Genetics in Medicine最新文献

{"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}

{"title":"Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability","authors":"Lachlan De Hayr ,&nbsp;Laura E.R. Blok ,&nbsp;Kerith-Rae Dias ,&nbsp;Jingyi Long ,&nbsp;Anaïs Begemann ,&nbsp;Robyn D. Moir ,&nbsp;Ian M. Willis ,&nbsp;Martina Mocera ,&nbsp;Gabriele Siegel ,&nbsp;Katharina Steindl ,&nbsp;Carey-Anne Evans ,&nbsp;Ying Zhu ,&nbsp;Futao Zhang ,&nbsp;Michael Field ,&nbsp;Alan Ma ,&nbsp;Lesley Adès ,&nbsp;Sarah Josephi-Taylor ,&nbsp;Rolph Pfundt ,&nbsp;Maha S. Zaki ,&nbsp;Hoda Tomoum ,&nbsp;Robert J. Harvey","doi":"10.1016/j.gim.2024.101253","DOIUrl":"10.1016/j.gim.2024.101253","url":null,"abstract":"<div><h3>Purpose</h3><div>This study details a novel syndromic form of autosomal recessive intellectual disability resulting from recessive variants in <em>GTF3C3</em>, encoding a key component of the DNA-binding transcription factor IIIC, which has a conserved role in RNA polymerase III-mediated transcription.</div></div><div><h3>Methods</h3><div>Exome sequencing, minigene analysis, molecular modeling, RNA polymerase III reporter gene assays, and <em>Drosophila</em> knockdown models were utilized to characterize <em>GTF3C3</em> variants.</div></div><div><h3>Results</h3><div>Twelve affected individuals from 7 unrelated families were identified with homozygous or compound heterozygous missense variants in <em>GTF3C3</em> including c.503C&gt;T p.(Ala168Val), c.1268T&gt;C p.(Leu423Pro), c.1436A&gt;G p.(Tyr479Cys), c.2419C&gt;T p.(Arg807Cys), and c.2420G&gt;A p.(Arg807His). The cohort presented with intellectual disability, variable nonfamilial facial features, motor impairments, seizures, and cerebellar/corpus callosum malformations. Consistent with disruptions in intra- and intermolecular interactions observed in molecular modeling, RNA polymerase III reporter assays confirmed that the majority of missense variants resulted in a loss of function. Minigene analysis of the recurrent c.503C&gt;T p.(Ala168Val) variant confirmed the introduction of a cryptic donor site into exon 4, resulting in mRNA missplicing. Consistent with the clinical features of this cohort, neuronal loss of <em>Gtf3c3</em> in <em>Drosophila</em> induced seizure-like behavior, motor impairment, and learning deficits.</div></div><div><h3>Conclusion</h3><div>These findings confirm that <em>GTF3C3</em> variants result in an autosomal recessive form of syndromic intellectual disability.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101253"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785029","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":"The Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses","authors":"Rocio Rius ,&nbsp;Alison G. Compton ,&nbsp;Naomi L. Baker ,&nbsp;Shanti Balasubramaniam ,&nbsp;Stephanie Best ,&nbsp;Kaustuv Bhattacharya ,&nbsp;Kirsten Boggs ,&nbsp;Tiffany Boughtwood ,&nbsp;Jeffrey Braithwaite ,&nbsp;Drago Bratkovic ,&nbsp;Alessandra Bray ,&nbsp;Marie-Jo Brion ,&nbsp;Jo Burke ,&nbsp;Sarah Casauria ,&nbsp;Belinda Chong ,&nbsp;David Coman ,&nbsp;Shannon Cowie ,&nbsp;Mark Cowley ,&nbsp;Michelle G. de Silva ,&nbsp;Martin B. Delatycki ,&nbsp;David R. Thorburn","doi":"10.1016/j.gim.2024.101271","DOIUrl":"10.1016/j.gim.2024.101271","url":null,"abstract":"<div><h3>Purpose</h3><div>Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. The Australian Genomics Mitochondrial Flagship, comprising clinicians, diagnostic, and research scientists, conducted a prospective national study to identify the diagnostic utility of singleton genomic sequencing using blood samples.</div></div><div><h3>Methods</h3><div>A total of 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomized to either exome + mitochondrial DNA (mtDNA) sequencing or genome sequencing.</div></div><div><h3>Results</h3><div>Diagnostic yield was 55% (<em>n</em> = 77) with variants in nuclear (<em>n</em> = 37) and mtDNA (<em>n</em> = 18) MD genes, as well as phenocopy genes (<em>n</em> = 22). A nuclear gene etiology was identified in 77% of diagnoses, irrespective of disease onset. Diagnostic rates were higher in pediatric-onset (71%) than adult-onset (31%) cases and comparable in children with non-European (78%) vs European (67%) ancestry. For children, higher MNC scores correlated with increased diagnostic yield and fewer diagnoses in phenocopy genes. Additionally, 3 adult patients had a mtDNA deletion discovered in skeletal muscle that was not initially identified in blood.</div></div><div><h3>Conclusion</h3><div>Genomic sequencing from blood can simplify the diagnostic pathway for individuals living with suspected MD, especially those with childhood onset diseases and high MNC scores.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101271"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284364","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":"Critically unwell infants and children with mitochondrial disorders diagnosed by ultrarapid genomic sequencing","authors":"Megan Ball ,&nbsp;Sophie E. Bouffler ,&nbsp;Christopher B. Barnett ,&nbsp;Mary-Louise Freckmann ,&nbsp;Matthew F. Hunter ,&nbsp;Benjamin Kamien ,&nbsp;Karin S. Kassahn ,&nbsp;Sebastian Lunke ,&nbsp;Chirag V. Patel ,&nbsp;Jason Pinner ,&nbsp;Tony Roscioli ,&nbsp;Sarah A. Sandaradura ,&nbsp;Hamish S. Scott ,&nbsp;Tiong Y. Tan ,&nbsp;Mathew Wallis ,&nbsp;Alison G. Compton ,&nbsp;David R. Thorburn ,&nbsp;Zornitza Stark ,&nbsp;John Christodoulou","doi":"10.1016/j.gim.2024.101293","DOIUrl":"10.1016/j.gim.2024.101293","url":null,"abstract":"<div><h3>Purpose</h3><div>To characterize the diagnostic and clinical outcomes of a cohort of critically ill infants and children with suspected mitochondrial disorders (MD) undergoing ultrarapid genomic testing as part of a national program.</div></div><div><h3>Methods</h3><div>Ultrarapid genomic sequencing was performed in 454 families (genome sequencing: <em>n</em> = 290, exome sequencing +/− mitochondrial DNA sequencing: <em>n</em> = 164). In 91 individuals, MD was considered, prompting analysis using an MD virtual gene panel. These individuals were reviewed retrospectively and scored according to modified Nijmegen Mitochondrial Disease Criteria.</div></div><div><h3>Results</h3><div>A diagnosis was achieved in 47% (43/91) of individuals, 40% (17/43) of whom had an MD. Seven additional individuals in whom an MD was not suspected were diagnosed with an MD after broader analysis. Gene-agnostic analysis led to the discovery of 2 novel disease genes, with pathogenicity validated through targeted functional studies (<em>CRLS1</em> and <em>MRPL39</em>). Functional studies enabled diagnosis in another 4 individuals. Of the 24 individuals ultimately diagnosed with an MD, 79% had a change in management, which included 53% whose care was redirected to palliation.</div></div><div><h3>Conclusion</h3><div>Ultrarapid genetic diagnosis of MD in acutely unwell infants and children is critical for guiding decisions about the need for additional investigations and clinical management.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101293"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463205","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":"Biomarker testing for lysosomal diseases: A technical standard of the American College of Medical Genetics and Genomics (ACMG)","authors":"Ashlee R. Stiles ,&nbsp;Taraka R. Donti ,&nbsp;Patricia L. Hall ,&nbsp;William R. Wilcox ,&nbsp;ACMG Laboratory Quality Assurance Committee","doi":"10.1016/j.gim.2024.101242","DOIUrl":"10.1016/j.gim.2024.101242","url":null,"abstract":"<div><div>Measurement of lysosomal disease (LD) biomarkers can reveal valuable information about disease status. Lyso-globotriaosylceramide (lyso-Gb₃), glucosylsphingosine (lyso-Gb₁), galactosylsphingosine (psychosine), and glucose tetrasaccharide (Glca1-6Glca1-4Glca1-4Glc, Glc₄) are biomarkers associated with Fabry, Gaucher, Krabbe, and Pompe disease, respectively. Clinical biomarker testing is performed to guide patient management, including monitoring disease progression and initiating treatment, and in diagnostic evaluations of either symptomatic patients or asymptomatic individuals with a positive family history or abnormal newborn screen. Biomarker analysis can be performed through independent analysis of a single analyte or as a multiplex assay measuring analytes for more than one disorder utilizing liquid chromatographic separation and tandem mass spectrometric detection. These guidelines were developed to provide technical standards for biomarker analysis, results interpretation, and results reporting, highlighting Fabry, Gaucher, Krabbe, and Pompe diseases as examples.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101242"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582845","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":"Expanding the phenotype and genotype spectrum of TAOK1 neurodevelopmental disorder and delineating TAOK2 neurodevelopmental disorder","authors":"Nour Elkhateeb ,&nbsp;Renarta Crookes ,&nbsp;Michael Spiller ,&nbsp;Lisa Pavinato ,&nbsp;Flavia Palermo ,&nbsp;Alfredo Brusco ,&nbsp;Michael Parker ,&nbsp;Soo-Mi Park ,&nbsp;Ariana Costa Mendes ,&nbsp;Jorge M. Saraiva ,&nbsp;Trine Bjørg Hammer ,&nbsp;Lusine Nazaryan-Petersen ,&nbsp;Tahsin Stefan Barakat ,&nbsp;Martina Wilke ,&nbsp;Elizabeth Bhoj ,&nbsp;Rebecca C. Ahrens-Nicklas ,&nbsp;Dong Li ,&nbsp;Tomoki Nomakuchi ,&nbsp;Eva H. Brilstra ,&nbsp;David Hunt ,&nbsp;Meena Balasubramanian","doi":"10.1016/j.gim.2024.101348","DOIUrl":"10.1016/j.gim.2024.101348","url":null,"abstract":"<div><h3>Purpose</h3><div>The thousand and one kinase (TAOK) proteins are a group of serine/threonine-protein kinases involved in signaling pathways, cytoskeleton regulation, and neuronal development. <em>TAOK1</em> variants are associated with a neurodevelopmental disorder (NDD) characterized by distinctive facial features, hypotonia, and feeding difficulties. <em>TAOK2</em> variants have been reported to be associated with autism and early-onset obesity. However, a distinct <em>TAOK2</em>-NDD has not yet been delineated.</div></div><div><h3>Methods</h3><div>We retrospectively studied the clinical and genetic data of individuals recruited from several centers with <em>TAOK1</em> and <em>TAOK2</em> variants that were detected through exome and genome sequencing.</div></div><div><h3>Results</h3><div>We report 50 individuals with <em>TAOK1</em> variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (83%), and hypotonia (58%). We report male genital anomalies and hypoglycemia as novel phenotypes. Thirty-seven unique <em>TAOK1</em> variants were identified. Most of the missense variants clustered in the protein kinase domain at residues that are intolerant to missense variation. We report 10 patients with <em>TAOK2</em> variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (75%), autism (75%), and obesity (70%).</div></div><div><h3>Conclusion</h3><div>We describe the largest cohort of <em>TAOK1</em>-NDD to date, to our knowledge, expanding its phenotype and genotype spectrum with 30 novel variants. We delineated the phenotype of a novel <em>TAOK2</em>-NDD associated with neurodevelopmental abnormalities, autism, macrocephaly, and obesity.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 3","pages":"Article 101348"},"PeriodicalIF":6.6,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907000","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":"Evaluating the impact of modeling choices on the performance of integrated genetic and clinical models","authors":"Theodore J. Morley ,&nbsp;Drew Willimitis ,&nbsp;Michael Ripperger ,&nbsp;Hyunjoon Lee ,&nbsp;Yu Zhou ,&nbsp;Lide Han ,&nbsp;Jooeun Kang ,&nbsp;William U. Meyerson ,&nbsp;Jordan W. Smoller ,&nbsp;Karmel W. Choi ,&nbsp;Colin G. Walsh ,&nbsp;Douglas M. Ruderfer","doi":"10.1016/j.gim.2024.101353","DOIUrl":"10.1016/j.gim.2024.101353","url":null,"abstract":"<div><h3>Purpose</h3><div>The value of genetic information for improving the performance of clinical risk prediction models has yielded variable conclusions. Many methodological decisions have the potential to contribute to differential results. We performed multiple modeling experiments integrating clinical and demographic data from electronic health records with genetic data to understand which decisions may affect performance.</div></div><div><h3>Methods</h3><div>Clinical data in the form of structured diagnostic codes, medications, procedural codes, and demographics were extracted from 2 large independent health systems, and polygenic risk scores (PRS) were generated across all patients of European ancestry with genetic data in the corresponding biobanks. Crohn’s disease was studied based on its substantial genetic component, established electronic health records-based definition, and sufficient prevalence for training and testing. We investigated the impact of choices regarding the PRS integration method, training sample, model complexity, and performance metrics.</div></div><div><h3>Results</h3><div>Overall, our results showed that including PRS resulted in higher performance, but this gain was only robust in situations with limited clinical information. We found consistent performance increases from more compute-intensive models, such as random forest, but the impact of other decisions varied by site.</div></div><div><h3>Conclusion</h3><div>This work highlights the importance of considering methodological decision points in interpreting the impact of PRS on prediction performance in clinical models.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 4","pages":"Article 101353"},"PeriodicalIF":6.6,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894015","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}