Journal of Medical Genetics最新文献

{"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":"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":"303-310"},"PeriodicalIF":3.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015019/pdf/","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":"OA","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":"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":"326-334"},"PeriodicalIF":3.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015070/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole-exome sequencing reveals sex difference in the genetic architecture of high myopia.","authors":"Xingchen Liu, Jiacheng Liang, Shasha Li, Yuhe Yang, Qinghao Zhu, Ruowen Qiu, Zheng Ji Chen, Yinghao Yao, Qing Ren, Xiaoguang Yu, Jia Qu, Jianzhong Su, Jian Yuan","doi":"10.1136/jmg-2024-110467","DOIUrl":"10.1136/jmg-2024-110467","url":null,"abstract":"<p><strong>Background: </strong>High myopia (HM) is one of the leading causes of visual impairment and blindness worldwide. To understand the sex difference in the genetic architecture of HM, which may contribute to understanding HM aetiology and help further the realisation of precision medicine for HM.</p><p><strong>Methods: </strong>We performed sex-stratified exome-wide association studies (ExWAS) with n (males)=7492 and n (females)=8090, along with gene- and pathway-based tests and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to HM in a sex-specific manner.</p><p><strong>Results: </strong>In our ExWAS, we identified that a male-specific gene, <i>CHRNB1</i> (Z_females=1.382, P_females=0.083; Z_males=4.029, P_males=2.80×10^-05; P_difference=0.003), was associated with higher risk scores of HM in males than in females. Rare variant burden tests showed a significant excess of rare protein-truncating variants among HM males in <i>CHRNB1</i>-related pathways, including cell-cell signalling and muscle structure development. Sex-based differences in gene expression within <i>CHRNB1</i>-enriched ciliary body cells were observed; specifically, increased expression of mitochondrial metabolism-related genes in males and antioxidant genes in females. Functional differences in mitochondrial metabolism were confirmed in male-derived H1 and female-derived H9 human embryonic stem cell lines, with H1 cells specifically exhibiting significant dysregulation of mitochondrial organisation and mitochondrial respiratory chain complex assembly after <i>CHRNB1</i> knockdown.</p><p><strong>Conclusion: </strong>Together, our study provides insight into the sex differences in the genetic architecture of HM and highlights <i>CHRNB1</i>'s role in HM pathogenesis in males.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"358-368"},"PeriodicalIF":3.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624999","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":"Impact of NICE Guideline NG241 'Ovarian Cancer: identifying and managing familial and genetic risk' on a regional NHS family history and clinical genetics service.","authors":"Alexander Roe, Andrea Forman, Fiona Lalloo, Terri P McVeigh, Helen Hanson, Katie Snape","doi":"10.1136/jmg-2024-110481","DOIUrl":"10.1136/jmg-2024-110481","url":null,"abstract":"<p><strong>Background: </strong>NICE Guideline NG241: identifying and managing familial and genetic risk of ovarian cancer (OC) was published by the National Institute for Health and Care Excellence (NICE) in March 2024. NG241 advises germline genetic testing of genes predisposing to OC in unaffected individuals with an OC family history at different mutation likelihood thresholds depending on age and sex, ranging from 2% to 10% likelihood of finding a germline pathogenic variant (GPV). Prior to implementation of NG241, updates to the NHS England National Genomic Test Directory would be required. Clinical genetics services have to consider equity of access to assessment and testing across all familial cancer types, best use of their limited resources and other factors such as complexity of delivery of clinical pathways.</p><p><strong>Methods: </strong>We analysed data from 8011 patients who provided digital family histories to the South West Thames Centre for Genomics between October 2019 and June 2024.</p><p><strong>Results: </strong>We estimate 527/782 (68%) females and 28/77 (36%) males would meet test criteria for NICE NG241. We estimate we would reject 2919/5485 (53%) females and 135/1208 (11%) males with the same likelihood of carrying a GPV, but with a breast cancer rather than OC family history. Testing the familial OC cohort at a universal 5% threshold in OC families would detect ~11 carriers for 229 tests compared with ~8 carriers for 278 tests following NG241 criteria.</p><p><strong>Conclusion: </strong>Our data highlight additional factors needing to be considered before the NICE Guideline NG241 can be implemented by regional genetics services.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"311-316"},"PeriodicalIF":3.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458222","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}

{"title":"Homozygous loss of function variant in <i>LMNB2</i> gene causes major brain malformation and perinatal death.","authors":"Camille Desgrouas, Igor Deryabin, Clémence Duvillier, Diane Frankel, Elise Kaspi, Thibaud Quibel, Gabriel Le Goff, Mathieu Cerino, Jérémie Mortreux, Bénédicte Gérard, Rodolphe Dard, Catherine Badens","doi":"10.1136/jmg-2024-110549","DOIUrl":"10.1136/jmg-2024-110549","url":null,"abstract":"<p><p>Lamins play a major role in the mechanical stability of cell nuclei, the organisation of chromatin and the DNA replication, transcription and repair. The expression profiles of A-type and B-type lamins vary depending on developmental stages, cell types and tissues. Lamin B2 is expressed very early in embryogenesis, especially in the central nervous system, where it is essential for neuronal migration and brain development. Pathogenic missense variants in lamin B2 have been linked to conditions such as lipodystrophy, progressive myoclonic epilepsy and primary microcephaly. Here, we report clinical data and molecular findings for two related newborns carrying a homozygous loss-of-function variant in the <i>LMNB2</i> gene. Both newborns died in the perinatal period and exhibited a similar phenotype at birth, including severe brain development abnormalities, which closely mirror findings observed in several <i>Lmnb2</i>-deficient mouse models. Western blot and immunofluorescence cell labelling performed on the patient's fibroblasts obtained at birth confirmed the complete absence of lamin B2 and revealed an increase in lamin B1, together with alterations in alpha-tubulin and vimentin organisation. This novel clinical form of laminopathy associated with lamin B2 deficiency expands the molecular causes of brain development abnormalities to <i>LMNB2</i> gene variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"345-349"},"PeriodicalIF":3.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515904","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":"Gene prioritisation for enhancing molecular diagnosis in rare skeletal muscle disease cohort.","authors":"Victoria Lillback, Gaber Bergant, Maria Francesca Di Feo, Ivana Babić Bozović, Annalaura Torella, Mridul Johari, Aleš Maver, Katarina Pelin, Filippo M M Santorelli, Vincenzo Nigro, Peter Hackman, Borut Peterlin, Bjarne Udd, Marco Savarese","doi":"10.1136/jmg-2024-110212","DOIUrl":"10.1136/jmg-2024-110212","url":null,"abstract":"<p><strong>Background: </strong>Inherited rare skeletal muscle diseases cause muscle weakness and wasting of variable severity. Without a molecular diagnosis, patients often endure prolonged diagnostic journeys, leading to delays in appropriate management of the disease. This occurs in approximately 60% of patients with rare diseases.</p><p><strong>Methods: </strong>To facilitate reanalysis of 278 unsolved patients, we used a gene prioritisation tool Exomiser, which standardises analysis by ranking causative variants based on phenotype relevance and variant pathogenicity. Before analysis, we benchmarked Exomiser for variant prioritisation with solved cases and for novel disease gene discovery with mock cases with variants in candidate disease genes. Additionally, we studied the significance of the specificity of the phenotype descriptions.</p><p><strong>Results: </strong>In our study, Exomiser ranked genes in the top 10 correctly in 97.4% of controls with previously detected causative variants. Moreover, 57.1% of candidate genes in mock cases were similarly prioritised in the top 10. We also showed that three parental muscle disease human phenotype ontologies describing the patient phenotype performed as well as patient-specific ones, with a p value of 0.68 for difference in performance. The provided automation and standardisation of variant interpretation resulted in two novel diagnoses and in findings, either in known muscle disease genes or in novel candidate genes, which need further investigation.</p><p><strong>Conclusions: </strong>Exomiser is recommended for initial and periodic reanalyses of exomes in unsolved patients with myopathy, as it benefits from literature updates and minimises effort. This approach could also extend to whole genome sequencing data, aiding the interpretation of variants beyond coding regions.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"350-357"},"PeriodicalIF":3.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566586","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":"Uptake, utility and resource requirements of a genetic counselling telephone helpline within the BRCA-DIRECT digital pathway for mainstreamed BRCA testing in patients with breast cancer.","authors":"Bethany Torr, Grace Kavanaugh, Monica Hamill, Christopher Jones, Helena Harder, Sophie Allen, Alice Garrett, Subin Choi, Rosalind Way, Rochelle Gold, Amy Taylor, Rhian Gabe, Anneke Lucassen, Ranjit Manchanda, Angela George, Michael Hubank, Stephen Bremner, Ashu Gandhi, Zoe Kemp, D Gareth Evans, Lesley Fallowfield, Valerie Jenkins, Clare Turnbull","doi":"10.1136/jmg-2024-110428","DOIUrl":"10.1136/jmg-2024-110428","url":null,"abstract":"<p><strong>Background: </strong>We trialled the first digital pathway (BRCA-DIRECT) aiming to improve capacity for mainstreamed BRCA testing within UK breast oncology services. Patients received standardised digital pretest information, with saliva sampling and consent to testing completed at home. For individualised support, we offered access to a clinical genetics professional via a telephone helpline (TH).</p><p><strong>Methods: </strong>To evaluate the utilisation, uptake and resource requirements for provision of the TH, we analysed data from structured call logs recorded in the BRCA-DIRECT Study. Mixed-methods analysis included combining quantitative data from call logs and patient demographics with thematic analysis of free-text notes establishing reasons for calls. Additional data were analysed from structured telephone interviews.</p><p><strong>Results: </strong>Calls were received from 201/1140 (17.6%) patients. We identified that 84.6% of calls (274 calls, 1097 min) pertained to 'administrative' support needs only. The remaining 15.4% required a clinical genetics professional (50 calls, 344 min). Of the clinical calls received: 26.0% were placed prior to test consent, 36.0% while awaiting results and 38.0% post results, with median (interquartile) call lengths of 8 (4-10) min; 5.5 (4-10) min; and 5 (3-7) min, respectively. Across all 1140 patients, a mean of 0.3 min of clinical time was required per patient.</p><p><strong>Conclusions: </strong>Our findings demonstrate that the 'BRCA-DIRECT' model of standardised information provision served most patients, with a minority using the helpline for supplementary clinical information or support. The modest per-patient requirement for clinical time supports the scalability of this model for expanding mainstream genetic testing within UK oncology services.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"317-325"},"PeriodicalIF":3.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624998","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}

{"title":"Arteriovenous malformation from a patient with JP-HHT harbours two second-hit somatic DNA alterations in <i>SMAD4</i>.","authors":"Evon DeBose-Scarlett, Andrew K Ressler, Cassi Friday, Kara K Prickett, James W Roberts, James R Gossage, Douglas A Marchuk","doi":"10.1136/jmg-2024-110569","DOIUrl":"10.1136/jmg-2024-110569","url":null,"abstract":"<p><strong>Background: </strong>Hereditary haemorrhagic telangiectasia (HHT) is an inherited disorder of vascular malformations. It is caused by inherited loss-of-function mutations in one of three genes, <i>ENG</i>, <i>ACVRL1</i> or <i>SMAD4</i>. We recently showed that HHT-associated vascular malformations from liver, lung, brain and skin develop via a two-hit genetic mechanism resulting from biallelic loss-of-function mutations in either <i>ENG</i> or <i>ACVRL1</i>. Second-hit somatic mutations in <i>SMAD4</i> have not been reported in HHT-associated vascular malformations. Here, we investigate a large, aggressively growing craniofacial arteriovenous malformation (AVM) from an individual with juvenile polyposis-HHT caused by a germline mutation in <i>SMAD4</i>.</p><p><strong>Methods: </strong>We sequenced DNA from the AVM using a targeted gene sequencing panel to at least 1000X to identify somatic mutations that might contribute to the development of the AVM. We analysed whole genome SNP genotyping data using the algorithm Mosaic Chromosomal Alterations (MoChA) to identify somatic loss of heterozygosity.</p><p><strong>Results: </strong>We confirmed the germline mutation in <i>SMAD4</i> (c.1610A>T, p.Asp537Val) and identified a second-hit somatic mutation also in <i>SMAD4</i> (c.350dup, p.Tyr117*) that occurred in <i>trans</i> relative to the germline mutation. We also identified somatic loss of heterozygosity on the q arm of chromosome 18, including <i>SMAD4</i>. Additionally, we confirmed that the loss of heterozygosity causes loss of the wild-type allele. Thus, we identified two independent somatic alterations in <i>SMAD4</i> causing biallelic loss of <i>SMAD4</i> function in the AVM tissue.</p><p><strong>Conclusion: </strong>We identified biallelic loss of function of <i>SMAD4</i> in a craniofacial AVM, evidence that <i>SMAD4</i> also follows the two-hit mutation mechanism of HHT-associated vascular malformation pathogenesis.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"281-288"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408749","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}

{"title":"Expanding the phenotypic spectrum of PROS: reclassifying isolated lateralised overgrowth.","authors":"Andrea Gazzin, Giuseppe Reynolds, Stefania Massuras, Maria Luca, Paola Coppo, Diana Carli, Marilidia Piglionica, Stefania Martino, Rosanna Bagnulo, Giovanni Battista Ferrero, Nicoletta Resta, Alessandro Mussa","doi":"10.1136/jmg-2024-110364","DOIUrl":"10.1136/jmg-2024-110364","url":null,"abstract":"<p><p>Lateralised overgrowth (LO) is characterised by the asymmetric increase in the size of any part of the body exceeding 10% compared with the unaffected contralateral one. LO is a key feature in various syndromic overgrowth disorders, such as Beckwith-Wiedemann spectrum and <i>PIK3CA</i>-related overgrowth spectrum (PROS). However, it can also present as isolated (ILO). Defining the aetiology of LO is critical due to the clinical implications and management strategies required for each condition. This report presents two patients who were followed up throughout childhood for ILO and were ultimately diagnosed with PROS through molecular analysis on DNA extracted from a skin biopsy, revealing the <i>PIK3CA</i>:c.263G>A (p.Arg88Gln) variant at a high variant allele frequency. This variant has been described in association with macrocephaly-capillary malformation syndrome but not with ILO. In conclusion, this is the first report of patients harbouring the (p.Arg88Gln) variant with a diagnosis of ILO, thus, highlighting the importance of considering ILO within the PROS and underscoring the necessity for somatic DNA testing. An early and accurate molecular diagnosis is crucial for guiding appropriate clinical management in order to ensure access to targeted therapies, emphasising the need for further research to refine diagnostic criteria and testing recommendations for ILO.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"276-280"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052802","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":"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}