European Journal of Human Genetics最新文献

{"title":"Novel variants impairing Sp1 transcription factor binding in the COL7A1 promoter cause mild cases of recessive dystrophic epidermolysis bullosa","authors":"Nathalie Pironon, Artyom Gasparyan, María Joao Yubero, Sabine Duchatelet, Kristina Hovhannesyan, Stephanie Leclerc-Mercier, Natella Kostandyan, Francis Palisson, Tamara Sarkisian, Matthias Titeux, Ignacia Fuentes, Alain Hovnanian","doi":"10.1038/s41431-024-01717-5","DOIUrl":"10.1038/s41431-024-01717-5","url":null,"abstract":"Recessive dystrophic epidermolysis bullosa (RDEB) is a rare and most often severe genodermatosis characterized by recurrent blistering and erosions of the skin and mucous membranes after minor trauma, leading to major local and systemic complications. RDEB is caused by loss-of-function mutations in COL7A1 encoding type VII collagen (C7), the main component of anchoring fibrils which form attachment structures stabilizing the cutaneous basement membrane zone. Most of the previously reported COL7A1 mutations are located in the coding or intronic regions. We describe 6 patients with localized or intermediate RDEB for whom one recessive pathogenic variant in the coding region and a second variant in the COL7A1 promoter were identified. These substitutions, three of which are novel, are localized in two Sp1 binding sites of the promoter region. DNA pull-down assay showed a drastic reduction of Sp1 binding consistent with a dramatic decrease in COL7A1 transcript and almost undetectable C7 protein levels. Our results reveal that mutations in the COL7A1 promoter on the background of a null allele can underlie localized or intermediate RDEB. They further emphasize the functional importance of Sp1 motifs in the proximal COL7A1 promoter which should be carefully investigated for regulatory mutations in the case of RDEB with only one pathogenic variant identified in the coding or intronic regions.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 3","pages":"344-350"},"PeriodicalIF":3.7,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-024-01717-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ELMO2-related intraosseous vascular malformation: new cases with novel pathogenic variants, clinical follow-up and therapeutic approaches","authors":"Mert Karakaya, Iman Ragab, Vera Riehmer, Florian Erger, Nihal Hussien Aly, Seung Woo Ryu, Go Hun Seo, Marc Hoemberg, Anne Maria Schultheis, Christian Netzer, Boris Decarolis","doi":"10.1038/s41431-024-01739-z","DOIUrl":"10.1038/s41431-024-01739-z","url":null,"abstract":"Primary intraosseous vascular malformation (VMPI, #606893) is an ultra-rare disorder caused by biallelic pathogenic variants in ELMO2. To date, only six families with pathogenic ELMO2 variants causing a VMPI phenotype have been described. VMPI is characterized by vascular malformations that compress the facial bones, often leading to life-threatening complications, such as massive bleeding and intracranial herniation. In VMPI, vascular malformations are progressive and there is no causal therapy available. We report on four unreported individuals with classical VMPI harbouring biallelic truncating variants in ELMO2, including a novel homozygous 25 bp duplication c.579_603dup; p.(Leu202Profs*47), detected by whole-exome sequencing. We present extensive clinical follow-up data, including a close monitoring of an individual from prenatal diagnosis onwards. Using computed tomography or magnetic resonance imaging angiography, we described the radiological characteristics of vascular malformations with fast-flow properties in the affected individuals. Additionally, we conducted a comprehensive histopathological evaluation of samples from one individual. This analysis revealed not only the similar morphological features described previously but also some atypical findings, such as increased de novo bone formation. Furthermore, we report for the first time the use of propranolol and sirolimus in VMPI. While we noted a reduction of bleeding episodes in one individual, no significant clinical improvement was observed overall in the other individuals treated with sirolimus. Moreover, sirolimus led to severe infectious complications with abscess formation in two individuals. Conversely, propranolol was relatively well tolerated, although it did not result in any notable clinical outcomes. During follow-up, one individual died due to severe bleeding.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 3","pages":"334-343"},"PeriodicalIF":3.7,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: SPARCL1 sparkles new insight into corneal dystrophies.","authors":"Joni A Turunen","doi":"10.1038/s41431-024-01757-x","DOIUrl":"https://doi.org/10.1038/s41431-024-01757-x","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population-based genetic carrier screening. A consensus statement from the Spanish societies: AEGH, AEDP, ASEBIR, SEAGEN, SEF and SEGCD.","authors":"Xavier Vendrell, Anna Abulí, Clara Serra, Juan José Guillén, Joaquín Rueda, Javier García-Planells, Fernando Santos-Simarro, Ramiro Quiroga, Fernando Abellán, Raluca Oancea-Ionescu, Encarna Guillén-Navarro","doi":"10.1038/s41431-024-01751-3","DOIUrl":"https://doi.org/10.1038/s41431-024-01751-3","url":null,"abstract":"<p><p>Autosomal recessive or X-linked disorders are passed from parents to offspring through Mendelian inheritance patterns and may lead to severe clinical manifestations in early childhood development. Together, the Spanish Association of Human Genetics (AEGH), Association for the Study of Reproductive Biology (ASEBIR), Spanish Association of Genetic Counselling (SEAGEN), Spanish Fertility Society (SEF), Spanish Society of Clinical Genetics and Dysmorphology (SEGCD), and the Spanish Association of Prenatal Diagnostics (AEDP) developed a consensus statement for population-based genetic carrier screening (GCS). The presented opinion statement recommends that preconception GCS services be included in the public healthcare system to support couples' reproductive autonomy and timely medical decision-making. Program design and implementation strategies, as well as key technical, ethical, and legal considerations are discussed.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of biallelic POLA2 variants in two families with an autosomal recessive telomere biology disorder.","authors":"Malin Kvarnung, Maria Pettersson, Pattra Chun-On, Maryam Rafati, Lisa J McReynolds, Anna Norberg, Pedro Luis Moura, Ida Pesonen, Roza Chaireti, Boa Grönros Söderholm, Julia Burlin, Jenny Rydén, Eva Hellström Lindberg, Neelam Giri, Sharon A Savage, Suneet Agarwal, Ann Nordgren, Bianca Tesi","doi":"10.1038/s41431-024-01722-8","DOIUrl":"https://doi.org/10.1038/s41431-024-01722-8","url":null,"abstract":"<p><p>POLA2 encodes the accessory subunit of DNA polymerase α (polα)/primase, which is crucial for telomere C-strand fill-in. Incomplete fill-in of the C-rich telomeric strand after DNA replication has been proposed as a mechanism for Coats plus syndrome, a phenotype within the broader spectrum of telomere biology disorders (TBD). Coats plus syndrome has so far been associated with pathogenic variants in POT1, CTC1, and STN1. Here we report the findings of biallelic deleterious rare variants in POLA2 gene detected by whole genome sequencing and segregation analysis in five young adults from two unrelated families. All five individuals displayed abnormally short telomeres and a clinical phenotype suggesting a TBD disorder with Coats plus features including retinal and gastrointestinal telangiectasias. Our results suggest POLA2 as a novel autosomal recessive gene for a TBD with Coats plus features.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating an approach for communicating integrated risk scores for melanoma.","authors":"Courtney K Wallingford, Adam Mothershaw, Clare Primiero, Tenielle Clinch, Tamara Dawson, Nathan Ingold, H Peter Soyer, Matthew H Law, Aideen McInerney-Leo, Tatiane Yanes","doi":"10.1038/s41431-024-01750-4","DOIUrl":"https://doi.org/10.1038/s41431-024-01750-4","url":null,"abstract":"<p><p>Integrated risk scores (polygenic and non-genetic risk factors) can facilitate risk-stratification, to inform targeted melanoma screening. This mixed-methods pilot study assessed satisfaction, attitudes, and psychosocial impact of a protocol for communicating integrated risk for melanoma using questionnaires (baseline and 1-month post-results) and semi-structured interviews. Affected and unaffected adults enroled in ongoing melanoma studies were recruited to receive their integrated risk booklets and attend a genetic counselling appointment. 35/73 consented to participate; 31 and 33 completed baseline and follow-up questionnaires, respectively. Participants rated the information as useful, felt it motivated favourable health behaviours and were satisfied with the quality and content of the booklet. All participants felt highly empowered managing melanoma risk at baseline and follow-up. Most participants were unsure or felt little to no control over preventing future melanomas, which did not change at follow-up (Chi-square p = 0.73). Genetic-specific distress, and uncertainty was low for all participants post-results. Qualitative interviews supported quantitative findings and highlighted importance of access to a clinician for results interpretation and risk-management. In this high-risk cohort, the communication model was acceptable, and did not result in negative psychosocial sequelae. Findings from this study highlight key considerations for effective communication and delivery of integrated risk which can be used to inform future research in more diverse cohorts for melanoma and other common conditions.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New guidelines for rare cancer syndromes","authors":"Alisdair McNeill","doi":"10.1038/s41431-024-01735-3","DOIUrl":"10.1038/s41431-024-01735-3","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"32 12","pages":"1517-1517"},"PeriodicalIF":3.7,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-024-01735-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A decade of public engagement regarding human germline gene editing: a systematic scoping review.","authors":"Wendy P Geuverink, Diewertje Houtman, Isabel R A Retel Helmrich, Joosje D Kist, Lidewij Henneman, Martina C Cornel, Sam R Riedijk","doi":"10.1038/s41431-024-01740-6","DOIUrl":"https://doi.org/10.1038/s41431-024-01740-6","url":null,"abstract":"<p><p>Following the discovery of the CRISPR-Cas technology in 2012, there has been a growing global call for public engagement regarding the potential use of human germline gene editing (HGGE). In this systematic scoping review, we aim to evaluate public engagement studies considering the following questions based on three points of attention: 1) Inclusion of underrepresented groups: who have been engaged? 2) Gathering values: what output has been reported? 3) Reaching societal impact: what objectives of public engagement have been reported? A systematic literature search from 2012 to 2023 identified 3464 articles reporting on public engagement studies regarding HGGE retrieved from 12 databases. After screening, 52 full-text articles were assessed for eligibility, resulting in 36 articles that cover 31 public engagement studies. We conclude that co-created efforts are needed to engage underrepresented groups as well as to yield values rather than acceptance levels, and to concretise how engagement might result in societal impact.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the unmet needs of genomic testing in Australia: a geospatial exploration.","authors":"Sarah Casauria, Felicity Collins, Susan M White, Paul Konings, Mathew Wallis, Nicholas Pachter, Julie McGaughran, Christopher Barnett, Stephanie Best","doi":"10.1038/s41431-024-01746-0","DOIUrl":"https://doi.org/10.1038/s41431-024-01746-0","url":null,"abstract":"<p><p>The role of genomic testing in rare disease clinical management is growing. However, geographical and socioeconomic factors contribute to inequitable uptake of testing. Geographical investigations of genomic testing across Australia have not been undertaken. Therefore, we aimed to investigate the geospatial distribution of genomic testing nationally between remoteness areas, and areas of varying socioeconomic advantage and disadvantage. We requested patient postcodes, age, and test type from genomic testing records from seven Australian laboratories for a 6-month period between August 2019 and June 2022. Postcode data were aggregated to Local Government Areas (LGAs) and visualised geospatially. Data were further aggregated to Remoteness Areas and Socio-Economic Index for Areas (SEIFA) quintiles for exploratory analysis. 11,706 records were eligible for analysis. Most tests recorded were paediatric (n = 8358, 71.4%). Microarray was the most common test captured (n = 8186, 69.9%). The median number of tests per LGA was 5.4 (IQR 1.0-21.0). Fifty-seven (10.4%) LGAs had zero tests recorded. Remoteness level was negatively correlated with number of tests across LGAs (rho = -0.781, p < 0.001). However, remote areas recorded the highest rate of testing per 100,000 populations. SEIFA score positively correlated with number of tests across LGAs (rho = 0.386, p < 0.001). The third SEIFA quintile showed the highest rate of testing per 100,000 populations. Our study establishes a foundation for ongoing assessment of genomic testing accessibility and equity and highlights the need to improve access to genomic testing for patients who are disadvantaged geographically or socioeconomically. Future research should include additional laboratories to achieve a larger representation of genomic testing rates nationally.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142727327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding clinical spectrum of PAICS deficiency: Comprehensive analysis of two sibling cases.","authors":"Wen-Chin Weng, Vaclava Skopova, Veronika Baresova, Yao-Lin Liu, Hsueh-Wen Hsueh, Yin-Hsiu Chien, Wuh-Liang Hwu, Olga Souckova, Ales Hnizda, Stanislav Kmoch, Ni-Chung Lee, Marie Zikanova","doi":"10.1038/s41431-024-01752-2","DOIUrl":"https://doi.org/10.1038/s41431-024-01752-2","url":null,"abstract":"<p><p>De novo synthesis of purines (DNPS) is a biochemical pathway that provides the purine bases for synthesis of essential biomolecules such as nucleic acids, energy transfer molecules, signaling molecules and various cofactors. Inborn errors of DNPS enzymes present with a wide spectrum of neurodevelopmental and neuromuscular abnormalities and accumulation of characteristic metabolic intermediates of the DNPS in body fluids and tissues. In this study, we present the second case of PAICS deficiency due to bi-allelic variants of PAICS gene encoding for a missense p.Ser179Pro and truncated p.Arg403Ter forms of the PAICS proteins. Two affected individuals were born at term after an uncomplicated pregnancy and delivery and presented later in life with progressive cerebral atrophy, epileptic encephalopathy, psychomotor retardation, and retinopathy. Plasma and urinary concentrations of dephosphorylated substrates of PAICS, AIr and CAIr were elevated, though they remained undetectable in skin fibroblasts. Both variants affect structural domains in SAICARs catalytic site and the oligomerization interface. In silico modeling predicted negative effects on PAICS oligomerization, enzyme stability and enzymatic activity. Consistent with these findings, affected skin fibroblasts were devoid of PAICS protein and enzyme activity. This was accompanied by alterations in contents of other DNPS proteins, which had co-localized in granular structures that are characteristic of purinosome formation. Our observation expands the clinical spectrum of PAICS deficiency from recurrent abortions and fatal neonatal form to later onset neurodevelopmental disorders. The rarity of this condition may be based on poor clinical recognition and limited access to specialized laboratory tests diagnostic for PAICS deficiency.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}