Sarah Ridd, Larissa Peck, Aniket Bankar, George S Charames, Jordan Lerner-Ellis, Radhika Mahajan, Peter J B Sabatini, Andrew Wong, Janet Malcolmson, Raymond H Kim
{"title":"Myelodysplastic syndrome diagnosed by genetic testing for hereditary cancer: a case report.","authors":"Sarah Ridd, Larissa Peck, Aniket Bankar, George S Charames, Jordan Lerner-Ellis, Radhika Mahajan, Peter J B Sabatini, Andrew Wong, Janet Malcolmson, Raymond H Kim","doi":"10.1038/s41525-025-00476-6","DOIUrl":"https://doi.org/10.1038/s41525-025-00476-6","url":null,"abstract":"<p><p>Genetic testing for solid tumor syndromes typically uses peripheral blood leukocytes (PBL) as the source of germline DNA. This approach has shortcomings in certain situations, such as somatic mosaicism and hematologic malignancies. Here we describe a case where germline genetic testing on PBL revealed an unsuspected diagnosis of myelodysplastic syndrome (MDS). A 68-year-old male with a history of three solid tumors and a significant family history of cancer underwent germline genetic testing with a 76-gene hereditary cancer panel. Initial testing using PBL revealed deletions of the entire APC and CTNNA1 genes, suggestive of a contiguous deletion of chromosome 5 (del(5q)). Subsequent testing on cultured fibroblasts was negative, indicating the deletions were somatic. Bone marrow analysis confirmed the presence of del(5q) and a diagnosis of MDS. This case demonstrates the potential to uncover hematologic disorders through hereditary cancer genetic testing, emphasizing the importance of careful results interpretation, multidisciplinary follow-up, and DNA source selection.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"39"},"PeriodicalIF":4.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12078474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jong Ho Cha, Jee Min Kim, Hee-Jeong Yun, Hyungjin Chin, Hye Jin Kim, Woojoong Kim, Soo Yeon Kim, Byung Chan Lim, Ki Joong Kim, Seungbok Lee, Jong-Hee Chae
{"title":"Exploring gene-phenotype relationships in GRIN-related neurodevelopmental disorders.","authors":"Jong Ho Cha, Jee Min Kim, Hee-Jeong Yun, Hyungjin Chin, Hye Jin Kim, Woojoong Kim, Soo Yeon Kim, Byung Chan Lim, Ki Joong Kim, Seungbok Lee, Jong-Hee Chae","doi":"10.1038/s41525-025-00499-z","DOIUrl":"10.1038/s41525-025-00499-z","url":null,"abstract":"<p><p>The GRIN family is implicated in neurological disorders, such as global developmental delay (GDD) and epilepsy. We reviewed 31 patients with GRIN-related neurodevelopmental disorders at Seoul National University Hospital; all exhibited profound GDD, with 58.1% unable to walk independently and 74.2% unable to speak meaningful words. In a pooled analysis with the GRIN portal data ( https://grin-portal.broadinstitute.org/ ), patients with missense or in-frame variants had significantly higher rates of profound GDD (74.3% vs. 30.4%, p < 0.001) and movement disorders (69.0% vs. 41.4%, p < 0.01) than those with protein-truncating variants. Furthermore, missense or in-frame variants in the M3 and M4 helices of the transmembrane domain were significantly associated with profound GDD (M3 helix: adjusted odds ratio [aOR] 8.48; 95% confidence interval [CI] 2.79-25.76; M4 helix: aOR 3.14; 95% CI 1.39-7.09) compared to those in other domains. Our findings highlight the importance of detailed variant characterization to inform personalized treatment strategies.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"40"},"PeriodicalIF":4.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bouchra Ouled Amar Bencheikh, Allison A Dilliott, Julie Gauthier, Sandra Beatrice Laurent, Amirthagowri Ambalavanan, Dan Spiegelman, Alexandre Dionne-Laporte, Jaber Lyahyai, Robert L Martuza, Jörn P Sieb, Sali M K Farhan, Patrick A Dion, Stefan-M Pulst, Guy A Rouleau
{"title":"Novel germline and somatic variants in familial and sporadic meningioma genes.","authors":"Bouchra Ouled Amar Bencheikh, Allison A Dilliott, Julie Gauthier, Sandra Beatrice Laurent, Amirthagowri Ambalavanan, Dan Spiegelman, Alexandre Dionne-Laporte, Jaber Lyahyai, Robert L Martuza, Jörn P Sieb, Sali M K Farhan, Patrick A Dion, Stefan-M Pulst, Guy A Rouleau","doi":"10.1038/s41525-025-00494-4","DOIUrl":"10.1038/s41525-025-00494-4","url":null,"abstract":"<p><p>Meningiomas arise from arachnoid cells in the meninges surrounding the brain and spinal cord and are attributed to NF2 pathogenic variants in, approximately 60% of cases. Using exome sequencing, we found heterozygous germline variants in nine potential novel meningioma genes across four families and four sporadic cases. We then screened for germline and somatic variants in these genes and 11 known meningioma genes in 76 sporadic meningiomas blood/tumor pairs. We identified 18 germline and 58 somatic variants in 18 of the 20 genes, including seven of our newly proposed meningioma genes: CSMD3, EXTL3, FAT3, RAB44, RARA, RECQL4, and TNRC6A. Chromosomal abnormalities were identified in 39 of 49 tumors that also carried germline or somatic variants, with 71.8% encompassing NF2. This study provides potential novel genetic risk factors of meningiomas appropriate for further exploration from the greater scientific community and pathways to consider in the design of future therapeutic approaches.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"41"},"PeriodicalIF":4.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alexandra C Keefe, Dana M Jensen, Meranda M Pham, Natalie Y T Au, Erika Beckman, Monica Penon-Portmann, Emily Shelkowitz, Renee Bend, Michelle M Morrow, Paul Kruszka, Divya Vats, Bianca E Russell, Erica Chan, Derek Wong, Ahna Rabani, Lauren O'Grady, Inderneel Sahai, Kimberly Widmeyer, Ethan D Sperry, Barbara E Hallinan, Rebecca Tryon, Troy C Lund, Florian S Eichler, Angela Sun, James T Bennett
{"title":"Mosaic X-linked adrenoleukodystrophy in males identified by newborn screening and next-generation sequencing.","authors":"Alexandra C Keefe, Dana M Jensen, Meranda M Pham, Natalie Y T Au, Erika Beckman, Monica Penon-Portmann, Emily Shelkowitz, Renee Bend, Michelle M Morrow, Paul Kruszka, Divya Vats, Bianca E Russell, Erica Chan, Derek Wong, Ahna Rabani, Lauren O'Grady, Inderneel Sahai, Kimberly Widmeyer, Ethan D Sperry, Barbara E Hallinan, Rebecca Tryon, Troy C Lund, Florian S Eichler, Angela Sun, James T Bennett","doi":"10.1038/s41525-025-00497-1","DOIUrl":"https://doi.org/10.1038/s41525-025-00497-1","url":null,"abstract":"<p><p>Somatic mosaicism produces genetic differences between cells in an individual and is an underrecognized contributor to phenotypic variability. Precise understanding of the natural history of genetic diseases, therefore, requires detection and recognition of low-level mosaicism, which remains technically challenging, particularly for X-linked genes. Here, we identify six males with mosaic X-linked adrenoleukodystrophy (X-ALD), a neurometabolic peroxisomal disorder caused by pathogenic variants in ABCD1 that is currently included in 44 state newborn screening (NBS) programs, and estimate the incidence of somatic mosaicism. Of 227 males from 2 laboratories performing ABCD1 next-generation sequencing, 1.8% (4/227) had pathogenic or likely pathogenic ABCD1 variants that were mosaic. In one mosaic male individual, allele-specific measurements across multiple tissues demonstrated ABCD1 variant allele fractions ranging from 66 to 82%. Our findings have implications for the identification of X-ALD through NBS, and additional studies could provide insight into the pathogenesis and natural history of X-ALD.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"38"},"PeriodicalIF":4.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Daffodil M Canson, Inés Llinares-Burguet, Cristina Fortuno, Lara Sanoguera-Miralles, Elena Bueno-Martínez, Miguel de la Hoya, Amanda B Spurdle, Eladio A Velasco-Sampedro
{"title":"TP53 minigene analysis of 161 sequence changes provides evidence for role of spatial constraint and regulatory elements on variant-induced splicing impact.","authors":"Daffodil M Canson, Inés Llinares-Burguet, Cristina Fortuno, Lara Sanoguera-Miralles, Elena Bueno-Martínez, Miguel de la Hoya, Amanda B Spurdle, Eladio A Velasco-Sampedro","doi":"10.1038/s41525-025-00498-0","DOIUrl":"https://doi.org/10.1038/s41525-025-00498-0","url":null,"abstract":"<p><p>We investigated the role of TP53 splicing regulatory elements (SREs) using exons 3 and 6 and their downstream introns as models. Minigene microdeletion assays revealed four SRE-rich intervals: c.573_598, c.618_641, c.653_669 and c.672+14_672 + 36. A diagnostically reported deletion c.655_670del, overlapping an SRE-rich interval, induced an in-frame transcript Δ(E6q21) from new donor site usage. Deletion of at least four intron 6 G-runs led to 100% aberrant transcript expression. Additionally, assay results suggested a donor-to-branchpoint distance <50 nt for complete splicing aberration due to spatial constraint, and >75 nt for low risk of splicing abnormality. Overall, splicing data for 134 single nucleotide variants (SNVs) and 27 deletions in TP53 demonstrated that SRE-disrupting SNVs have weak splicing impact (up to 26% exon skipping), while deletions spanning multiple SREs have profound splicing effects. Our findings may prove relevant for identifying novel germline TP53 variants causing hereditary cancer predisposition and/or somatic variants contributing to tumorigenesis.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"37"},"PeriodicalIF":4.7,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143995853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Martin Man-Chun Chui, Anna Ka-Yee Kwong, Hiu Yu Cherie Leung, Chingyiu Pang, Ines F Scheller, Sheila Suet-Na Wong, Cheuk-Wing Fung, Vicente A Yépez, Julien Gagneur, Christopher Chun-Yu Mak, Brian Hon-Yin Chung
{"title":"An outlier approach: advancing diagnosis of neurological diseases through integrating proteomics into multi-omics guided exome reanalysis.","authors":"Martin Man-Chun Chui, Anna Ka-Yee Kwong, Hiu Yu Cherie Leung, Chingyiu Pang, Ines F Scheller, Sheila Suet-Na Wong, Cheuk-Wing Fung, Vicente A Yépez, Julien Gagneur, Christopher Chun-Yu Mak, Brian Hon-Yin Chung","doi":"10.1038/s41525-025-00493-5","DOIUrl":"https://doi.org/10.1038/s41525-025-00493-5","url":null,"abstract":"<p><p>Neurodevelopmental disorders (NDDs) often have unknown genetic causes. Current efforts in identifying disease-related genetic variants using exome or genome sequencing still lead to an excessive number of variants of uncertain significance (VUS). There is an increasing interest in transcriptomics and, more recently, proteomics for variant detection and interpretation. In this study, we integrated quantitative liquid chromatography-mass spectrometry proteomics, RNA sequencing, and exome reanalysis to resolve VUS and detect novel causal variants in 34 patients with undiagnosed NDDs, using the software PROTRIDER and DROP to detect protein outliers and RNA outliers, respectively. We obtained a diagnosis in 11 cases (32%) resulting from the increased amount of information provided by the two additional levels of omics (n = 5) and the updated literature evidence (n = 6). Our experience suggests the potential of this outlier-detection multi-omics workflow for improving diagnostic yield in NDDs and other rare disorders.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"36"},"PeriodicalIF":4.7,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dimitrios Kioroglou, Rubén Gil-Redondo, Nieves Embade, Maider Bizkarguenaga, Ricardo Conde, Oscar Millet, José M Mato, Urko M Marigorta
{"title":"Multi-omic integration sets the path for early prevention strategies on healthy individuals.","authors":"Dimitrios Kioroglou, Rubén Gil-Redondo, Nieves Embade, Maider Bizkarguenaga, Ricardo Conde, Oscar Millet, José M Mato, Urko M Marigorta","doi":"10.1038/s41525-025-00491-7","DOIUrl":"https://doi.org/10.1038/s41525-025-00491-7","url":null,"abstract":"<p><p>Precision medicine requires biomarkers that stratify patients and improve clinical outcomes. Although longitudinal multi-omic analyses provide insights into pathological states, their utility in stratifying healthy individuals remains underexplored. We performed a cross-sectional integrative study of three omic layers, including genomics, urine metabolomics, and serum metabolomics/lipoproteomics, on a cohort of 162 individuals without pathological manifestations. We studied each omic layer separately and after integration, concluding that multi-omic integration provides optimal stratification capacity. We identified four subgroups and, for a subset of 61 individuals, longitudinal data for two additional time-points allowed us to evaluate the temporal stability of the molecular profiles of each identified subgroup. Additional functional annotation uncovered accumulation of risk factors associated with dyslipoproteinemias in one subgroup, suggesting targeted monitoring could reduce future cardiovascular risks. Overall, our methodology uncovers the potential of multi-omic profiling to serve as a framework for precision medicine aimed at early prevention strategies.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"35"},"PeriodicalIF":4.7,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tamra Lysaght, Rachel Ankeny, Alex Brown, Rebekah McWhirter, Dianne Nicol, Margaret Otlowski, Bernadette Richards, Ainsley J Newson
{"title":"The Australian LINEAGE Study: advancing and implementing international guidance on genomic data within local governance frameworks.","authors":"Tamra Lysaght, Rachel Ankeny, Alex Brown, Rebekah McWhirter, Dianne Nicol, Margaret Otlowski, Bernadette Richards, Ainsley J Newson","doi":"10.1038/s41525-025-00492-6","DOIUrl":"https://doi.org/10.1038/s41525-025-00492-6","url":null,"abstract":"","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"34"},"PeriodicalIF":4.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12043809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Suzanne E de Bruijn, L Ingeborgh van den Born, Ronny Derks, Lonneke Haer-Wigman, Luke O'Gorman, Frans P M Cremers, Ronald van Beek, Alexander Hoischen, Susanne Roosing, Kornelia Neveling
{"title":"Long-read technologies identify a hidden LINE-1/ERV1 insertion in IQCB1 as causative variant for Senior-Løken syndrome.","authors":"Suzanne E de Bruijn, L Ingeborgh van den Born, Ronny Derks, Lonneke Haer-Wigman, Luke O'Gorman, Frans P M Cremers, Ronald van Beek, Alexander Hoischen, Susanne Roosing, Kornelia Neveling","doi":"10.1038/s41525-025-00490-8","DOIUrl":"https://doi.org/10.1038/s41525-025-00490-8","url":null,"abstract":"<p><p>Senior-Løken syndrome is a rare ciliopathy characterized by retinal dystrophy and nephronophthisis. This autosomal recessive inherited disease is caused by pathogenic variants in several genes, including IQCB1. We present a Senior-Løken case that remained genetically unexplained after routine genetic testing, including exome and genome sequencing. To identify the genetic cause for this individual, a combination of innovative long-read technologies was employed. Using optical genome mapping, an intronic 6.2-kb insertion in IQCB1 was revealed. Validation by long-read genome sequencing determined that this insertion consisted of a LINE-1/ERV1-mobile element. The variant was found in trans with a pathogenic IQCB1 2-bp deletion previously identified by exome sequencing. To investigate the consequences of the insertion, targeted long-read RNA-sequencing was performed, revealing a complex splice defect causing the introduction of a premature stop codon. This finding suggests that mobile element insertions represent a yet underestimated variant type that is difficult to detect using short-read sequencing.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"33"},"PeriodicalIF":4.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144031779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ryan E Schmidt, Amy E Pohodich, David Birch, Kaylie Jones, Byron L Lam, Emily H Jung, Nieraj Jain, Michalis Georgiou, Omar A Mahroo, Andrew R Webster, Michel Michaelides, Benjamin Bakall, Alessandro Iannaccone, Ajoy Vincent, Deepika C Parameswarappa, Elise Heon, Hendrik P N Scholl, Lucas Janeschitz-Kriegl, Elias I Traboulsi, Wadih Zein, Brian P Brooks, Catherine Cukras, Robert Hufnagel, Tomas S Aleman, Mohamed M Sylla, Stephen H Tsang, Michelle Alabek, Jose Sahel, Michael B Gorin, Maria M van Genderen, Katarina Stingl, Milda Reith, Susanne Kohl, Rebeca Azevedo Souza Amaral, Juliana Maria Ferraz Sallum, Andrea L Vincent, Sarah Hull, Jacque L Duncan, James V M Hanson, Matthias Tedeus, Jordi Maggi, Urs Graf, Samuel Koller, Wolfgang Berger, Christina Gerth-Kahlert, Molly Marra, Lesley A Everett, Paul Yang, Mark E Pennesi
{"title":"Variants in CFAP410 cause a range of retinal and skeletal phenotypes.","authors":"Ryan E Schmidt, Amy E Pohodich, David Birch, Kaylie Jones, Byron L Lam, Emily H Jung, Nieraj Jain, Michalis Georgiou, Omar A Mahroo, Andrew R Webster, Michel Michaelides, Benjamin Bakall, Alessandro Iannaccone, Ajoy Vincent, Deepika C Parameswarappa, Elise Heon, Hendrik P N Scholl, Lucas Janeschitz-Kriegl, Elias I Traboulsi, Wadih Zein, Brian P Brooks, Catherine Cukras, Robert Hufnagel, Tomas S Aleman, Mohamed M Sylla, Stephen H Tsang, Michelle Alabek, Jose Sahel, Michael B Gorin, Maria M van Genderen, Katarina Stingl, Milda Reith, Susanne Kohl, Rebeca Azevedo Souza Amaral, Juliana Maria Ferraz Sallum, Andrea L Vincent, Sarah Hull, Jacque L Duncan, James V M Hanson, Matthias Tedeus, Jordi Maggi, Urs Graf, Samuel Koller, Wolfgang Berger, Christina Gerth-Kahlert, Molly Marra, Lesley A Everett, Paul Yang, Mark E Pennesi","doi":"10.1038/s41525-025-00489-1","DOIUrl":"https://doi.org/10.1038/s41525-025-00489-1","url":null,"abstract":"<p><p>Ciliopathies are associated with a range of phenotypes including retinal degeneration and skeletal abnormalities. We present a retrospective study of 49 patients with variants in Cilia and Flagella Associated Protein 410 (CFAP410) from multiple ophthalmic centers across the world. Common clinical features included early-onset reduced visual acuity, photophobia, and delayed light-to-dark adaptation. A cone-rod dystrophy pattern was observed roughly two times more commonly than rod-cone dystrophy. A minority of patients (22.4%) presented with skeletal abnormalities consistent with axial spondylometaphyseal dysplasia (SMDAX). Patients with the most severe ophthalmic and skeletal phenotypes had disease-associated variants within conserved leucine-rich regions of CFAP410, and the structural effects of these variants were modelled using ChimeraX. This report furthers our understanding of CFAP410-associated clinical phenotypes such as retinal dystrophy and skeletal dysplasia.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"10 1","pages":"32"},"PeriodicalIF":4.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12006490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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