Journal of Medical Genetics最新文献

{"title":"Enhancing clinical decision-making for CNVs of uncertain significance in neurodevelopmental disorders: the relevance (or uselessness) of scoring and segregating.","authors":"Jorge Diogo Da Silva, Nuno Maia, Paula Jorge, Vanessa Sousa, Nataliya Tkachenko, Ana Rita Soares","doi":"10.1136/jmg-2024-110144","DOIUrl":"10.1136/jmg-2024-110144","url":null,"abstract":"<p><strong>Background: </strong>Clinicians often deal with copy-number variants of unknown significance (CNVUS) when managing neurodevelopmental disorders (NDDs). Variant classification is often complemented with textual comments, while the American College of Medical Genetics and Genomics (ACMG)/Clinical Genome Resource (ClinGen) numerical scores are rarely reported. Our aim was to determine if the application of ACMG/ClinGen scoring and inheritance/segregation studies are relevant for the reclassification of CNVUS.</p><p><strong>Methods: </strong>We retrieved 167 CNVUS (112 duplications, 55 heterozygous deletions) from test reports of 141 patients with NDD in a 5-year period. None of those testing reports included ACMG/ClinGen scoring information for the CNVUS. One clinical and one laboratorial geneticist independently applied the ACMG/ClinGen scoring system for CNVs. Final scores/categories were assessed for potential modification when adding inheritance/segregation criteria.</p><p><strong>Results: </strong>138 (83%) of the CNVUS retained the VUS classification, 14 (8%) changed to benign and 15 (9%) to (likely) pathogenic. Variants deemed benign (11 duplications, 3 deletions) mostly overlapped with ClinGen-established benign regions or were common in the general population; variants deemed (likely) pathogenic (all deletions) were either associated with unrelated autosomal recessive/later-onset autosomal dominant (AD) conditions, or with an AD NDD phenotype in a single case. Inheritance studies were available for 20 (12%) variants (17 inherited, 3 de novo), and none led to a change in classification. A simulation showed that adding inheritance information would also not change the classification of any other variant.</p><p><strong>Conclusion: </strong>Application of the ACMG/ClinGen scoring system led by itself to reclassification of 17% of VUS, despite a very low increase in diagnostic yield (1/141, 0.7%). Additionally, segregation/inheritance studies in CNVUS were mostly irrelevant in most NDD cases, challenging their routine broad application in clinical practice.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"298-302"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>FLNA</i> genomic rearrangements in a 391 French bilateral periventricular nodular heterotopia cohort: prevalence and phenotypic correlations.","authors":"Henri Margot, Natalia Hernandez Poblete, Chloé Angelini, Julie Desforges, Julie Bouron, Benoit Arveiler, Caroline Rooryck, Cyril Goizet, Patricia Fergelot","doi":"10.1136/jmg-2024-110336","DOIUrl":"10.1136/jmg-2024-110336","url":null,"abstract":"<p><strong>Background: </strong><i>FLNA</i> loss of function manifests across a broad spectrum of phenotypes, ranging from severe prenatal onset to asymptomatic cases. Bilateral periventricular nodular heterotopia (BPNH) consistently occurs in affected individuals. This retrospective study involving French patients with BPNH evaluates the prevalence of <i>FLNA</i> gene dosage anomalies and investigates genotype-phenotype correlations in a large cohort of French patients with BPNH.</p><p><strong>Methods: </strong>A retrospective observational study was conducted on 391 individuals diagnosed with BPNH confirmed by brain MRI. Sequencing analysis using Sanger or next-generation sequencing was complemented by targeted array-comparative genomic hybridisation to identify copy number variants (CNVs).</p><p><strong>Results: </strong><i>FLNA</i> variants were identified in 40% of females and 12% of males. Among these, 87% were single nucleotide variants (SNVs), while CNVs accounted for 13%, all of which were deletions. Half of the CNVs involved a recurrent deletion spanning exons 31-48, often accompanied by a duplication of the neighbouring <i>EMD</i> gene. This del-dup was associated with a milder phenotype, whereas smaller de novo deletions correlated with severe outcomes. Mosaicism was also detected in three cases.</p><p><strong>Conclusion: </strong><i>FLNA</i> CNV analysis, particularly for recurrent deletions and mosaicism, is essential in the genetic evaluation of BPNH. Integrating CNV detection with SNV analysis improves diagnostic accuracy and enhances understanding of genotype-phenotype correlations.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"227-230"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parental knowledge, attitudes, satisfaction and decisional conflict regarding whole genome sequencing in the Genomic Medicine Service: a multisite survey study in England.","authors":"Ria Patel, Bettina Friedrich, Saskia C Sanderson, Holly Ellard, Celine Lewis","doi":"10.1136/jmg-2024-110458","DOIUrl":"10.1136/jmg-2024-110458","url":null,"abstract":"<p><strong>Background: </strong>Whole genome sequencing (WGS) for paediatric rare disease diagnosis is now available as a first-line test for certain clinical indications in the Genomic Medicine Service in England. The aim of this study was to assess decisional conflict regarding WGS at the time of consent as well as parental knowledge, attitudes and satisfaction.</p><p><strong>Methods: </strong>We conducted a multisite quantitative survey including validated measures. Surveys were sent out across seven National Health Service Trusts in England to parents of children offered WGS, within 4 weeks of their appointment.</p><p><strong>Results: </strong>374/1366 survey responses were included in the final dataset. Parents were highly satisfied with their WGS appointment (mean=24.47/28), had low decisional conflict (mean=20.09/100) and felt they had received enough information and support to make an informed decision (83.9%). Parents had positive attitudes towards WGS (mean=18.17/20), and those who had discussed WGS with a genetic counsellor or genomic associate had significantly more positive attitudes than those seen by genetic consultants (p<0.001). Most parents (84.3%) strongly agreed (27.2%) or agreed (67.1%) that they had a clear understanding of what a genomic test is. Parents whose child's condition was reported as more serious (p=0.0011) felt less conflicted about their decision.</p><p><strong>Conclusions: </strong>The parents in this study had low decisional conflict and most felt they had made an informed decision. Further research after parents receive WGS results to assess whether any, and if so who, regrets their decision, is important.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"289-297"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurodevelopmental delay, musculoskeletal disorders and dysmorphia associated with a novel pathogenic interstitial deletion of chromosome 10q21.1q21.3.","authors":"Dibyendu Dutta, Jennifer Black, Emily A Montoya, Thomas Andrew Burrow, Joseph Shieh, Bobbi McGivern, Michelle Raymond, Christina B Sheedy, Scott C Smith, Ria Garg","doi":"10.1136/jmg-2024-110367","DOIUrl":"10.1136/jmg-2024-110367","url":null,"abstract":"<p><strong>Background: </strong>Previous reports of distal deletions in chromosome 10q in patients have described distinct facial features combined with other neurodevelopmental abnormalities, including intellectual disability. However, the association of interstitial deletions in chromosome 10q with global developmental delay, musculoskeletal abnormalities, and dysmorphic features has not been previously reported.</p><p><strong>Methods: </strong>Genetic testing using whole exome sequencing (WES) was performed on three patients with neurodevelopmental delay, musculoskeletal abnormalities and dysmorphic features. Sequencing reads were aligned to the human genome build GRCh37/UCSC hg19 and analysed for both sequence and copy number variants.</p><p><strong>Results: </strong>WES identified similar interstitial deletions in the 10q21.1q21.3 locus in all three patients. The deleted region includes online Mendelian inheritance in man (OMIM)-annotated genes with clinical significance, such as <i>ANK3</i> (*600465), <i>JMJD1C</i> (*604503), <i>EGR2</i> (*129010), <i>BICC1</i> (*614295), <i>ZNF365</i> (*607818) and <i>TFAM</i> (*600438). Deletion of this region is considered pathogenic and is implicated in the aetiology of the clinical phenotypes observed in these patients.</p><p><strong>Conclusions: </strong>This is the first report associating interstitial deletions in the 10q21.1q21.3 locus with neurodevelopmental delay, musculoskeletal abnormalities and dysmorphic features. Our findings highlight the clinical significance of this deleted region and suggest possible mechanisms underlying the observed pathological phenotypes.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"268-275"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic and clinical analysis of <i>OPTN</i> in amyotrophic lateral sclerosis.","authors":"Yi Xiao, Yushan Tan, Chunyu Li, Qianqian Wei, Qirui Jiang, Shichan Wang, Tianmi Yang, Junyu Lin, Lingyu Zhang, Huifang Shang","doi":"10.1136/jmg-2024-109978","DOIUrl":"10.1136/jmg-2024-109978","url":null,"abstract":"<p><strong>Background: </strong>Considerable heterogeneity in genotypes and phenotypes has been observed among patients with amyotrophic lateral sclerosis (ALS) harbouring optineurin gene (<i>OPTN</i>) mutations, as reported in prior studies. The study aimed to elucidate the correlation between <i>OPTN</i> genotypes and phenotypes.</p><p><strong>Methods: </strong><i>OPTN</i> gene variants were screened within a substantial Chinese cohort of patients with ALS, encompassing LoF and rare missense variants. Additionally, a systematic literature review was conducted to compile the spectrum of <i>OPTN</i> mutations and explore the relationship between the genotype and phenotype of patients with ALS with <i>OPTN</i>.</p><p><strong>Results: </strong>A total of 33 unrelated patients with ALS with 24 rare <i>OPTN</i> variants, including 17 novel variants, were identified in 2279 patients with ALS. Among 24 variants in our cohort and 106 variants in previous studies, only 33.3% and 35.8% were pathogenic/likely pathogenic variants. Moreover, the frequency of <i>OPTN</i> variants in the Asian ALS population was higher (1.08%) than that of the Caucasian population (0.55%). For the phenotype of patients with ALS carrying OPTN variants, we found that patients with pathogenic/likely pathogenic variants had the highest baseline progression rate and the shortest survival time among groups in our cohort.</p><p><strong>Conclusion: </strong>Our study contributed to a broader understanding of the genotype and phenotype spectrum of patients with ALS carrying <i>OPTN</i> variants. Further investigations are warranted to definitively establish the genotype-phenotype associations.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"242-248"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aarskog-Scott syndrome: a clinical study based on a large series of 111 male patients with a pathogenic variant in <i>FGD1</i> and management recommendations.","authors":"Médéric Jeanne, Nathalie Ronce, Solène Remizé, Stéphanie Arpin, Geneviève Baujat, Sylvain Breton, Florence Petit, Clémence Vanlerberghe, Anne Coeslier-Dieux, Sylvie Manouvrier-Hanu, Catherine Vincent-Delorme, Philippe Khau Van Kien, Julien Van-Gils, Chloé Quélin, Laurent Pasquier, Sylvie Odent, Florence Demurger, Fanny Laffargue, Christine Francannet, Dominique Martin-Coignard, Alexandra Afenjar, Sandra Whalen, Alain Verloes, Yline Capri, Andrée Delahaye, Julie Plaisancié, Philippe Labrune, Anne Destree, Isabelle Maystadt, Viorca Ciorna Monferrato, Bertrand Isidor, Marie Vincent, Nolwen Jean Marçais, Sophie Nambot, Elise Schaefer, Salima El Chehadeh, James Lespinasse, Patrick Collignon, Tiffany Busa, Nicole Philip, Marjolaine Willems, Marc Planes, Olivier M Vanakker, Laetitia Lambert, Bruno Leheup, Michèle Mathieu-Dramard, Gilles Morin, Klaus Dieterich, Emmanuelle Ginglinger, Allan Bayat, Meena Balasubramanian, Benjamin Dauriat, Damien Haye, Jeanne Amiel, Marlène Rio, Valérie Cormier-Daire, Annick Toutain","doi":"10.1136/jmg-2022-108868","DOIUrl":"10.1136/jmg-2022-108868","url":null,"abstract":"<p><strong>Background: </strong>Aarskog-Scott syndrome (AAS) is a rare condition with multiple congenital anomalies, caused by hemizygote variants in the <i>FGD1</i> gene. Its description was based mostly on old case reports, in whom a molecular diagnosis was not always available, or on small series. The aim of this study was to better delineate the phenotype and the natural history of AAS and to provide clues for the diagnosis and the management of the patients.</p><p><strong>Methods: </strong>Phenotypic characterisation of the largest reported AAS cohort, comprising 111 male patients with proven causative variants in <i>FGD1</i>, through comprehensive analyses of clinical data including congenital anomalies, growth and neurodevelopment. Review of photographs and radiographs by experts in dysmorphology and skeletal disorders.</p><p><strong>Results: </strong>This study refines the phenotypic spectrum of AAS, with the description of new morphological and radiological features, and refines the prevalence of the features. Short stature is less frequent than previously reported and has a prenatal onset in more than half of the patients. The growth has a specific course with a catch-up during the first decade often leading to low-normal stature in adulthood. Whereas intellectual disability is rare, patients with AAS have a high prevalence of specific learning difficulties and attention hyperactivity disorder. In light of this better knowledge of AAS, we provide management recommendations.</p><p><strong>Conclusion: </strong>A better knowledge of the natural history and phenotypic spectrum of AAS will be helpful for the clinical diagnosis and for the interpretation of <i>FGD1</i> variants using a retrophenotyping strategy, which is becoming the most common way of diagnosis nowadays. Recommendations for care will improve the management of the patients.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"258-267"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disease burden by <i>ALPL</i> variant number in patients with non-life-threatening hypophosphatasia in the Global HPP Registry.","authors":"Priya S Kishnani, Lothar Seefried, Kathryn M Dahir, Gabriel Á Martos-Moreno, Wolfgang Högler, Cheryl R Greenberg, Shona Fang, Anna Petryk, William R Mowrey, Agnès Linglart, Keiichi Ozono","doi":"10.1136/jmg-2024-110383","DOIUrl":"10.1136/jmg-2024-110383","url":null,"abstract":"<p><strong>Background: </strong>Hypophosphatasia (HPP) is a rare metabolic disease caused by autosomal dominant or recessive inheritance of <i>ALPL</i> variants resulting in low alkaline phosphatase activity. The objective of this analysis was to compare HPP disease burden between patients with non-life-threatening disease in the Global HPP Registry who have one <i>ALPL</i> variant versus two or more <i>ALPL</i> variants.</p><p><strong>Methods: </strong>Patients were included if they had one or more <i>ALPL</i> variants identified through genetic testing and first HPP manifestations after 6 months of age. Assessments included history of HPP manifestations, Brief Pain Inventory-Short Form (BPI-SF), Health Assessment Questionnaire-Disability Index (HAQ-DI), 6-Min Walk Test (6MWT), Paediatric Quality of Life Inventory (PedsQL) and 36-Item Short-Form Survey V.2 (SF-36v2).</p><p><strong>Results: </strong>Of 685 included patients, 568 (82.9%) had one <i>ALPL</i> variant, 116 (16.9%) had two variants, and one (0.1%) had three variants. Patients with two or more <i>ALPL</i> variants had higher proportions of skeletal (52.1% vs 32.6%), dental (73.5% vs 56.0%), muscular (36.8% vs 23.6%) and neurological (22.2% vs 8.8%) manifestations at last assessment. BPI-SF, HAQ-DI, PedsQL and SF-36v2 scores were similar between groups. Distances walked on the 6MWT were similar between groups for children. Distance walked was lower among adults with two or more variants (293 m (n=8)) than adults with one variant (466 m (n=103)), although the former group was very small.</p><p><strong>Conclusion: </strong>HPP disease burden is high in patients with HPP, regardless of <i>ALPL</i> variant number. While prevalence of HPP-specific manifestations was higher in patients with two or more variants than those with one variant, patient-reported outcomes were similar between groups.</p><p><strong>Trial registration number: </strong>NCT02306720; EUPAS13514.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"249-257"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinicogenetic characterisation of SLC29A3-related syndromes: a case series, tracing ancestral variants and molecular dynamics simulation.","authors":"Sajjad Biglari, Mohammad Shahrooei, Fatemeh Vahidnezhad, Leila Youssefian, Vahid Ziaee, Nima Rezaei, Atefeh Sohanforooshan Moghaddam, Sahar Sedighzadeh, Hossein Moravej, Parisa Safari Foroushani, Majid Keivanfar, Homa Ilkhanipoor, Amir Hozhabrpour, Hooria Seyedhosseini-Ghaheh, Iraj Mohammadzadeh, Majid Naderi, Elham Sheikhi Ghayur, Nader Mansour Samaei, Saeed Dorgaleleh, Emran Esmaeilzadeh, Roya Sherkat, Hamid Reza Khorram Khorshid, Mohammad Amin Tabatabaiefar, Hakon Hakonarson, Hassan Vahidnezhad","doi":"10.1136/jmg-2024-110606","DOIUrl":"https://doi.org/10.1136/jmg-2024-110606","url":null,"abstract":"<p><strong>Background: </strong>SLC29A3-related syndromes (SLC29A3-RS) are characterised by severe and multiorgan involvement that has a severe impact on the quality of life of the affected persons and therefore merit further genetic and clinical research. We investigated the clinical and genetic aspects of patients with SLC29A3-RS.</p><p><strong>Methods: </strong>Six pathogenic variants of the <i>SLC29A3</i> gene were identified in eight families in the current study. RNA sequencing was used for evaluating <i>SLC29A3</i> variant gene expression and protein stability by molecular dynamics (MD) simulations. This study conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review of cases across five electronic databases.</p><p><strong>Results: </strong>Genetic analysis revealed six pathogenic variants of the <i>SLC29A3</i> gene in eight families; one variant was shared among three families, indicating a possible founder effect. The estimated most recent common ancestor for these patients lived approximately 8.5 generations ago. MD studies revealed structural instability in mutant proteins. RNA sequencing also demonstrated that the expression of SLC29A3 was downregulated while the expression of the immune markers CD68 and LYZ was upregulated. A systematic search of 197 patients of different ethnic backgrounds revealed that the following symptoms were frequent findings: hyperpigmentation, hypertrichosis, hearing loss, short stature and hepatomegaly. The age of onset of SLC29A3-RS was 5.53±5.24 years with an IQR of 1.4-8.25 years.</p><p><strong>Conclusions: </strong>The characterisation of the founder variants and the genotype-phenotype correlations helps delineate the phenotype spectrum of SLC29A3-RS, which will facilitate the genetic counselling and screening of the high-risk population. Findings on <i>SLC29A3</i> variants show the way to proceed in the process of developing the diagnostic and therapeutic methods in the management of SLC29A3-RS.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Limitations of genomics to predict and treat autism: a disorder born in the womb.","authors":"Yehezkel Ben-Ari, Étienne É Danchin","doi":"10.1136/jmg-2024-110224","DOIUrl":"https://doi.org/10.1136/jmg-2024-110224","url":null,"abstract":"<p><p>Brain development involves the sequential expression of vulnerable biological processes including cell proliferation, programmed cell death, neuronal migration, synapse and functional unit formation. All these processes involve gene and activity-dependent events that can be distorted by many extrinsic and intrinsic environmental factors, including stress, microbiota, inflammatory signals, hormonal signals and epigenetic factors, hence leading to disorders born in the womb that are manifested later in autism spectrum disorders (ASDs) and other neurodevelopmental disorders. Predicting and treating such disorders call for a conceptual framework that includes all aspects of developmental biology. Here, taking the high incidence of ASDs as an example, we first discuss the intrinsic limitations of the genetic approach, notably the widely used twin studies and SNPs. We then review the long list of in utero events that can deviate developmental sequences, leading to persistent aberrant activity generated by immature misplaced and misconnected neuronal ensembles that are the direct cause of ASD. In a clinical perspective, we suggest analysing non-genetic maternity data to enable an early prediction of babies who will develop ASD years later, thereby facilitating early psycho-educative techniques. Subsequently, agents capable of selectively silencing malformed immature networks offer promising therapeutic perspectives. In summary, understanding developmental processes is critical to predicting, understanding and treating ASD, as well as most other disorders that arise in the womb.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Canadian consensus for the assessment and testing of Lynch syndrome.","authors":"Melyssa Aronson, Laura Palma, Kara Semotiuk, Jennifer Nuk, Aaron Pollett, Harminder Singh, Heidi Rothenmund, Hilary Racher, Jaime Jessen, Stephen E Pautler, Alison Rusnak, Mari Rutka, Holly Etchegary, Teresa Tiano, Pardeep Kaurah, Lesa Dawson, Andrea Hawrysh, Thomas Ward, Angela Bedard, Brandon S Sheffield, Jordan Lerner-Ellis, Karine Jacob, Sarah Ferguson, Christina A Kim, Erin Chamberlain, Kimberly Dornan, Larissa Waldman, Spring Holter, Janice Horte, Angela Hyde, Janice Kwon, Andree MacMillan, Melanie O'Loughlin, Uri Tabori, Steven Gallinger, Raymond Kim","doi":"10.1136/jmg-2024-110465","DOIUrl":"https://doi.org/10.1136/jmg-2024-110465","url":null,"abstract":"<p><strong>Background: </strong>Lynch syndrome (LS) is an autosomal dominant cancer predisposition syndrome caused by a germline pathogenic variant, or epigenetic silencing, of a mismatch repair (MMR) gene, leading to a wide cancer spectrum with gene-specific penetrance. Ascertainment, assessment and testing of LS individuals is complex. A Canadian national guideline is needed to ensure equitable access to patient care across the country.</p><p><strong>Methods: </strong>The Canadian Lynch Syndrome (CDN-LS) working group was formed in 2021, consisting of 37 multidisciplinary LS experts and patient partners. To formulate consensus statements, a national environmental scan, Canadian clinical survey and literature review were undertaken. The e-Delphi method was used to reach consensus statements among the CDN-LS group.</p><p><strong>Results: </strong>The CDN-LS group voted on 21 statements, and 18 statements were adopted with over 80% agreement, including 16 statements that had over 90% agreement. These statements provide comprehensive guidelines on universal MMR reflex testing, cascade tumour testing (<i>MLH1</i> promoter methylation, <i>BRAF</i>, somatic MMR), germline testing, therapeutics and patient advocacy.</p><p><strong>Conclusion: </strong>This is the first comprehensive Canadian guideline for LS providing guidance to genetic specialists, laboratories, primary care providers and healthcare providers caring for patients with LS. It is endorsed by the Canadian College of Medical Genetics and the Canadian Association of Genetic Counsellors. The consensus statements are presented as a model for standard of care that improves equitable access to health services for LS across the country. Future work should include a national consensus on LS surveillance, with a goal to harmonise LS care across all provincial and territorial healthcare authorities.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}