Genetics in Medicine最新文献

{"title":"Longitudinal outcomes in Noonan syndrome","authors":"Alyssa L. Rippert ,&nbsp;Rebecca Reef ,&nbsp;Ashika Mani ,&nbsp;Arianna K. Stefanatos ,&nbsp;Rebecca C. Ahrens-Nicklas","doi":"10.1016/j.gim.2025.101355","DOIUrl":"10.1016/j.gim.2025.101355","url":null,"abstract":"<div><h3>Purpose</h3><div>Noonan syndrome and related disorders (NS) are multisystemic conditions affecting approximately 1:1000 individuals. Previous natural history studies were conducted before widespread comprehensive genetic testing. This study provides updated longitudinal natural history data in participants with molecularly confirmed NS.</div></div><div><h3>Methods</h3><div>Comprehensive medical, developmental, and health care utilization (HCU) data were abstracted from the medical records of participants with molecularly confirmed NS. Primary outcomes included developmental outcomes, classroom setting, and HCU.</div></div><div><h3>Results</h3><div>A total of 172 patients with molecularly confirmed NS were followed for 1142.2 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 (<em>P</em> = .003, <em>P</em> = .001, and <em>P</em> &lt; .0001, respectively). Genotype influenced the age at milestones and classroom setting; feeding difficulties also influenced the age at milestones. HCU was significantly higher in patients with NS compared with peers (<em>P</em> &lt; .0001) and highest in infancy and adolescence.</div></div><div><h3>Conclusion</h3><div>Developmental outcomes have improved compared with 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 with their peers. Multidisciplinary care coordination is needed to decrease medical burden and improve health of patients and families.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 4","pages":"Article 101355"},"PeriodicalIF":6.6,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of genetic counselor involvement in genetic and genomic test order review: A scoping review","authors":"Courtney B. Cook ,&nbsp;Carly Pistawka ,&nbsp;Alison M. Elliott","doi":"10.1016/j.gim.2025.101354","DOIUrl":"10.1016/j.gim.2025.101354","url":null,"abstract":"<div><h3>Purpose</h3><div>The increasing complexity of genetic technologies paired with more genetic tests being ordered by nongenetic health care 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.</div></div><div><h3>Methods</h3><div>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 gray literature were searched. We considered literature published in English since 2010.</div></div><div><h3>Results</h3><div>A total of 51 studies were included. The 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 health care providers.</div></div><div><h3>Conclusion</h3><div>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 health care providers’ ordering practices and the patient experience.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 3","pages":"Article 101354"},"PeriodicalIF":6.6,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum","authors":"Daniel G. Calame ,&nbsp;Jovi Huixin Wong ,&nbsp;Puravi Panda ,&nbsp;Dat Tuan Nguyen ,&nbsp;Nancy C.P. Leong ,&nbsp;Riccardo Sangermano ,&nbsp;Sohil G. Patankar ,&nbsp;Mohamed S. Abdel-Hamid ,&nbsp;Lama AlAbdi ,&nbsp;Sylvia Safwat ,&nbsp;Kyle P. Flannery ,&nbsp;Zain Dardas ,&nbsp;Jawid M. Fatih ,&nbsp;Chaya Murali ,&nbsp;Varun Kannan ,&nbsp;Timothy E. Lotze ,&nbsp;Isabella Herman ,&nbsp;Farah Ammouri ,&nbsp;Brianna Rezich ,&nbsp;Stephanie Efthymiou ,&nbsp;Long N. Nguyen","doi":"10.1016/j.gim.2024.101273","DOIUrl":"10.1016/j.gim.2024.101273","url":null,"abstract":"<div><h3>Purpose</h3><div><em>FLVCR1</em> encodes a solute carrier protein implicated in heme, choline, and ethanolamine transport. Although <em>Flvcr1</em>^−/− mice exhibit skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia (DBA), biallelic <em>FLVCR1</em> variants in humans have previously only been linked to childhood or adult-onset ataxia, sensory neuropathy, and retinitis pigmentosa.</div></div><div><h3>Methods</h3><div>We identified individuals with undiagnosed neurodevelopmental disorders and biallelic <em>FLVCR1</em> variants through international data sharing and characterized the functional consequences of their <em>FLVCR1</em> variants.</div></div><div><h3>Results</h3><div>We ascertained 30 patients from 23 unrelated families with biallelic <em>FLVCR1</em> variants and characterized a novel <em>FLVCR1</em>-related phenotype: severe developmental disorders with profound developmental delay, microcephaly (<em>z</em>-score −2.5 to −10.5), brain malformations, epilepsy, spasticity, and premature death. Brain malformations ranged from mild brain volume reduction to hydranencephaly. Severely affected patients share traits, including macrocytic anemia and skeletal malformations, with <em>Flvcr1</em>^−/− mice and DBA. <em>FLVCR1</em> variants significantly reduce choline and ethanolamine transport and/or disrupt mRNA splicing.</div></div><div><h3>Conclusion</h3><div>These data demonstrate a broad <em>FLVCR1</em>-related phenotypic spectrum ranging from severe multiorgan developmental disorders resembling DBA to adult-onset neurodegeneration. Our study expands our understanding of Mendelian choline and ethanolamine disorders and illustrates the importance of anticipating a wide phenotypic spectrum for known disease genes and incorporating model organism data into genome analysis to maximize genetic testing yield.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101273"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-ethnic heterozygote frequencies of cancer susceptibility genes to inform counseling of reproductive risk","authors":"Jacquelyn Powers ,&nbsp;Heather Wachtel ,&nbsp;Erica Trujillo ,&nbsp;Heena Desai ,&nbsp;Ryan Hausler ,&nbsp;Laura Conway ,&nbsp;Bradley Wubbenhorst","doi":"10.1016/j.gim.2024.101246","DOIUrl":"10.1016/j.gim.2024.101246","url":null,"abstract":"<div><h3>Purpose</h3><div>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.</div></div><div><h3>Methods</h3><div>Estimated heterozygote frequencies across ancestries were calculated for AD CPGs with AR risk (<em>ATM</em>, <em>BRCA1</em>, <em>BRCA2</em>, <em>BRIP1</em>, <em>FH</em>, <em>NBN</em>, <em>MLH1</em>, <em>MSH2</em>, <em>MSH6</em>, <em>PMS2</em>, <em>RAD51C</em>, <em>SDHA</em>, <em>SDHB</em>, and <em>SDHD</em>) from gnomADv.3.0, the Penn Medicine Biobank, and FLOSSIES.</div></div><div><h3>Results</h3><div>Average frequencies of heterozygotes with PGVs across ancestries for <em>BRCA1</em> and <em>BRCA2</em> 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. <em>ATM</em> had the next highest PGV heterozygote frequency (0.31% ± 0.12%) and <em>SDHD</em> 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.</div></div><div><h3>Discussion</h3><div>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.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101246"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical factors associated with genetic diagnosis in suspected neurogenetic disorders in a tertiary care clinic","authors":"Nicole R. Wong ,&nbsp;Alexandra Klomhaus ,&nbsp;David J. Adams ,&nbsp;Benjamin N. Schneider ,&nbsp;Sunil Mehta ,&nbsp;Charlotte DiStefano ,&nbsp;Rujuta B. Wilson ,&nbsp;Julian A. Martinez-Agosto ,&nbsp;Shafali S. Jeste ,&nbsp;Aaron D. Besterman","doi":"10.1016/j.gim.2024.101252","DOIUrl":"10.1016/j.gim.2024.101252","url":null,"abstract":"<div><h3>Purpose</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101252"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curation and reporting of pathogenic genome-wide copy-number variants in a prenatal cell-free DNA screen","authors":"Samuel G. Cox ,&nbsp;Ashley Acevedo ,&nbsp;Anand Ahuja ,&nbsp;Heather G. LaBreche ,&nbsp;Maria P. Alfaro ,&nbsp;Summer Pierson ,&nbsp;Thomas Westover ,&nbsp;Sarah Ratzel ,&nbsp;Susan Hancock ,&nbsp;Krista Moyer ,&nbsp;Dale Muzzey","doi":"10.1016/j.gim.2024.101223","DOIUrl":"10.1016/j.gim.2024.101223","url":null,"abstract":"<div><h3>Purpose</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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).</div></div><div><h3>Conclusion</h3><div>This framework for genome-wide fetal-CNV reporting carefully prioritizes findings with the potential to affect reproductive decision making.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101223"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenylalanine hydroxylase deficiency diagnosis and management: A 2023 evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG)","authors":"Wendy E. Smith ,&nbsp;Susan A. Berry ,&nbsp;Kaitlyn Bloom ,&nbsp;Christine Brown ,&nbsp;Barbara K. Burton ,&nbsp;Olivia M. Demarest ,&nbsp;Gabrielle P. Jenkins ,&nbsp;Jennifer Malinowski ,&nbsp;Kim L. McBride ,&nbsp;H. Joel Mroczkowski ,&nbsp;Curt Scharfe ,&nbsp;Jerry Vockley ,&nbsp;ACMG Board of Directors","doi":"10.1016/j.gim.2024.101289","DOIUrl":"10.1016/j.gim.2024.101289","url":null,"abstract":"<div><h3>Purpose</h3><div>To replace an existing clinical practice guideline for the diagnosis and management of phenylalanine hydroxylase (PAH) deficiency.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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 &gt;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 <em>PAH</em> variants is recommended at birth to confirm diagnosis and guide therapy.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101289"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142768140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Management of individuals with heterozygous germline pathogenic variants in ATM: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)","authors":"Tuya Pal ,&nbsp;Katherine R. Schon ,&nbsp;Esteban Astiazaran-Symonds ,&nbsp;Judith Balmaña ,&nbsp;William D. Foulkes ,&nbsp;Paul James ,&nbsp;Susan Klugman ,&nbsp;Alicia A. Livinski ,&nbsp;Julie S. Mak ,&nbsp;Joanne Ngeow ,&nbsp;Nicoleta Voian ,&nbsp;Myra J. Wick ,&nbsp;Helen Hanson ,&nbsp;Douglas R. Stewart ,&nbsp;Marc Tischkowitz ,&nbsp;ACMG Professional Practice and Guidelines Committee","doi":"10.1016/j.gim.2024.101243","DOIUrl":"10.1016/j.gim.2024.101243","url":null,"abstract":"<div><h3>Purpose</h3><div><em>ATM</em> germline pathogenic variants (GPVs) are associated with a moderately increased risk of female breast cancer, pancreatic cancer, and prostate cancer. Resources for managing <em>ATM</em> heterozygotes in clinical practice are limited.</div></div><div><h3>Methods</h3><div>An international workgroup developed a clinical practice resource to guide management of <em>ATM</em> heterozygotes using peer-reviewed publications and expert opinion.</div></div><div><h3>Results</h3><div>Although <em>ATM</em> is a moderate (intermediate) penetrance gene, cancer risks may be considered as a continuous variable, influenced by family history and other modifiers. <em>ATM</em> 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 <em>ATM</em> 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 <em>ATM</em> GPVs, the evidence-base is currently weak.</div></div><div><h3>Conclusion</h3><div>Systematic prospective data collection is needed to establish the spectrum of <em>ATM</em>-associated cancer and determine the outlines of surveillance, response to cancer treatment, and survival.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101243"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Clinical Genome Resource (ClinGen): Advancing genomic knowledge through global curation","authors":"The ClinGen Consortium","doi":"10.1016/j.gim.2024.101228","DOIUrl":"10.1016/j.gim.2024.101228","url":null,"abstract":"<div><div>The Clinical Genome Resource (ClinGen) is a National Institutes of Health-funded program founded 10 years ago that defines the clinical relevance of genes and variants for medical and research use. ClinGen working groups develop standards for data sharing and curating genomic knowledge. Expert panels, with &gt;2500 active members from 67 countries, curate the validity of monogenic disease relationships, pathogenicity of genetic variation, dosage sensitivity of genes, and actionability of gene-disease interventions using ClinGen standards, infrastructure, and curation interfaces. Results are available on <span><span>clinicalgenome.org</span><svg><path></path></svg></span> and classified variants are also submitted to ClinVar, a publicly available database hosted by the National Institutes of Health. As of January 2024, over 2700 genes have been curated (2420 gene-disease relationships for validity, 1557 genes for dosage sensitivity, and 447 gene-condition pairs for actionability), and 5161 unique variants have been classified for pathogenicity. New efforts are underway in somatic cancer, complex disease and pharmacogenomics, and a systematic approach to addressing justice, equity, diversity, and inclusion. ClinGen’s knowledge can be used to build evidence-based genetic testing panels, interpret copy-number variation, resolve discrepancies in variant classification, guide disclosure of genomic findings to patients, and assess new predictive algorithms. To get involved in ClinGen activities go to <span><span>https://www.clinicalgenome.org/start</span><svg><path></path></svg></span>.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101228"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fetal fraction amplification within prenatal cfDNA screening enables detection of genome-wide copy-number variants at enhanced resolution","authors":"Ashley Acevedo ,&nbsp;Oyang Teng ,&nbsp;Heather G. LaBreche ,&nbsp;Alison Nguyen ,&nbsp;Luis Jazo ,&nbsp;Sun Hae Hong ,&nbsp;John Suk ,&nbsp;Summer Pierson ,&nbsp;Thomas Westover ,&nbsp;Sarah Ratzel ,&nbsp;Kevin R. Haas ,&nbsp;Dale Muzzey","doi":"10.1016/j.gim.2024.101269","DOIUrl":"10.1016/j.gim.2024.101269","url":null,"abstract":"<div><h3>Purpose</h3><div>Clinically significant copy-number variants (CNVs) occur in 1% to 2% of pregnancies and are difficult to detect via prenatal cell-free DNA (cfDNA) screening because of the low fraction of fetal-derived cfDNA in maternal plasma. Here, we use fetal fraction amplification (FFA) and improved computational algorithms to enhance the resolution and sensitivity of CNV detection.</div></div><div><h3>Methods</h3><div>We implemented and characterized the performance of a hidden Markov model that identifies fetal CNVs. This CNV caller was analytically validated on 117 FFA samples, including 57 fetal-CNV-containing samples, and applied retrospectively to a cohort of more than 300k patient samples.</div></div><div><h3>Results</h3><div>Our assay was concordant with orthogonal testing and detected fetal CNVs ≥5 Mb with estimated aggregate sensitivity and specificity of &gt;95.1% and &gt;99.7%, respectively. The resolution of CNV detection was fetal fraction dependent, but 97.2% of samples reached ≥5-Mb resolution. Overall, CNVs ≥5 Mb were found in 1 in 500 pregnancies.</div></div><div><h3>Conclusion</h3><div>FFA improves the sensitivity and resolution of CNV detection in prenatal cfDNA screening, allowing accurate detection of fetal CNVs as small as 1 Mb. Using our approach, we found that clinically significant fetal CNVs were detected more frequently than the common trisomies 13 and 18 that are recommended as part of guideline-based screening.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101269"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}