Journal of Medical Genetics最新文献

{"title":"Authors' response to the commentary by Kivela <i>et al</i> on Hany <i>et al</i> (2024).","authors":"Alan J Mighell, Chris Inglehearn","doi":"10.1136/jmg-2024-110345","DOIUrl":"10.1136/jmg-2024-110345","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"2"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391094","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":"Clonazepam repurposing in <i>ARID1B</i> patients through conventional RCT and N-of-1 trials: an experimental strategy for orphan disease development.","authors":"Pleuntje J van der Sluijs, Koshar Safai Pour, Cécile L Berends, Matthijs D Kruizinga, Annelieke R Müller, Agnies M van Eeghen, Mar Rodríguez-Girondo, Maria J Juachon, Duco Steenbeek, Adam F Cohen, Rob G J A Zuiker, Gijs W E Santen","doi":"10.1136/jmg-2024-109951","DOIUrl":"https://doi.org/10.1136/jmg-2024-109951","url":null,"abstract":"<p><strong>Background: </strong>Clinical trials for rare disorders have unique challenges due to low prevalence, patient phenotype variability and high expectations. These challenges are highlighted by our study on clonazepam in <i>ARID1B</i> patients, a common cause of intellectual disability. Previous studies on Arid1b-haploinsufficient mice showed positive effects of clonazepam on various cognitive aspects.</p><p><strong>Methods: </strong>This study used a randomised, double-blinded, placebo-controlled, two-way crossover study (RCT), followed by an N-of-1 design. In the crossover study, <i>ARID1B</i> patients received clonazepam (max 0.5 mg, two times per day) or a placebo for 22 days with a 3-week washout period. Assessments included safety, tolerability, pharmacokinetics, pharmacodynamics on neurocognitive tasks, behaviour and cognitive function. During phase I of the N-of-1 trial the optimal dosage and individual treatment goals were determined. Phase II evaluated the treatment effect. This phase was composed of three periods: an open-label period with placebo (4 weeks), followed by a double-blinded period (6 weeks), followed by an open-label period in which the patient received clonazepam (4 weeks).</p><p><strong>Results: </strong>In the clonazepam group (<i>n</i>=16, 15 completing both periods), seven (44%) reported improvement on Clinician Global Impression of Improvement versus two (13%) on placebo. 13 (87%) showed 'no change' after placebo (two (13%) on clonazepam), while seven (44%) on clonazepam reported deterioration, often linked to side effects (<i>n</i>=6), suggesting potential benefit from lower dosing. Three N-of-1 trials with RCT responders saw two patients improve on clonazepam during double-blinding, but clinical evaluation deemed the improvements insufficient.</p><p><strong>Conclusions: </strong>Our approach shows the feasibility and strength of combining conventional RCT and N-of-1 studies for therapeutic studies in populations with intellectual disabilities, distinguishing real treatment effects from expectation bias. Our findings suggest that clonazepam has no additional therapeutic value in <i>ARID1B</i> patients.</p><p><strong>Trial registration number: </strong>EUCTR2019-003558-98, ISRCTN11225608.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909689","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":"National survey on the prevalence of single-gene aetiologies for genetic developmental and epileptic encephalopathies in Italy.","authors":"Davide Mei, Simona Balestrini, Elena Parrini, Antonio Gambardella, Grazia Annesi, Valentina De Giorgis, Simone Gana, Maria Teresa Bassi, Claudio Zucca, Maurizio Elia, Luigi Vetri, Barbara Castellotti, Francesca Ragona, Mario Mastrangelo, Francesco Pisani, Giuseppe d'Orsi, Massimo Carella, Dario Pruna, Sabrina Giglio, Carla Marini, Elisabetta Cesaroni, Antonella Riva, Marcello Scala, Laura Licchetta, Raffaella Minardi, Ilaria Contaldo, Maria Luigia Gambardella, Alberto Cossu, Jacopo Proietti, Gaetano Cantalupo, Marina Trivisano, Angela De Dominicis, Nicola Specchio, Laura Tassi, Renzo Guerrini","doi":"10.1136/jmg-2024-110328","DOIUrl":"10.1136/jmg-2024-110328","url":null,"abstract":"<p><strong>Background: </strong>We aimed to estimate real-world evidence of the prevalence rate of genetic developmental and epileptic encephalopathies (DEEs) in the Italian population over a 11-year period.</p><p><strong>Methods: </strong>Fifteen paediatric and adult tertiary Italian epilepsy centres participated in a survey related to 98 genes included in the molecular diagnostic workflows of most centres. We included patients with a clinical diagnosis of DEE, caused by a pathogenic or likely pathogenic variant in one of the selected genes, with a molecular diagnosis established between 2012 and 2022. These data were used as a proxy to estimate the prevalence rate of DEEs.</p><p><strong>Results: </strong>We included 1568 unique patients and found a mean incidence proportion of 2.6 patients for 100.000 inhabitants (SD=1.13) with consistent values across most Italian regions. The number of molecular diagnoses showed a continuing positive trend, resulting in more than a 10-fold increase between 2012 and 2022. The mean age at molecular diagnosis was 11.2 years (range 0-75). Pathogenic or likely pathogenic variants in genes with an autosomal dominant inheritance pattern occurred in 77% (n=1207) patients; 17% (n=271) in X-linked genes and 6% (n=90) in genes with autosomal recessive inheritance. The most frequently reported genes in the survey were <i>SCN1A</i> (16%), followed by <i>KCNQ2</i> (5.6%) and <i>SCN2A</i> (5%).</p><p><strong>Conclusion: </strong>Our study provides a large dataset of patients with monogenic DEE, from a European country. This is essential for informing decision-makers in drug development on the appropriateness of initiatives aimed at developing precision medicine therapies and is instrumental in implementing disease-specific registries and natural history studies.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"25-31"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755205","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":"Cystic fibrosis carrier screening in Australia: comparing sequencing and targeted panels across diverse ancestries.","authors":"Eric Lee, Kaylee Orton","doi":"10.1136/jmg-2024-110365","DOIUrl":"https://doi.org/10.1136/jmg-2024-110365","url":null,"abstract":"<p><strong>Background: </strong>Targeted cystic fibrosis (CF) carrier screening panels may lack sensitivity in non-European ancestry groups. This study aims to evaluate the sensitivity of various panels in Australian CF carriers identified through sequencing.</p><p><strong>Methods: </strong>The following panels were evaluated in 869 CF carriers: Asuragen, Elucigene, Devyser, American College of Medical Genetics and Genomics and Victorian Clinical Genetics Services. Ancestry-specific CF carrier frequencies from population databases and Bayesian analysis were used to estimate post-test residual carrier risks.</p><p><strong>Results: </strong>When variants with varying clinical consequences (VCC) were not considered, mean test sensitivity was highest in the Northern Europe group (95.6%) and lowest in the Southern Asia group (64.0%). The post-test residual carrier risk in the Northern Europe group was approximately 1 in 546, with only the Southern Asia group having a higher residual carrier risk of 1 in 179.</p><p><strong>Conclusion: </strong>The Southern Asia group exhibited the lowest test sensitivity and the highest post-test residual carrier risk, surpassing that of the Northern Europe group. The inclusion or exclusion of VCC significantly impacted the calculated test sensitivities. Further research is suggested to better characterise <i>CFTR</i> variants in non-European ancestry groups and to determine which VCC, if any, should be included in carrier screening reports.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909692","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":"Heterozygous de novo variants in <i>HSPD1</i> cause hypomyelinating leukodystrophy through impaired HSP60 oligomerisation.","authors":"Marina Eskin-Schwartz, Shaikah Seraidy, Eyal Paz, Maism Molhem, Emmanuelle Ranza, Stylianos E Antonarakis, Xavier Blanc, Kristin Herman, William S Benko, Stephanie Libzon, Liat Ben Sira, Aviva Fattal-Valevski, Vadim Dolgin, Ohad S Birk, Amit Kessel, Peter Bross, Celeste Weiss, Abdussalam Azem, Ayelet Zerem","doi":"10.1136/jmg-2024-109862","DOIUrl":"10.1136/jmg-2024-109862","url":null,"abstract":"<p><strong>Introduction: </strong>Hypomyelinating leukodystrophies are a group of genetic disorders, characterised by severe permanent myelin deficiency. Their clinical features include developmental delay with or without neuroregression, nystagmus, central hypotonia, progressing to spasticity and ataxia. <i>HSPD1</i> encodes the HSP60 chaperonin protein, mediating ATP-dependent folding of imported proteins in the mitochondrial matrix. Pathogenic variants in <i>HSPD1</i> have been related to a number of neurological phenotypes, including the dominantly inherited pure hereditary spastic paraplegia (MIM 605280) and the recessively inherited hypomyelinating leukodystrophy 4 (MIM 612233). Subsequently, an additional phenotype of hypomyelinating leukodystrophy has been reported due to de novo heterozygous <i>HSPD1</i> variants.In the current work, we expand the clinical and genetic spectrum of this hypomyelinating disorder by describing a cohort of three patients, being heterozygous for <i>HSPD1</i> variants involving residue Ala536 of HSP60 (the novel p.Ala536Pro variant and the previously reported p.Ala536Val).</p><p><strong>Methods: </strong>Clinical and radiological evaluation; whole exome sequencing, in vitro reconstitution assay and patient fibroblast cell lysate analysis.</p><p><strong>Results: </strong>Clinical manifestation was of early-onset nystagmus, tremor and hypotonia evolving into spasticity and ataxia and childhood-onset neuroregression in one case. Brain MRI studies revealed diffuse hypomyelination.The 3D protein structure showed these variants to lie in spatial proximity to the previously reported Leu47Val variant, associated with a similar clinical phenotype. In vitro reconstitution assay and patient fibroblast cell lysate analysis demonstrated that these mutants display aberrant chaperonin protein complex assembly.</p><p><strong>Discussion: </strong>We provide evidence that impaired oligomerisation of the chaperonin complex might underlie this HSPD1-related phenotype, possibly through exerting a dominant negative effect.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"15-24"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582367","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":"Congenital urinary tract anomalies are a variable finding associated with nevoid basal cell carcinoma syndrome.","authors":"Isha Harshe, Talia Donenberg, Marie Jeanjean, Jesus Ramirez Castano, Frankie Fann, Stephanie Feupe Fotsing, Jamie D Weyandt, Xiaolin Hu, Aditi Dhir, Nicholas A Borja","doi":"10.1136/jmg-2024-110340","DOIUrl":"https://doi.org/10.1136/jmg-2024-110340","url":null,"abstract":"<p><strong>Introduction: </strong>Nevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant disorder classically associated with multiple basal cell carcinomas, odontogenic keratocysts and skeletal anomalies. However, its significant phenotypic heterogeneity often delays the diagnosis. Here, we undertake the first comprehensive characterisation of NBCCS and congenital urinary tract anomalies.</p><p><strong>Methods: </strong>Clinical evaluation followed by genetic testing was performed on a proband with congenital hydronephrosis due to ureteropelvic obstruction. Then, a cohort of patients with molecularly confirmed NBCCS evaluated at a single institution was analysed, followed by a comprehensive review of the literature.</p><p><strong>Results: </strong>The novel, non-canonical splice-site variant c.349+4 delA in <i>PTCH1</i> was detected in a proband, with RNA analysis confirming exon 2 skipping. Of the additional nine NBCCS cases examined at our institution, a second proband with a nonsense variant in <i>PTCH1</i> was identified with renal agenesis and a bladder diverticulum. A literature review then yielded 11 case reports of patients with congenital urinary tract anomalies, most frequently renal agenesis.</p><p><strong>Discussion: </strong>Congenital urinary tract anomalies are a variable finding in NBCCS. Renal ultrasound may be warranted at the time of initial diagnosis, if not previously performed. Moreover, <i>PTCH1</i> should be included in multigene panels that assess for congenital urinary tract disorders.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909691","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>TFAP2E</i> is implicated in central nervous system, orofacial and maxillofacial anomalies.","authors":"Jeshurun C Kalanithy, Enrico Mingardo, Jil D Stegmann, Ramgopal Dhakar, Tikam Chand Dakal, Jill A Rosenfeld, Wen-Hann Tan, Stephanie A Coury, Audrey C Woerner, Jessica Sebastian, Paul A Levy, Leah R Fleming, Lea Waffenschmidt, Tobias T Lindenberg, Öznur Yilmaz, Khadija Channab, Bimaljeet K Babra, Andrea Christ, Britta Eiberger, Selina Hölzel, Clara Vidic, Felix Häberlein, Nina Ishorst, Juan E Rodriguez-Gatica, Behnaz Pezeshkpoor, Patrick A Kupczyk, Olivier M Vanakker, Sara Loddo, Antonio Novelli, Maria L Dentici, Albert Becker, Holger Thiele, Jennifer E Posey, James R Lupski, Alina C Hilger, Heiko M Reutter, Waltraut M Merz, Gabriel C Dworschak, Benjamin Odermatt","doi":"10.1136/jmg-2023-109799","DOIUrl":"10.1136/jmg-2023-109799","url":null,"abstract":"<p><strong>Background: </strong>Previous studies in mouse, <i>Xenopus</i> and zebrafish embryos show strong <i>tfap2e</i> expression in progenitor cells of neuronal and neural crest tissues suggesting its involvement in neural crest specification. However, the role of human transcription factor activator protein 2 (<i>TFAP2E)</i> in human embryonic central nervous system (CNS), orofacial and maxillofacial development is unknown.</p><p><strong>Methods: </strong>Through a collaborative work, exome survey was performed in families with congenital CNS, orofacial and maxillofacial anomalies. Exome variant prioritisation prompted <i>TFAP2E</i> gene for functional analysis in zebrafish embryos. Embryonic morphology and development were assessed after antisense morpholino (MO) knockdown (KD), CRISPR/Cas9 knockout and overexpression of <i>tfap2e</i> in fluorescent zebrafish reporter lines using in vivo microscopy. Computational structural protein modelling of the identified human variants was performed.</p><p><strong>Results: </strong>In total, exome survey identified novel or ultra-rare heterozygous missense variants in <i>TFAP2E</i> in seven individuals from five independent families with predominantly CNS, orofacial and maxillofacial anomalies. One variant was found de novo and another variant segregated in an affected multiplex family. Protein modelling of the identified variants indicated potential distortion of TFAP2E in the transactivation or dimerisation domain. MO KD and CRISPR/Cas9 knockout of <i>tfap2e</i> in zebrafish revealed hydrocephalus and a significant reduction of brain volume, consistent with a microencephaly phenotype. Furthermore, mRNA overexpression of <i>TFAP2E</i> indicates dosage-sensitive phenotype expression. In addition, zebrafish showed orofacial and maxillofacial anomalies following <i>tfap2e</i> KD, recapitulating the human phenotype.</p><p><strong>Conclusion: </strong>Our human genetic data and analysis of Tfap2e manipulation in zebrafish indicate a potential role of <i>TFAP2E</i> in human CNS, orofacial and maxillofacial anomalies.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881570","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":"A tandem duplication of exon 42 of the <i>DMD</i> gene is a likely benign variant.","authors":"Jesse B G Hayesmoore, Ruth Newbury-Ecob, Sarah Durell, Amy Dillon, Farah Kanani, Fiona Beecroft, Joanna Jarvis, Deirdre Cilliers, Carl Fratter","doi":"10.1136/jmg-2024-110159","DOIUrl":"10.1136/jmg-2024-110159","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881586","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":"The NHS England Jewish BRCA Testing Programme: overview after first year of implementation (2023-2024).","authors":"Bethany Torr, Nicola Bell, Ruth McCarthy, Monica Hamill, Joshua Nolan, Sudeekshna Muralidharan, Charlotte Andrews, Mikel Valganon-Petrizan, Yasmin Clinch, Suzanne MacMahon, Alison Morilla, Angela George, Paul Ryves, Pooja Dasani, Moses Adegoroye, Helene Schlecht, George J Burghel, Wendy Ornadel, Nicole Gordon, Lisa Steele, Susana Lukic, Emily Watts, D Gareth Evans, Ranjit Manchanda, Clare Turnbull","doi":"10.1136/jmg-2024-110390","DOIUrl":"10.1136/jmg-2024-110390","url":null,"abstract":"<p><strong>Background: </strong>The NHS Jewish BRCA Testing Programme is offering germline <i>BRCA1</i> and <i>BRCA2</i> genetic testing to people with ≥1 Jewish grandparent. Who have an increased likelihood of having an Ashkenazi Jewish (AJ) founder germline pathogenic variant (gPV) compared with the general population.Testing is offered via a self-referral, home-based saliva sampling pathway, supported by a genetic counsellor telephone helpline. A first-of-its-kind in the United Kingdom (UK) for population genetic testing, outside of research.</p><p><strong>Methods: </strong>We reviewed data from germline testing of 5389 people who registered during the soft-launch phase (January 2023-January 2024) and their families to observe trends in uptake and outcomes of testing.</p><p><strong>Results: </strong>Of the 5389 self-referrals, 4339 (80.5%) consented to testing. Of those with results returned, 2.3% (98/4,274) had a gPV (89.8% AJ founder and 10.2% non-AJ founder).Notably, the detection rate was higher in men (42/790, 5.3%) compared with women (56/3484, 1.6%), with the proportion reporting known BRCA variants within the family prior to consent also significantly increased (13.1% compared with 9.2%, respectively).</p><p><strong>Conclusion: </strong>Overall detection rates of gPVs are similar to those reported elsewhere from Jewish population testing. The pathway, particularly for males, may attract uptake of testing by those previously aware of familial gPVs.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881802","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":"Reassessment and reclassification of variants of unknown significance in patients with cardiomyopathy in a specialist department.","authors":"Sinead Horgan, Huafrin Kotwal, Antonetta Malan, Neha Sekhri, Luis R Lopes","doi":"10.1136/jmg-2024-110208","DOIUrl":"https://doi.org/10.1136/jmg-2024-110208","url":null,"abstract":"<p><strong>Background: </strong>The utility of diagnostic genetic testing in cardiomyopathy has grown significantly, due to the discovery of novel genes and greater awareness among healthcare professionals. However, a substantial proportion of cases (around 50%) yield no causative genetic variants or have variants of unknown significance (VUS), limiting their use in clinical management and familial screening. The increase in data quantity and quality in reference databases, coupled with variant interpretation guidelines, allows for periodic reanalysis of VUS, potentially reducing diagnostic gaps.</p><p><strong>Methods: </strong>This study presents a review of VUS results identified in hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) probands over a 5-year period, using American College of Medical Genetics and Genomics criteria. A total of 248 VUS from 233 reports were reviewed, with the majority of patients with a diagnosis of HCM (n=112), followed by DCM (n=99) and ACM (n=22).</p><p><strong>Results: </strong>Four (1.6%) VUS showed sufficient evidence to upgrade to likely pathogenic/pathogenic status, while 8 (3.2%) were downgraded to benign. The majority 236 (95.2%) remained VUS after reanalysis, of which 12 (4.7%) had potential to reclassification to benign or likely pathogenic/pathogenic depending on further data.</p><p><strong>Conclusion: </strong>The study emphasises the importance of periodic re-evaluation of VUS results for clinical management of probands as well as cascade testing. We show feasibility of conducting reclassification analysis in a referral centre, but highlight the need for ongoing collaboration between clinical and laboratory experts. Our work supports the current recommendation of reclassification every 3-5 years to keep pace with evolving evidence.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853438","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}