American journal of human genetics最新文献

{"title":"Bi-allelic variants in POPDC2 cause an autosomal recessive syndrome presenting with cardiac conduction defects and hypertrophic cardiomyopathy.","authors":"Michele Nicastro, Alexa M C Vermeer, Pieter G Postema, Rafik Tadros, Forrest Z Bowling, Hildur M Aegisdottir, Vinicius Tragante, Lukas Mach, Alex V Postma, Elisabeth M Lodder, Karel van Duijvenboden, Rob Zwart, Leander Beekman, Lingshuang Wu, Sean J Jurgens, Paul A van der Zwaag, Mariëlle Alders, Mona Allouba, Yasmine Aguib, J Luis Santome, David de Una, Lorenzo Monserrat, Antonio M A Miranda, Kazumasa Kanemaru, James Cranley, Ingeborg E van Zeggeren, Eleonora M A Aronica, Michela Ripolone, Simona Zanotti, Gardar Sveinbjornsson, Erna V Ivarsdottir, Hilma Hólm, Daníel F Guðbjartsson, Ástrós Th Skúladóttir, Kári Stefánsson, Lincoln Nadauld, Kirk U Knowlton, Sisse Rye Ostrowski, Erik Sørensen, Ole Birger Vesterager Pedersen, Jonas Ghouse, Søren A Rand, Henning Bundgaard, Henrik Ullum, Christian Erikstrup, Bitten Aagaard, Mie Topholm Bruun, Mette Christiansen, Henrik K Jensen, Deanna Alexis Carere, Christopher T Cummings, Kristen Fishler, Pernille Mathiesen Tørring, Klaus Brusgaard, Trine Maxel Juul, Lotte Saaby, Bo Gregers Winkel, Jens Mogensen, Francesco Fortunato, Giacomo Pietro Comi, Dario Ronchi, J Peter van Tintelen, Michela Noseda, Michael V Airola, Imke Christiaans, Arthur A M Wilde, Ronald Wilders, Sally-Ann Clur, Arie O Verkerk, Connie R Bezzina, Najim Lahrouchi","doi":"10.1016/j.ajhg.2025.04.016","DOIUrl":"10.1016/j.ajhg.2025.04.016","url":null,"abstract":"<p><p>POPDC2 encodes the Popeye domain-containing protein 2, which has an important role in cardiac pacemaking and conduction, due in part to its cyclic AMP (cAMP)-dependent binding and regulation of TREK-1 potassium channels. Loss of Popdc2 in mice results in sinus pauses and bradycardia, and morpholino-mediated knockdown of popdc2 in zebrafish results in atrioventricular (AV) block. We identified bi-allelic variants in POPDC2 in four families with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects, and hypertrophic cardiomyopathy. Using homology modeling, we show that the identified variants are predicted to diminish the ability of POPDC2 to bind cAMP. In in vitro electrophysiological studies, we demonstrated that, in contrast with wild-type POPDC2, variants found in affected individuals failed to increase TREK-1 current density. While muscle biopsy of an affected individual did not show clear myopathic disease, it showed significantly reduced abundance of both POPDC1 and POPDC2, suggesting that stability and/or membrane trafficking of the POPDC1-POPDC2 complex is impaired by pathogenic variants in either protein. Single-cell RNA sequencing from human hearts demonstrated that co-expression of POPDC1 and POPDC2 was most prevalent in AV node, AV node pacemaker, and AV bundle cells. Using population-level genetic data of more than 1 million individuals, we show that none of the familial variants were associated with clinical outcomes in heterozygous state, suggesting that heterozygous family members are unlikely to develop clinical manifestations and therefore might not necessitate clinical follow-up. Our findings provide evidence for bi-allelic variants in POPDC2 causing a Mendelian autosomal recessive cardiac syndrome.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toward whole-genome inference of polygenic scores with fast and memory-efficient algorithms.","authors":"Shadi Zabad, Chirayu Anant Haryan, Simon Gravel, Sanchit Misra, Yue Li","doi":"10.1016/j.ajhg.2025.05.002","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.05.002","url":null,"abstract":"<p><p>With improved whole-genome sequencing and variant imputation techniques, modern genome-wide association studies (GWASs) have enriched our understanding of the landscape of genetic associations for thousands of disease phenotypes. However, translating the marginal associations for millions of genetic variants to integrated polygenic risk scores (PRSs) that capture their joint effects on the phenotype remains a major challenge. Due to technical and statistical constraints, commonly used PRS methods in this setting either perform heuristic pruning and thresholding or overlook most genetic association signals by restricting inference to small variant sets, such as HapMap3. Here, we present a set of algorithmic improvements and compact data structures that enable scaling summary-statistics-based PRS inference to tens of millions of variants while avoiding numerical instabilities common in such high-dimensional settings. These enhancements consist of highly compressed linkage-disequilibrium (LD) matrix format, which integrates with streamlined and parallel coordinate-ascent updating schemes. When incorporated into our existing PRS method (VIPRS), the proposed algorithms yield over 50-fold reductions in storage requirements and lead to orders-of-magnitude improvements in runtime and memory efficiency. The updated VIPRS software can now perform variational Bayesian regression over 1.1 million HapMap3 variants in under a minute. Using this scalable implementation, we applied VIPRS to 75 of the most heritable, continuous phenotypes in the UK Biobank, leveraging marginal associations for up to 18 million bi-allelic variants. These experiments demonstrated that VIPRS is 1-2 orders of magnitude more efficient than popular baselines while being competitive with the best-performing methods in terms of prediction accuracy.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prioritizing disease-associated missense variants with chemoproteomic-detected amino acids.","authors":"Maria F Palafox,Lisa Boatner,Blake R Wilde,Heather Christofk,Keriann M Backus,Valerie A Arboleda","doi":"10.1016/j.ajhg.2025.04.017","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.04.017","url":null,"abstract":"Missense variants are the most common type of protein-altering genetic variation. Due to their wide-ranging potential functional consequences, missense variants are challenging to interpret and, as a result, are often classified as unknown pathogenicity or as variants of uncertain significance (VUSs). Genomic-based predictive tools have made significant inroads into the challenge of accurately pinpointing functional missense variants by providing genome-wide assessments of deleteriousness or potential pathogenicity. Complementary to these tools, here we provide an initial study into the utility of harnessing protein-based measures of amino acid reactivity to delineate functionally significant missense variants. These reactivity measurements, which are generated using mass spectrometry-based chemoproteomic methods, have already proved capable of pinpointing functional sites on proteins, which provide the added value of delineating potential sites suitable for drug-development efforts. Here, using published chemoproteomic datasets for three specific privileged amino acids, cysteine, lysine, and tyrosine, we assessed the utility of proteomic reactivity measurements to identify clinically important variants and regions within monogenic-disease-associated genes. We found that genes where amino acids are detected via chemoproteomics are enriched for monogenic-disease phenotypes, indicative of functional importance. Chemoproteomic-detected amino acids (CpDAAs) are enriched at and around sites with known pathogenic missense variants when assessed with either one- or three-dimensional protein structures. To further illustrate the utility of our findings, we found that regions at or around CpDAAs in fumarate hydratase (FH) were enriched for VUSs and pathogenic variants, which we validate through demonstration of an altered FH oligomerization state. Collectively, our study highlights the potential of chemoproteomic and genetic data integration for enhancing the identification of functional genetic variants and protein sites with potential value for drug-development efforts.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"34 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variants in BSN, encoding the presynaptic protein Bassoon, result in a distinct neurodevelopmental disorder with a broad phenotypic range.","authors":"Stacy G Guzman, Sarah M Ruggiero, Shiva Ganesan, Colin A Ellis, Alicia G Harrison, Katie R Sullivan, Zornitza Stark, Natasha J Brown, Sajel L Kana, Anabelle Tuttle, Jair Tenorio, Pablo Lapunzina, Julián Nevado, Marie T McDonald, Courtney Jensen, Patricia G Wheeler, Lila Stange, Jennifer Morrison, Boris Keren, Solveig Heide, Meg W Keating, Kameryn M Butler, Mike A Lyons, Shailly Jain, Mehdi Yeganeh, Michelle L Thompson, Molly Schroeder, Hoanh Nguyen, Jorge Granadillo, Kari M Johnston, Chaya N Murali, Katie Bosanko, T Andrew Burrow, Syreeta Morgan, Deborah J Watson, Hakon Hakonarson, Ingo Helbig","doi":"10.1016/j.ajhg.2025.04.011","DOIUrl":"10.1016/j.ajhg.2025.04.011","url":null,"abstract":"<p><p>Disease-causing variants in synaptic function genes are a common cause of neurodevelopmental disorders (NDDs) and epilepsy. Here, we describe 14 individuals with de novo disruptive variants in BSN, which encodes the presynaptic protein Bassoon. To expand the phenotypic spectrum, we identified 15 additional individuals with protein-truncating variants (PTVs) from large biobanks. Clinical features were standardized using the Human Phenotype Ontology (HPO) across all 29 individuals, which revealed common clinical characteristics including epilepsy (13/29, 45%), febrile seizures (7/29, 25%), generalized tonic-clonic seizures (5/29, 17%), and focal-onset seizures (3/29, 10%). Behavioral phenotypes were present in almost half of all individuals (14/29, 48%), which included ADHD (7/29, 25%) and autistic behavior (5/29, 17%). Additional common features included developmental delay (11/29, 38%), obesity (10/29, 34%), and delayed speech (8/29, 28%). In adults with BSN PTVs, milder features were common, suggesting phenotypic variability, including a range of individuals without obvious neurodevelopmental features (7/29, 24%). To detect gene-specific signatures, we performed association analysis in a cohort of 14,895 individuals with NDDs. A total of 66 clinical features were associated with BSN, including febrile seizures (p = 1.26e-06) and behavioral disinhibition (p = 3.39e-17). Furthermore, individuals carrying BSN variants were phenotypically more similar than expected by chance (p = 0.00014), exceeding phenotypic relatedness in 179/256 NDD-related conditions. In summary, integrating information derived from community-based gene matching and large data repositories through computational phenotyping approaches, we identify BSN variants as the cause of a synaptic disorder with a broad phenotypic range across the age spectrum.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping chromatin interactions at melanoma susceptibility loci uncovers distant cis-regulatory gene targets.","authors":"Rohit Thakur, Mai Xu, Hayley Sowards, Joshuah Yon, Lea Jessop, Timothy Myers, Tongwu Zhang, Raj Chari, Erping Long, Thomas Rehling, Rebecca Hennessey, Karen Funderburk, Jinhu Yin, Mitchell J Machiela, Matthew E Johnson, Andrew D Wells, Alessandra Chesi, Struan F A Grant, Mark M Iles, Maria Teresa Landi, Matthew H Law, Jiyeon Choi, Kevin M Brown","doi":"10.1016/j.ajhg.2025.04.015","DOIUrl":"10.1016/j.ajhg.2025.04.015","url":null,"abstract":"<p><p>Genome-wide association studies (GWASs) of melanoma risk have identified 68 independent signals at 54 loci. For most loci, specific functional variants and their respective target genes remain to be established. Capture-HiC is an assay that links fine-mapped risk variants to candidate target genes by comprehensively mapping chromatin interactions. We performed a melanoma GWAS region-focused capture-HiC assay in human primary melanocytes to identify physical interactions between fine-mapped risk variants and potential causal melanoma-susceptibility genes. Overall, chromatin-interaction data alone nominated potential causal genes for 61 of the 68 melanoma risk signals, identifying many candidates beyond those reported by previous studies. We further integrated these data with epigenomic (chromatin state, accessibility), gene expression (expression quantitative trait locus [eQTL]/transcriptome-wide association study [TWAS]), DNA methylation (methylation QTL [meQTL]/methylome-wide association study [MWAS]), and massively parallel reporter assay (MPRA) data generated from melanoma-relevant cell types to prioritize potentially cis-regulatory variants and their respective candidate gene targets. From the set of fine-mapped variants across these loci, we identified 140 prioritized credible causal variants linked to 195 candidate genes at 42 risk signals. In addition, we developed an integrative scoring system to facilitate candidate gene prioritization, integrating melanocyte and melanoma datasets. Notably, at several GWAS risk signals, we observed long-range chromatin connections (500 kb to >1 Mb) with distant candidate target genes. We validated several such cis-regulatory interactions using CRISPR inhibition, providing evidence for known cancer driver genes MDM4 and CBL, as well as the SRY-box transcription factor SOX4, as likely melanoma risk genes.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying active and inhibitor-resistant MGMT variants for gene therapy.","authors":"Ana Cheong, Adam Fisher, Ashvin Bashyam, Anthony Forget, Robert Peters, Zachary David Nagel","doi":"10.1016/j.ajhg.2025.04.014","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.04.014","url":null,"abstract":"<p><p>O6-methylguanine-DNA methyltransferase (MGMT) reverses alkylating-agent-induced methylation by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) at the O⁶ position of guanine. MGMT is irreversibly inhibited by O⁶-benzylguanine (O6BG), while the Pro140Lys (P140K) variant is resistant. Combining the use of O6BG/BCNU with gene transfer of MGMT P140K into hematopoietic stem cells (HSCs) has enabled in vivo enrichment of gene-modified HSCs for therapeutic effect in preclinical studies. However, the P140K substitution cannot reliably be made using currently available gene-editing approaches. Identifying functional MGMT variants that are resistant to inhibitors and amenable to gene editing would enable in vivo enrichment of HSCs edited at both MGMT and a therapeutic locus. We used computational analyses to select putative variants and generated a library of MGMT variant-expressing plasmids (pMGMTs). For our functional screen, we treated MGMT-deficient U251 cells with O6BG and co-transfected them with pMGMT together with a plasmid cocktail including a fluorescent host cell reactivation reporter plasmid (mPlum_O⁶MeG) for MGMT activity. Flow cytometric analysis of MGMT activity identified active and O6BG-resistant MGMT variants. Treatment with a second MGMT inhibitor, PaTrin-2, confirmed these results. We also found MGMT variants that are detectable in the general population and tumors to be active and O6BG sensitive. Taken together, our findings establish a functional database for MGMT variants and a cell-based platform for screening DNA-repair proteins for unknown functional properties.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A flexible machine learning Mendelian randomization estimator applied to predict the safety and efficacy of sclerostin inhibition.","authors":"Marc-André Legault, Jason Hartford, Benoît J Arsenault, Archer Y Yang, Joelle Pineau","doi":"10.1016/j.ajhg.2025.04.010","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.04.010","url":null,"abstract":"<p><p>Mendelian randomization (MR) enables the estimation of causal effects while controlling for unmeasured confounding factors. However, traditional MR's reliance on strong parametric assumptions can introduce bias if these are violated. We describe a machine learning MR estimator named quantile instrumental variable (Quantile IV) that achieves a low estimation error in a wide range of plausible MR scenarios. Quantile IV is distinctive in its ability to estimate nonlinear and heterogeneous causal effects and offers a flexible approach for subgroup analysis. Applying quantile IV, we investigate the impact of circulating sclerostin levels on heel bone mineral density, osteoporosis, and cardiovascular outcomes. Employing various MR estimators and colocalization techniques, our analysis reveals that a genetically predicted reduction in sclerostin levels significantly increases heel bone mineral density and reduces the risk of osteoporosis while showing no discernible effect on ischemic cardiovascular diseases. As a second application, we estimated the effect of increases in low-density lipoprotein cholesterol and waist-to-hip ratio on ischemic cardiovascular diseases using this well-known association as a positive control analysis. Quantile IV contributes to the advancement of MR methodology, and the selected applications demonstrate the applicability of our estimator in various MR contexts.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of function of the zinc finger homeobox 4 gene, ZFHX4, underlies a neurodevelopmental disorder.","authors":"María Del Rocío Pérez Baca, María Palomares-Bralo, Michiel Vanhooydonck, Lisa Hamerlinck, Eva D'haene, Sebastian Leimbacher, Eva Z Jacobs, Laurenz De Cock, Erika D'haenens, Annelies Dheedene, Zoë Malfait, Lies Vantomme, Ananilia Silva, Kathleen Rooney, Xiaonan Zhao, Amir Hossein Saeidian, Nichole Marie Owen, Fernando Santos-Simarro, Roser Lleuger-Pujol, Sixto García-Miñaúr, Itsaso Losantos-García, Björn Menten, Gaia Gestri, Nicola Ragge, Bekim Sadikovic, Elke Bogaert, Kris Vleminckx, Thomas Naert, Delfien Syx, Bert Callewaert, Sarah Vergult","doi":"10.1016/j.ajhg.2025.04.008","DOIUrl":"10.1016/j.ajhg.2025.04.008","url":null,"abstract":"<p><p>8q21.11 microdeletions involving ZFHX4 have previously been associated with a syndromic form of intellectual disability, hypotonia, unstable gait, and hearing loss. We report on 63 individuals-57 probands and 6 affected family members-with protein-truncating variants (n = 41), (micro)deletions (n = 21), or an inversion (n = 1) affecting ZFHX4. Probands display variable developmental delay and intellectual disability, distinctive facial characteristics, morphological abnormalities of the central nervous system, behavioral alterations, short stature, hypotonia, and occasionally cleft palate and anterior segment dysgenesis. The phenotypes associated with 8q21.11 microdeletions and ZFHX4 intragenic loss-of-function (LoF) variants largely overlap, although leukocyte-derived DNA shows a mild common methylation profile for (micro)deletions. ZFHX4 shows increased expression during human brain development and neuronal differentiation. Furthermore, ZFHX4-interacting factors identified via immunoprecipitation followed by mass spectrometry (IP-MS) suggest an important role for ZFHX4 in cellular pathways, especially during histone modifications, protein trafficking, signal transduction, cytosolic transport, and development. Additionally, using CUT&RUN, we observed that ZFHX4 binds the promoter of genes with crucial roles in embryonic, neuronal, and axonal development. Moreover, we investigated whether the disruption of zfhx4 causes craniofacial abnormalities in zebrafish. First-generation (F0) zfhx4 crispant zebrafish, a (mosaic) mutant for zfhx4 LoF variants, have significantly shorter Meckel's cartilage and smaller ethmoid plates compared to control zebrafish. Behavioral assays showed a decreased movement frequency in the zfhx4 crispant zebrafish in comparison with controls. Furthermore, structural abnormalities were found in the zebrafish hindbrain. In conclusion, our findings delineate a ZFHX4-associated neurodevelopmental disorder and suggest a role for zfhx4 in facial skeleton patterning, palatal development, and behavior.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benefits and barriers to broad implementation of genomic sequencing in the NICU.","authors":"Melissa R Goldin, Douglas M Ruderfer, Alexander Bick, Dan M Roden, Bryce A Schuler, Jamie R Robinson","doi":"10.1016/j.ajhg.2025.04.007","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.04.007","url":null,"abstract":"<p><p>Genome (GS) and exome (ES) sequencing as first-tier diagnostic tests have the potential to increase rates of genetic diagnoses and acutely change the management of neonates in the neonatal intensive care unit (NICU). However, the widespread implementation of genomic sequencing has been limited by several barriers. In this systematic review, we analyze the current literature on the utilization of GS and ES in infants in the NICU to identify the benefits, barriers, and components of successful implementation. Across the 42 studies that discussed GS and ES in the NICU setting, six themes were identified: disease detection, timeliness of results, cost, provider attitudes, parental attitudes, and equitable access. Benefits of GS and ES include high disease detection rates, timely results, and possible reduction in healthcare costs by reducing time spent in the NICU. Additionally, clinicians find GS/ES to be important and useful, and parents and caregivers largely perceive GS/ES to be beneficial. Barriers to widespread GS/ES include availability of personnel to facilitate timely diagnosis and coverage of cost. Additionally, clinicians report worries about a lack of genetics knowledge, informed consent, results return, and potential harm. Parents consistently report low levels of anxiety, decisional conflict, harm, or regret. Finally, the lack of availability of translated consent documents limits the participation of families who do not speak English or Spanish. Continued work is essential to optimize these technologies and ensure equitable access.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reannotation of cancer mutations based on expressed RNA transcripts reveals functional non-coding mutations in melanoma.","authors":"Daniele Pepe, Xander Janssens, Kalina Timcheva, Grecia M Marrón-Liñares, Benno Verbelen, Vasileios Konstantakos, Dylan De Groote, Jolien De Bie, Amber Verhasselt, Barbara Dewaele, Arne Godderis, Charlotte Cools, Mireia Franco-Tolsau, Jonathan Royaert, Jelle Verbeeck, Kim R Kampen, Karthik Subramanian, David Cabrerizo Granados, Gerben Menschaert, Kim De Keersmaecker","doi":"10.1016/j.ajhg.2025.04.005","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.04.005","url":null,"abstract":"<p><p>The role of synonymous mutations in cancer pathogenesis is currently underexplored. We developed a method to detect significant clusters of synonymous and missense mutations in public cancer genomics data. In melanoma, we show that 22% (11/50) of these mutation clusters are misannotated as coding mutations because the reference transcripts used for their annotation are not expressed. Instead, these mutations are actually non-coding. This, for instance, applies to the mutation clusters targeting known cancer genes kinetochore localized astrin (SPAG5) binding protein (KNSTRN) and BCL2-like 12 (BCL2L12), each affecting 4%-5% of melanoma tumors. For the latter, we show that these mutations are functional non-coding mutations that target the shared promoter region of interferon regulatory factor 3 (IRF3) and BCL2L12. This results in downregulation of IRF3, BCL2L12, and tumor protein p53 (TP53) expression in a CRISPR-Cas9 primary melanocyte model and in melanoma tumors. In individuals with melanoma, these mutations were also associated with a worse response to immunotherapy. Finally, we propose a simple automated method to more accurately annotate cancer mutations based on expressed transcripts. This work shows the importance of integrating DNA- and RNA-sequencing data to properly annotate mutations and identifies a number of previously overlooked and wrongly annotated functional non-coding mutations in melanoma.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}