American journal of human genetics最新文献

{"title":"Functional characterization of eQTLs and asthma risk loci with scATAC-seq across immune cell types and contexts.","authors":"Julong Wei, Justyna A Resztak, Ali Ranjbaran, Adnan Alazizi, Henriette E Mair-Meijers, Richard B Slatcher, Samuele Zilioli, Xiaoquan Wen, Francesca Luca, Roger Pique-Regi","doi":"10.1016/j.ajhg.2024.12.017","DOIUrl":"10.1016/j.ajhg.2024.12.017","url":null,"abstract":"<p><p>cis-regulatory elements (CREs) control gene transcription dynamics across cell types and in response to the environment. In asthma, multiple immune cell types play an important role in the inflammatory process. Genetic variants in CREs can also affect gene expression response dynamics and contribute to asthma risk. However, the regulatory mechanisms underlying control of transcriptional dynamics across different environmental contexts and cell types at single-cell resolution remain to be elucidated. To resolve this question, we performed single-cell ATAC-seq (scATAC-seq) in peripheral blood mononuclear cells (PBMCs) from 16 children with asthma. PBMCs were activated with phytohemagglutinin (PHA) or lipopolysaccharide (LPS) and treated with dexamethasone (DEX), an anti-inflammatory glucocorticoid. We analyzed changes in chromatin accessibility, measured transcription factor motif activity, and identified treatment- and cell-type-specific transcription factors that drive changes in both gene expression mean and variability. We observed a strong positive linear dependence between motif response and their target gene expression changes but a negative relationship with changes in target gene expression variability. This result suggests that an increase of transcription factor binding tightens the variability of gene expression around the mean. We then annotated genetic variants in chromatin accessibility peaks and response motifs, followed by computational fine-mapping of expression quantitative trait loci (eQTL) from a pediatric asthma cohort. We found that eQTLs were 5-fold enriched in peaks with response motifs and refined the credible set for 410 asthma risk genes, with 191 having the causal variant in response motifs. In conclusion, scATAC-seq enhances the understanding of molecular mechanisms for asthma risk variants mediated by gene expression.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"301-317"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"No evidence for sex-differential transcriptomes driving genome-wide sex-differential natural selection.","authors":"Matthew J Ming, Changde Cheng, Mark Kirkpatrick, Arbel Harpak","doi":"10.1016/j.ajhg.2024.12.016","DOIUrl":"10.1016/j.ajhg.2024.12.016","url":null,"abstract":"<p><p>Sex differences in human transcriptomes have been argued to drive sex-differential selection (SDS). Here, we show that previous evidence supporting this hypothesis has been largely unfounded. We develop a method to test for a genome-wide relationship between sex differences in expression and selection on expression-influencing alleles (expression quantitative trait loci [eQTLs]). We apply it across 34 human tissues and find no evidence for a general relationship. We offer possible explanations for the lack of evidence, including that it is due in part to eQTL ascertainment bias toward sites under weak selection. We conclude that the drivers of ongoing SDS in humans remain to be identified.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"254-260"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sequence variants in HECTD1 result in a variable neurodevelopmental disorder.","authors":"Gazelle Zerafati-Jahromi,Elias Oxman,Hieu D Hoang,Wu-Lin Charng,Tanvitha Kotla,Weimin Yuan,Keito Ishibashi,Sonia Sebaoui,Kathryn Luedtke,Bryce Winrow,Rebecca D Ganetzky,Anna Ruiz,Carmen Manso-Basúz,Nino Spataro,Peter Kannu,Taryn Athey,Christina Peroutka,Caitlin Barnes,Richard Sidlow,George Anadiotis,Kari Magnussen,Irene Valenzuela,Alejandro Moles-Fernandez,Seth Berger,Christina L Grant,Eric Vilain,Gudny A Arnadottir,Patrick Sulem,Telma S Sulem,Kari Stefansson,Shavonne Massey,Natalie Ginn,Annapurna Poduri,Alissa M D'Gama,Rozalia Valentine,Sara K Trowbridge,Chaya N Murali,Rachel Franciskovich,Yen Tran,Bryn D Webb,Kim M Keppler-Noreuil,April L Hall,Bobbi McGivern,Kristin G Monaghan,Maria J Guillen Sacoto,Dustin Baldridge,Gary A Silverman,Sonika Dahiya,Tychele N Turner,Tim Schedl,Joshua G Corbin,Stephen C Pak,Irene E Zohn,Christina A Gurnett","doi":"10.1016/j.ajhg.2025.01.001","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.01.001","url":null,"abstract":"Dysregulation of genes encoding the homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases has been linked to cancer and structural birth defects. One member of this family, the HECT-domain-containing protein 1 (HECTD1), mediates developmental pathways, including cell signaling, gene expression, and embryogenesis. Through GeneMatcher, we identified 14 unrelated individuals with 15 different variants in HECTD1 (10 missense, 3 frameshift, 1 nonsense, and 1 splicing variant) with neurodevelopmental disorders (NDDs), including autism, attention-deficit/hyperactivity disorder, and epilepsy. Of these 15 HECTD1 variants, 10 occurred de novo, 3 had unknown inheritance, and 2 were compound heterozygous. While all individuals in this cohort displayed NDDs, no genotype-phenotype correlation was apparent. Conditional knockout of Hectd1 in the neural lineage in mice resulted in microcephaly, severe hippocampal malformations, and complete agenesis of the corpus callosum, supporting a role for Hectd1 in embryonic brain development. Functional studies of select variants in C. elegans revealed dominant effects, including either change-of-function or loss-of-function/haploinsufficient mechanisms, which may explain phenotypic heterogeneity. Significant enrichment of de novo variants in HECTD1 was also shown in an independent cohort of 53,305 published trios with NDDs or congenital heart disease. Thus, our clinical and functional data support a critical requirement of HECTD1 for human brain development.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"27 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062085","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":"Gene and phenome-based analysis of the shared genetic architecture of eye diseases.","authors":"Alexandra Scalici,Tyne W Miller-Fleming,Megan M Shuey,James T Baker,Michael Betti,Jibril Hirbo,Ela W Knapik,Nancy J Cox","doi":"10.1016/j.ajhg.2025.01.004","DOIUrl":"https://doi.org/10.1016/j.ajhg.2025.01.004","url":null,"abstract":"While many eye disorders are linked through defects in vascularization and optic nerve degeneration, genetic correlation studies have yielded variable results despite shared features. For example, glaucoma and myopia both share optic neuropathy as a feature, but genetic correlation studies demonstrated minimal overlap. By leveraging electronic health record (EHR) resources that contain genetic variables such as genetically predicted gene expression (GPGE), researchers have the potential to improve the identification of shared genetic drivers of disease by incorporating knowledge of shared features to identify disease-causing mechanisms. In this study, we examined shared genetic architecture across eye diseases. Our gene-based approach used transcriptome-wide association methods to identify shared transcriptomic profiles across eye diseases within BioVU, Vanderbilt University Medical Center's (VUMC's) EHR-linked biobank. Our phenome-based approach leveraged phenome-wide association studies (PheWASs) to identify eye disease comorbidities. Using the beta estimates from the significantly associated comorbidities, we constructed a phenotypic risk score (PheRS) representing a weighted sum of an individual's eye disease comorbidities. This PheRS is predictive of eye disease status and associated with the altered GPGE of significant genes in an independent population. The implementation of both gene- and phenome-based approaches can expand genetic associations and shed greater insight into the underlying mechanisms of shared genetic architecture across eye diseases.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"60 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062016","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":"Discovery of a DNA methylation profile in individuals with Sifrim-Hitz-Weiss syndrome.","authors":"Karim Karimi,Yael Lichtenstein,Jack Reilly,Haley McConkey,Raissa Relator,Michael A Levy,Jennifer Kerkhof,Arjan Bouman,Joseph D Symonds,Jamal Ghoumid,Thomas Smol,Katie Clarkson,Katy Drazba,Raymond J Louie,Valancy Miranda,Cathleen McCann,Jamie Motta,Emily Lancaster,Suzanne Sallevelt,Richard Sidlow,Jennifer Morrison,Mark Hannibal,Jessica O'Shea,Victor Marin,Chitra Prasad,Chirag Patel,Salmo Raskin,Seco Moro Maria-Noelia,Aranzazú Diaz de Bustamante,Daphna Marom,Tali Barkan,Boris Keren,Celine Poirsier,Lior Cohen,Estelle Colin,Kathleen Gorman,Emily Gallant,Leonie A Menke,Irene Valenzuela Palafoll,Natalie Hauser,Ingrid M Wentzensen,Julia Rankin,Peter D Turnpenny,Philippe M Campeau,Tugce B Balci,Matthew L Tedder,Bekim Sadikovic,Karin Weiss","doi":"10.1016/j.ajhg.2024.12.020","DOIUrl":"https://doi.org/10.1016/j.ajhg.2024.12.020","url":null,"abstract":"Pathogenic heterozygous variants in CHD4 cause Sifrim-Hitz-Weiss syndrome, a neurodevelopmental disorder associated with brain anomalies, heart defects, macrocephaly, hypogonadism, and additional features with variable expressivity. Most individuals have non-recurrent missense variants, complicating variant interpretation. A few were reported with truncating variants, and their role in disease is unclear. DNA methylation episignatures have emerged as highly accurate diagnostic biomarkers in a growing number of rare diseases. We aimed to study evidence for the existence of a CHD4-related DNA methylation episignature. We collected blood DNA samples and/or clinical information from 39 individuals with CHD4 variants, including missense and truncating variants. Genomic DNA methylation analysis was performed on 28 samples. We identified a sensitive and specific DNA methylation episignature in samples with pathogenic missense variants within the ATPase/helicase domain. The same episignature was observed in a family with variable expressivity, a de novo variant near the PHD domain, variants of uncertain significance within the ATPase/helicase domain, and a sample with compound heterozygous variants. DNA methylation data revealed higher percentages of shared probes with BAFopathies, CHD8, and the terminal ADNP variants encoding a protein known to form the ChAHP complex with CHD4. Truncating variants, as well as a sample with a recurrent pathogenic missense variant, exhibited DNA methylation profiles distinct from the ATPase/helicase domain episignature. These DNA methylation differences, together with the distinct clinical features observed in those individuals, provide preliminary evidence for clinical and molecular sub-types in the CHD4-related disorder.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"6 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989721","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":"Bi-allelic KICS2 mutations impair KICSTOR complex-mediated mTORC1 regulation, causing intellectual disability and epilepsy.","authors":"Rebecca Buchert,Martin D Burkhalter,Chrisovalantou Huridou,Linda Sofan,Timo Roser,Kirsten Cremer,Javeria Raza Alvi,Stephanie Efthymiou,Tawfiq Froukh,Sughra Gulieva,Ulviyya Guliyeva,Moath Hamdallah,Muriel Holder-Espinasse,Rauan Kaiyrzhanov,Doreen Klingler,Mahmoud Koko,Lars Matthies,Joohyun Park,Marc Sturm,Ana Velic,Stephanie Spranger,Tipu Sultan,Hartmut Engels,Holger Lerche,Henry Houlden,Alistair T Pagnamenta,Ingo Borggraefe,Yvonne Weber,Penelope E Bonnen,Reza Maroofian,Olaf Riess,Jonasz J Weber,Melanie Philipp,Tobias B Haack","doi":"10.1016/j.ajhg.2024.12.019","DOIUrl":"https://doi.org/10.1016/j.ajhg.2024.12.019","url":null,"abstract":"Nutrient-dependent mTORC1 regulation upon amino acid deprivation is mediated by the KICSTOR complex, comprising SZT2, KPTN, ITFG2, and KICS2, recruiting GATOR1 to lysosomes. Previously, pathogenic SZT2 and KPTN variants have been associated with autosomal recessive intellectual disability and epileptic encephalopathy. We identified bi-allelic KICS2 variants in eleven affected individuals presenting with intellectual disability and epilepsy. These variants partly affected KICS2 stability, compromised KICSTOR complex formation, and demonstrated a deleterious impact on nutrient-dependent mTORC1 regulation of 4EBP1 and S6K. Phosphoproteome analyses extended these findings to show that KICS2 variants changed the mTORC1 proteome, affecting proteins that function in translation, splicing, and ciliogenesis. Depletion of Kics2 in zebrafish resulted in ciliary dysfunction consistent with a role of mTORC1 in cilia biology. These in vitro and in vivo functional studies confirmed the pathogenicity of identified KICS2 variants. Our genetic and experimental data provide evidence that variants in KICS2 are a factor involved in intellectual disability due to its dysfunction impacting mTORC1 regulation and cilia biology.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"28 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989722","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":"Leveraging diverse genomic data to guide equitable carrier screening: Insights from gnomAD v.4.1.0.","authors":"Matthew J Schmitz, Aryan Bashar, Vishal Soman, Esther A F Nkrumah, Hajer Al Mulla, Helia Darabi, John Wang, Paris Kiehl, Rahil Sethi, Jeffrey Dungan, Anthony R Gregg, Aleksandar Rajkovic, Svetlana A Yatsenko, Uma Chandran, Mahmoud Aarabi","doi":"10.1016/j.ajhg.2024.11.004","DOIUrl":"10.1016/j.ajhg.2024.11.004","url":null,"abstract":"<p><p>Analysis of exome data from the latest release of the Genome Aggregation Database (gnomAD v.4.1.0) revealed a significant carrier burden of pathogenic/likely pathogenic (P/LP) variants in genes associated with autosomal-recessive conditions across diverse ancestral populations. Carrier screening panels are routinely offered to reproductive partners to inform their risk of having an affected child. Current guidelines from the American College of Medical Genetics and Genomics (ACMG) recommend screening for genes with a carrier frequency of at least 1/200 and associated with moderate/severe conditions. Here, we systematically analyzed >700,000 gnomAD v.4.1.0 exomes spanning eight ancestries to estimate the carrier frequency of P/LP variants in 2,987 genes associated with autosomal-recessive conditions. After expert curation for clinical severity, we identified 286 genes meeting the criteria for carrier screening. The number of genes exceeding the 1/200 threshold varied across populations, with 40 in the South Asian ancestry and up to 119 in the Ashkenazi Jewish population. Simulations showed that pan-ethnic screening panels offer advantages for individuals of diverse or admixed ancestry, while ancestry-specific panels may be preferable for genetically homogeneous populations. This study leveraged the most comprehensive genomic dataset to date to provide an updated candidate gene list for equitable carrier screening across diverse populations. Our findings highlight the need for continued expansion of genomic resources to better understand rare disease risk and inform screening efforts in underrepresented groups.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"181-195"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bi-allelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered apoptosis and a Perrault-syndrome-spectrum phenotype.","authors":"Thomas B Smith, Robert Kopajtich, Leigh A M Demain, Alessandro Rea, Huw B Thomas, Manuel Schiff, Christian Beetz, Shelagh Joss, Gerard S Conway, Anju Shukla, Mayuri Yeole, Periyasamy Radhakrishnan, Hatem Azzouz, Amel Ben Chehida, Monique Elmaleh-Bergès, Ruth I C Glasgow, Kyle Thompson, Monika Oláhová, Langping He, Emma M Jenkinson, Amir Jahic, Inna A Belyantseva, Melanie Barzik, Jill E Urquhart, James O'Sullivan, Simon G Williams, Sanjeev S Bhaskar, Samantha Carrera, Alexander J M Blakes, Siddharth Banka, Wyatt W Yue, Jamie M Ellingford, Henry Houlden, Kevin J Munro, Thomas B Friedman, Robert W Taylor, Holger Prokisch, Raymond T O'Keefe, William G Newman","doi":"10.1016/j.ajhg.2024.11.007","DOIUrl":"10.1016/j.ajhg.2024.11.007","url":null,"abstract":"<p><p>The mitochondrial ribosome (mitoribosome) synthesizes 13 protein subunits of the oxidative phosphorylation system encoded by the mitochondrial genome. The mitoribosome is composed of 12S rRNA, 16S rRNA, and 82 mitoribosomal proteins encoded by nuclear genes. To date, variants in 12 genes encoding mitoribosomal proteins are associated with rare monogenic disorders and frequently show combined oxidative phosphorylation deficiency. Here, we describe five unrelated individuals with bi-allelic variants in death-associated protein 3 (DAP3), a nuclear gene encoding mitoribosomal small subunit 29 (MRPS29), with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. Assessment of respiratory-chain function and proteomic profiling of fibroblasts from affected individuals demonstrated reduced MRPS29 protein amounts and, consequently, decreased levels of additional protein components of the mitoribosomal small subunit, as well as an associated combined deficiency of complexes I and IV. Lentiviral transduction of fibroblasts from affected individuals with wild-type DAP3 cDNA increased DAP3 mRNA expression and partially rescued protein levels of MRPS7, MRPS9, and complex I and IV subunits, demonstrating the pathogenicity of the DAP3 variants. Protein modeling suggested that DAP3 disease-associated missense variants can impact ADP binding, and in vitro assays demonstrated that DAP3 variants can consequently reduce both intrinsic and extrinsic apoptotic sensitivity, DAP3 thermal stability, and DAP3 GTPase activity. Our study presents genetic and functional evidence that bi-allelic variants in DAP3 result in a multisystem disorder of combined oxidative phosphorylation deficiency with pleiotropic presentations, consistent with mitochondrial dysfunction.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"59-74"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to Bodmer and Charlesworth: Mendelian genetics and eugenics.","authors":"Adam Rutherford","doi":"10.1016/j.ajhg.2024.12.004","DOIUrl":"10.1016/j.ajhg.2024.12.004","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 1","pages":"198"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic variants in DDX53 contribute to autism spectrum disorder associated with the Xp22.11 locus.","authors":"Marcello Scala, Clarrisa A Bradley, Jennifer L Howe, Brett Trost, Nelson Bautista Salazar, Carole Shum, Marla Mendes, Miriam S Reuter, Evdokia Anagnostou, Jeffrey R MacDonald, Sangyoon Y Ko, Paul W Frankland, Jessica Charlebois, Mayada Elsabbagh, Leslie Granger, George Anadiotis, Verdiana Pullano, Alfredo Brusco, Roberto Keller, Sarah Parisotto, Helio F Pedro, Laina Lusk, Pamela Pojomovsky McDonnell, Ingo Helbig, Sureni V Mullegama, Emilie D Douine, Rosario Ivetth Corona, Bianca E Russell, Stanley F Nelson, Claudio Graziano, Maria Schwab, Laurie Simone, Federico Zara, Stephen W Scherer","doi":"10.1016/j.ajhg.2024.11.003","DOIUrl":"10.1016/j.ajhg.2024.11.003","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) exhibits an ∼4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males. This locus includes the three-exon PTCHD1, an adjacent multi-isoform long noncoding RNA (lncRNA) named PTCHD1-AS (spanning ∼1 Mb), and a poorly characterized single-exon RNA helicase named DDX53 that is intronic to PTCHD1-AS. While the relationship between PTCHD1/PTCHD1-AS and ASD is being studied, the role of DDX53 has not been comprehensively examined, in part because there is no apparent functional murine ortholog. Through clinical testing, here, we identified 8 males and 2 females with ASD from 8 unrelated families carrying rare, predicted damaging or loss-of-function variants in DDX53. Additionally, we identified a family consisting of a male proband and his affected mother with high-functioning autism, both harboring a gene deletion involving DDX53 and exons of the noncoding RNA PTCHD1-AS. Then, we examined databases, including the Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, as well as population controls. We identified 26 additional individuals with ASD harboring 19 mostly maternally inherited, rare, damaging DDX53 variations, including two variants detected in families from the original clinical analysis. Our findings in humans support a direct link between DDX53 and ASD, which will be important in clinical genetic testing. These same autism-related findings, coupled with the observation that a functional orthologous gene is not found in mice, may also influence the design and interpretation of murine modeling of ASD.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"154-167"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}