Saturation mapping of MUTYH variant effects using DNA repair reporters DOI Creative Commons
Shelby L. Hemker, Ashley P.L. Marsh,

Felicia Hernandez

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 6, 2025

Variants of uncertain significance (VUS) limit the actionability genetic testing. A prominent example is MUTYH , a base excision repair factor associated with polyposis and colorectal cancer, which has pathogenic variant carrier rate approaching 1 in 50 individuals some populations. To systematically interrogate function we coupled deep mutational scanning DNA reporter containing its lesion substrate, 8OG:A. Our variant-to-function map covers >97% all possible point variants (n=10,941) achieves 100% accuracy classifying pathogenicity known clinical (n=247). Leveraging large registry, observe significant associations polyps more severely impaired missense conferring greater risk. We recapitulate functional differences between founder alleles, highlight sites complete intolerance, including residues that intercalate coordinate essential Zn 2+ or Fe-S clusters. This provides resource to resolve 1,032 existing VUS 90 conflicting interpretations demonstrates scalable strategy other clinically relevant factors.

Язык: Английский

Experience using conventional compared to ancestry-based population descriptors in clinical genomics laboratories DOI Creative Commons
Kathryn E. Hatchell, Sarah Poll, Emily M. Russell

и другие.

The American Journal of Human Genetics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

1
Newborn Screening Using Genome Sequencing for Early Actionable Conditions DOI
Gujie Wu, Lin Cheng,

Caiyun Lei

и другие.

JAMA, Год журнала: 2025, Номер unknown

Опубликована: Фев. 24, 2025

Our website uses cookies to enhance your experience. By continuing use our site, or clicking "Continue," you are agreeing Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors JAMA+ AI Journals Network Open Cardiology Dermatology Health Forum Internal Medicine Neurology Oncology Ophthalmology Otolaryngology–Head & Neck Surgery Pediatrics Psychiatry Archives of (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions LibrariansReprints Permissions Terms Use Privacy Accessibility Statement 2025 American Association. All Rights Reserved Search Archive Input Term Sign In Individual inCreate an Account Access through institution Purchase Options: Buy this article Rent Subscribe the journal

Язык: Английский

Процитировано

1
The incremental yield of prenatal exome sequencing over chromosome microarray for congenital heart abnormalities: A systematic review and meta‐analysis DOI

K. Reilly,

S. Sonner, Nicola McCay

и другие.

Prenatal Diagnosis, Год журнала: 2024, Номер 44(6-7), С. 821 - 831

Опубликована: Май 6, 2024

Abstract Objectives To determine the incremental yield of prenatal exome sequencing (PES) over standard testing in fetuses with an isolated congenital heart abnormality (CHA), CHA associated extra‐cardiac malformations (ECMs) and dependent upon anatomical subclassification. Methods A systematic review literature was performed using MEDLINE, EMBASE, Web Science grey January 2010‐February 2023. Studies were selected if they included greater than 20 cases prenatally diagnosed when (QF‐PCR/chromosome microarray/karyotype) negative. Pooled determined. PROSPERO CRD 42022364747. Results Overall, 21 studies, incorporating 1957 included. The PES (causative pathogenic likely variants) 17.4% (95% CI, 13.5%–21.6%), 9.3% 6.6%–12.3%) 35.9% 21.0%–52.3%) for all CHAs, CHAs ECMs. subgroup greatest complex lesions/heterotaxy; 35.2% CI 9.7%–65.3%). most common syndrome Kabuki (31/256, 12.1%) variants occurred de novo autosomal dominant (monoallelic) disease causing genes (114/224, 50.9%). Conclusion likelihood a monogenic aetiology multi‐system is high. Clinicians must consider clinical utility offering cardiac lesions.

Язык: Английский

Процитировано

6
The Clinical Genome Resource (ClinGen): Advancing genomic knowledge through global curation DOI Creative Commons
Erica Andersen, Danielle R. Azzariti, Lawrence Babb

и другие.

Genetics in Medicine, Год журнала: 2024, Номер unknown, С. 101228 - 101228

Опубликована: Окт. 1, 2024

Язык: Английский

Процитировано

6
Clinical Variant Reclassification in Hereditary Disease Genetic Testing DOI Creative Commons
Yuya Kobayashi, Elaine Chen, Flavia M. Facio

и другие.

JAMA Network Open, Год журнала: 2024, Номер 7(11), С. e2444526 - e2444526

Опубликована: Ноя. 6, 2024

Importance Because accurate and consistent classification of DNA sequence variants is fundamental to germline genetic testing, understanding patterns initial variant (VC) subsequent reclassification from large-scale, empirical data can help improve VC methods, promote equity among race, ethnicity, ancestry (REA) groups, provide insights inform clinical practice. Objectives To measure the degree which VCs met certainty thresholds set by professional guidelines quantify rates of, factors associated with, impact more than 2 million variants. Design, Setting, Participants This cohort study used multigene panel exome sequencing diagnostic testing for hereditary disorders, carrier screening, or preventive screening individuals whom was performed between January 1, 2015, June 30, 2023. Exposure were classified into 1 5 categories: benign, likely uncertain significance (VUS), pathogenic, pathogenic. Main Outcomes Measures The main outcomes accuracy classifications, directions reclassifications, evidence contributing their across different areas REA groups. One-way analysis variance followed post hoc pairwise Tukey honest significant difference tests analyze differences means, Pearson χ with Bonferroni corrections compare categorical variables Results comprised 3 272 035 (median [range] age, 44 [0-89] years; 240 506 female [68.47%] 030 729 male [31.50%]; 216 752 Black [6.62%]; 336 414 Hispanic [10.28%]; 804 273 White [55.14%]). Among 051 736 observed over 8 years in this cohort, 94 453 (4.60%) reclassified. Some reclassified once, resulting 105 172 total events. majority (64 events [61.65%]) changes VUS either pathogenic categories. An additional 37.66% reclassifications (39 608 events) gains terminal categories (ie, benign pathogenic). Only a small fraction (663 [0.63%]) moved toward less certainty, very rarely (61 [0.06%]) reversals. When normalized number tested, higher specific underrepresented populations (Ashkenazi Jewish, Asian, Black, Hispanic, Pacific Islander, Sephardic Jewish). Approximately one-half (37 074 64 840 [57.18%]) resulted improved use computational modeling. Conclusions Relevance In undergoing empirically estimated classifications exceeded current guidelines, suggesting need reevaluate definitions these classifications. relative contribution various strategies resolve VUS, including emerging machine learning–based RNA analysis, cascade family provides useful that be applied further improving reducing rate generating definitive results patients.

Язык: Английский

Процитировано

5
Expanding Applications of Clinical Genetic Testing — Ethical Challenges DOI
Stephanie M. Fullerton, Kyle B. Brothers

New England Journal of Medicine, Год журнала: 2024, Номер 390(15), С. 1349 - 1351

Опубликована: Апрель 13, 2024

The widening scope and scale of genetic tests are posing new challenges, the need to address these challenges is becoming immediately relevant for all clinicians, not just genetics experts.

Язык: Английский

Процитировано

4
Whole Exome Sequencing in a Population of Fetuses With Structural Anomalies DOI
Natalie Burrill,

Erica Schindewolf,

Lisa Pilchman

и другие.

Prenatal Diagnosis, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

ABSTRACT Objective To investigate the exome sequencing (ES) detection rate among fetuses with congenital anomalies and describe rates in setting of multiple versus isolated anomalies, perinatal autopsy, family history a previously affected child. Methods A single‐center retrospective chart review was conducted on 397 anomalous that underwent ES from May 2012 through December 2023. Medical record included demographics, imaging, genetic testing. Results The overall diagnostic 34.3%. diagnosis 31.6% single anomaly 42.6% 4 or more major organ systems involved. Of anomaly, lymphatic, craniofacial, skeletal, neurological had highest ES. 38.6% deceased who autopsy diagnosis. Additionally, families child 45.5% rate. Conclusions is an important tool should be offered pregnancies abnormalities at time fetal demise termination. prenatal also highly dependent comprehensive phenotyping. With results, reproductive technology testing options are available subsequent pregnancies.

Язык: Английский

Процитировано

0
A Multidisciplinary Approach to Navigating Variants of Uncertain Significance in Sudden Infant Deaths DOI
Renee Ouellette,

Austin Pagani,

Lydia D. Hellwig

и другие.

American Journal of Forensic Medicine & Pathology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 2, 2025

The sudden death of a previously healthy infant is devastating event for family-the 2 even more unimaginable. Prior to the debunking Meadow's law, legal concept attributing multiple unexplained deaths Munchausen by proxy, these events could lead wrongful prosecution those who had lost their children "sudden unexpected (SUID)." Today, cases, wherein infants within one family pass inexplicably, raise suspicion possible genetic cause and point toward need postmortem testing.We present case siblings passed suddenly in infancy, with no structural identified at autopsy. Genetic testing both found same variant uncertain significance, heterozygous single nucleotide substitution, denoted c.3191C>T, SCN10A, which encodes sodium channel pathogenic variants possibly implicated cardiac syndromes. Although it unclear this time if significance was contributing factor deaths, emphasized importance involving multidisciplinary team ensure appropriate pretest posttest counseling, interpretation nuanced results, medical follow-up surviving members SUID.

Язык: Английский

Процитировано

0
Cerebrotendinous xanthomatosis: A complex interplay between a clinically and genetically heterogeneous condition DOI Creative Commons
E. O’Keefe, Matthew C. Kiernan, William Huynh

и другие.

European Journal of Neurology, Год журнала: 2025, Номер 32(1)

Опубликована: Янв. 1, 2025

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease characterized by abnormal bile acid synthesis. It often presents with systemic and neurological manifestations; however, atypical presentations can lead to significant diagnostic challenges. This case report highlights the complexities management considerations in patient an uncommon presentation of CTX.

Язык: Английский

Процитировано

0
A retrospective single-center pilot study of the genetic background of the transplanted kidney DOI Creative Commons

Anna Novotná,

Klara Horáčková, Jana Soukupová

и другие.

PLoS ONE, Год журнала: 2025, Номер 20(1), С. e0316192 - e0316192

Опубликована: Янв. 8, 2025

Introduction Renal cell carcinoma (RCC) is one of the most prevalent cancers in kidney transplant recipients (KTR). The hereditary background RCC native kidneys has been determined, implicating its clinical importance. Materials and methods This retrospective single-center pilot study aimed to identify a potential genetic predisposition transplanted outcome KTR who underwent single transplantation between January 2000 December 2020 manifested kidney. Next-generation sequencing (NGS) based germline analysis from peripheral blood-derived genomic DNA (gDNA) was performed both recipient donor using gene panel targeting 226 cancer genes. Results calculated incidence among 4146 0.43%. In fifteen donors, NGS performed. mean age at diagnosis 50.3 years (median 54; 5–67 years) 66 66; 24–79 years), respectively. graft 39.7 42; 7–68 50.2 46; 20–83 follow-up after 47 months 39.1; 0–112 months). Papillary (n = 8), followed by clear 6) unspecified 1). Thirteen RCCs were low-stage (pT1a/b) diseases, pT3, unknown stage. Most higher graded. No pathogenic cancer-predisposition variant found either or donors except for several variants uncertain significance. Conclusion very rare. Germline testing identified significance, but no KTR. Further research needed assess relevance risk

Язык: Английский

Процитировано

0