways in which GCs can be integrated into testing workflows to reduce the number of inappropriate tests and have wider impacts on nongenetic healthcare providers ordering practices and the patient experience.

Purpose: Pathogenic germline variants (PGVs) in a subset of cancer predisposition genes (CPGs) are associated with adult-onset autosomal dominant (AD) cancer susceptibility and life-limiting autosomal recessive (AR) disease. Counseling in adult cancer genetics clinics regarding reproductive risk for PGV heterozygotes is limited.

Methods: Estimated heterozygote frequencies across ancestries were calculated for AD CPGs with AR risk (ATM, BRCA1, BRCA2, BRIP1, FH, NBN, MLH1, MSH2, MSH6, PMS2, RAD51C, SDHA, SDHB, and SDHD) from gnomADv.3.0, the Penn Medicine Biobank, and FLOSSIES.

Results: Average frequencies of heterozygotes with PGVs across ancestries for BRCA1 and BRCA2 were 0.33% ± 0.41% and 0.43% ± 0.36%, with variability cross-ancestry from 0.06% to 1.32% and 0.17% to 1.29%, respectively. ATM had the next highest PGV heterozygote frequency (0.31% ± 0.12%) and SDHD the lowest (0.01% ± 0.01%) average PGV heterozygote frequency. Heterozygote PGV frequencies from gnomAD were similar as cancer-free individuals in Penn Medicine Biobank and higher than in the FLOSSIES data.

Discussion: Heterozygote frequency estimates for AD CPGs that cause AR disease provides information to facilitate discussions regarding reproductive risk. Future studies are needed to assess whether utilization of these data will influence couples' reproductive risk planning.

Purpose: To replace an existing clinical practice guideline for the diagnosis and management of phenylalanine hydroxylase (PAH) deficiency.

Methods: The PAH Deficiency Guideline Workgroup used the Grading of Recommendations Assessment, Development, and Evaluation evidence-to-decision framework to develop evidence summaries and practice recommendations based on the recent American College of Medical Genetics and Genomics systematic review.

Results: Many recommendations from the 2014 PAH practice guideline are recognized as standard of care in this evidence-based guideline. Key recommendations from the previous guideline that were not supported by strong evidence are now strongly supported; (1) treatment for PAH deficiency should be lifelong for individuals with untreated phenylalanine (Phe) levels >360 μmol/L, (2) individuals with lifelong Phe levels ≤360 μmol/L have better intellectual outcomes than those who do not, (3) achieving Phe levels ≤360 μmol/L before conception is strongly recommended to prevent pregnancy complications and negative outcomes for the offspring, and (4) genetic testing for PAH variants is recommended at birth to confirm diagnosis and guide therapy.

Conclusion: We strongly recommend lifelong maintenance of Phe ≤360 μmol/L (using plasma or whole blood) for optimal intellectual outcomes and for reduced teratogenicity, utilizing all available and necessary dietary, pharmaceutical, and patient-educational modalities.

Purpose: Advances in fetal fraction amplification in prenatal cell-free DNA screening now allow for high-resolution detection of copy-number variants (CNVs). However, approaches to interpreting CNVs as part of a primary screen are still evolving and require consensus. Here, we present a conservative, patient-centered framework for reporting fetal CNVs.

Methods: Syndromes described in the literature were evaluated for inclusion based on a definable minimal critical region, disease severity, penetrance, and age of onset. The reporting framework required that a CNV overlap a defined minimal critical region and/or that it be ≥5 Mb and contain at least 1 OMIM disease-associated gene. This framework was then applied to CNVs identified from a cohort of 313,544 prenatal cfDNA screening patient samples. Patient-friendly terminology describing syndrome phenotypes was developed by scientists with training in genetic counseling.

Results: 65 syndromes met criteria for inclusion and represented the second most common class of CNVs in a retrospective cohort, more so than an established panel of microdeletions (1p36, 4p, 5p, 15q11.2-q13, and 22q11.2). Frequencies were concordant with reported syndrome incidence rates. The most common CNVs were those ≥5 Mb encompassing an OMIM disease gene(s).

Conclusion: This framework for genome-wide fetal-CNV reporting carefully prioritizes findings with the potential to affect reproductive decision making.

Purpose: This study aimed to identify phenotypic factors associated with genetic diagnoses in patients with neurodevelopmental disorders and generate a decision tree to assist clinicians in identifying patients most likely to receive a positive result on genetic testing.

Methods: We retrospectively reviewed the charts of 316 patients evaluated in a neurodevelopmental clinic between 2014 and 2019. Patients were categorized based on genetic test results. Analyses were performed to identify variables that discriminate between patients with and without a genetic diagnosis.

Results: Patients with a genetic diagnosis were more likely to be female and have a history of motor delay, hypotonia, congenital heart disease, and early intervention. Classification and regression tree analysis revealed that 75% of patients with motor delay had a genetic diagnosis. In patients without motor delay, hypotonia, age of walking, and age at initial evaluation were important indicators of a genetic diagnosis.

Conclusion: Our findings suggest that motor delay and hypotonia are associated with genetic diagnoses in children with neurodevelopmental disorders. The decision tree highlights patient subsets at greater risk and suggests possible phenotypic screens. Future studies could develop validated decision trees based on phenotypic data to assist clinicians in stratifying patients for genetic testing.

Purpose: ATM germline pathogenic variants (GPVs) are associated with a moderately increased risk of female breast cancer, pancreatic cancer, and prostate cancer. Resources for managing ATM heterozygotes in clinical practice are limited.

Methods: An international workgroup developed a clinical practice resource to guide management of ATM heterozygotes using peer-reviewed publications and expert opinion.

Results: Although ATM is a moderate (intermediate) penetrance gene, cancer risks may be considered as a continuous variable, influenced by family history and other modifiers. ATM GPV heterozygotes should generally be offered enhanced breast surveillance according to their personalized risk estimate and country-specific guidelines and, generally, risk-reducing mastectomy is not recommended. Prostate cancer surveillance should be considered. Pancreatic cancer surveillance should be considered based on assessment of family history, ideally as part of a clinical trial, with existence of country-specific guidelines. For ATM GPV heterozygotes who develop cancer, radiation therapy decisions should not be influenced by the genetic result. Although poly-adenosine diphosphate ribose polymerase inhibitors are licensed for use in metastatic castration-resistant prostate cancer and ATM GPVs, the evidence-base is currently weak.

Conclusion: Systematic prospective data collection is needed to establish the spectrum of ATM-associated cancer and determine the outlines of surveillance, response to cancer treatment, and survival.