Journal of Medical Genetics最新文献

{"title":"Heterozygous <i>TBX2</i> frameshift variants cause a novel syndromic hearing loss with incompletely penetrant nystagmus.","authors":"Wan Hua, Yanfei Wang, Xiang Li, Wenyu Xiong, Lanchen Wang, Meilin Chen, Fengxiao Bu, Libo Liu, Fangyi Chen, Mingjun Zhong, Yu Lu, Zhiyong Liu, Jing Cheng, Huijun Yuan","doi":"10.1136/jmg-2025-110997","DOIUrl":"https://doi.org/10.1136/jmg-2025-110997","url":null,"abstract":"<p><strong>Background: </strong>A substantial fraction of hereditary hearing loss (HL) remains unexplained by known HL genes. Tbx2 is a developmental transcription factor critical for inner ear hair cell differentiation in mice, while its pathogenic role in genetic HL in humans has yet to be documented. Here, we identified heterozygous <i>TBX2</i> frameshift variants that cause human HL, establishing a previously unrecognised genetic link.</p><p><strong>Methods: </strong>Linkage analysis combined with whole-genome sequencing (WGS) was applied to identify the causative gene in two unrelated Chinese families with autosomal dominant progressive sensorineural HL (SNHL) accompanied by incomplete penetrance nystagmus. Functional evaluation of <i>TBX2</i> variants was performed through protein expression, localisation and transcriptional activity analysis <i>in vitro</i>, phenotypic analysis and mechanism study in knockout and knock-in mice model <i>in vivo</i>.</p><p><strong>Results: </strong>Linkage analysis in Family 1 mapped SNHL to chr17q23.2 (maximum logarithm of odds=3.01), WGS identified two rare heterozygous <i>TBX2</i> variants (c.977delA, p.Asp326Alafs*42 and c.987delC, p.Ala330Argfs*38) each segregating with the phenotype in a separate family. Affected individuals exhibited isolated auditory and oculomotor phenotypes, without additional syndromic features seen in previously described <i>TBX2</i>-associated disorders. <i>In vitro</i> assays demonstrated that the truncated TBX2 proteins maintained normal expression and nuclear localisation but exhibited 80% reduction in transcriptional activity. <i>In vivo</i>, heterozygous <i>Tbx2</i> knockout mice (<i>Tbx2^+/-</i> ) developed progressive HL and transient postnatal misexpression of outer hair cell marker in inner hair cells, supporting haploinsufficiency as the pathogenic mechanism.</p><p><strong>Conclusion: </strong>These findings establish <i>TBX2</i> as a novel gene for syndromic HL, defining a new autosomal dominant disorder characterised by progressive HL with variable nystagmus. This discovery expands the spectrum of T-box transcription factor disorders and informs molecular diagnosis and genetic counselling in hereditary HL.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080973","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":"GAPO syndrome: a comprehensive examination and review of 105 clinical cases.","authors":"Clarissa Modafferi, Pino D'Ambrosio, Silvia Andaloro, Giulia Lauretti, Fulvia Antignani, Maurizio Pompili, Felice Giuliante, Marco Biolato, Benedetta Niccolini, Arcangelo Fargnoli, Francesco Bogliardi, Paola Concolino, Giuseppe Zampino, Angelo Minucci, Maurizio Genuardi, Elisabetta Tabolacci, Pietro Chiurazzi","doi":"10.1136/jmg-2025-110832","DOIUrl":"https://doi.org/10.1136/jmg-2025-110832","url":null,"abstract":"<p><p>Growth retardation, alopecia, pseudoanodontia and optic atrophy (GAPO) syndrome is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the <i>ANTXR1</i> gene. While significant progress has been made in understanding its molecular basis, no systematic description of the clinical phenotype is available.We conducted a comprehensive review of 105 cases reported in the available literature since the first description of GAPO syndrome in 1947. We summarise here the current understanding of the clinical phenotype and the genetic basis of the condition.Our findings point out the multisystemic nature of GAPO syndrome, primarily featuring skeletal, dermatological and ophthalmological manifestations. The condition is caused by the biallelic loss-of-function of <i>ANTXR1</i> Histological findings throughout the reported cases underscore the critical role of excessive extracellular matrix deposition in the pathogenesis of GAPO syndrome. The evidence gathered suggests <i>ANTXR1</i> as an important regulator of extracellular matrix homeostasis.This study highlights the clinical and molecular spectrum of GAPO syndrome. Early recognition, multidisciplinary care and genetic counselling are essential for improving patient outcomes. Future studies should focus on targeted therapies addressing extracellular matrix dysregulation.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080960","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":"Further evidence of <i>RNU4ATAC</i> variants causing Joubert syndrome with skeletal involvement.","authors":"Fulvio D'Abrusco, Simone Gana, Enrico Alfei, Emanuela Scarano, Francesco Nicita, Enrico Silvio Bertini, Maria Cristina Digilio, Ginevra Zanni, Domenico Barbuti, Eleonora Carlicchi, Anna Pichiecchio, Stefano D'Arrigo, Valentina Serpieri, Enza Maria Valente","doi":"10.1136/jmg-2025-110987","DOIUrl":"https://doi.org/10.1136/jmg-2025-110987","url":null,"abstract":"<p><p><i>RNU4ATAC</i> is a non-coding gene involved in the minor spliceosome, and is mutated in a spectrum of syndromic skeletal disorders with recessive inheritance. Recently, biallelic <i>RNU4ATAC</i> pathogenic variants were detected in five patients presenting a complex syndromic phenotype and a brain malformation resembling the 'molar tooth sign' (MTS). This is the hallmark of Joubert syndrome (JS), a neurodevelopmental ciliopathy with multiorgan involvement.We reanalysed exome sequencing (ES) from 53 patients with JS, who lacked coding variants in known JS-associated genes. Four <i>RNU4ATAC</i> variants (n.16G>A, n.51G>A, n.13C>T and n.30G>A) were identified in compound heterozygosity in three probands, accounting for 5.6% of negative cases. All patients displayed the MTS and clinical features overlapping those of JS and <i>RNU4ATAC</i>-related skeletal disorders.These findings expand the phenotypic spectrum of <i>RNU4ATAC</i>-related disorders to include a complex neurological-skeletal ciliopathy phenotype, and highlight the relevance of ES reanalysis to uncover non-coding variants often undetected by conventional diagnostics.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040410","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":"Mixed functional consequences of the N651D <i>GRIA3</i> variant: a case of early-onset developmental and epileptic encephalopathy with parkinsonism.","authors":"Carmen Fons, Yu-Han Ge, Laura Kristine Rasmussen, Yun Stone Shi, Allan Bayat","doi":"10.1136/jmg-2025-110855","DOIUrl":"https://doi.org/10.1136/jmg-2025-110855","url":null,"abstract":"<p><p>Rare variants in <i>GRIA3</i>, the gene encoding the GluA3 subunit of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs), are associated with defects in early brain development. Disease-causing variants are generally categorised as either loss of function (LoF) or gain of function (GoF) that appear to be linked to different symptoms. Here, we reported a de novo variant (N651D) that has mixed LoF and GoF in a female patient with a devastating developmental and epileptic encephalopathy, parkinsonism and cortical malformation. N651D is located in the M3 segment, which forms the filter pore of AMPAR tetramers. Interestingly, functional assays revealed that glutamate induced no currents in GluA3_N651D homomeric receptors, likely indicating an LoF effect. However, when co-expressed with the GluA2 subunit, the GluA2/A3_N651D heteromeric receptors showed slower deactivation and desensitisation curves, along with elevated non-desensitising steady-state currents, features typically observed in GoF variants. We speculate that variants with mixed LoF and GoF effects may lead to a more devastating phenotype compared with variants with GoF effects only.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033537","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":"Inefficiencies in precision medicine: can genetic counsellors (GC) be the solution? The experience from the first GC-led cancer genetics service in Asia.","authors":"Jeanette Yuen, Shao-Tzu Li, Eliza Kate Courtney, Manasadevi Karthikeyan, Tasmyn Scriven, Nur Diana Binte Ishak, Hui Xuan Goh, Tiffany Lim, Zewen Zhang, Jianbang Chiang, Ravindran Kanesvaran, Rebecca Dent, Joanne Ngeow","doi":"10.1136/jmg-2025-110995","DOIUrl":"https://doi.org/10.1136/jmg-2025-110995","url":null,"abstract":"<p><strong>Purpose: </strong>The utility of genetic testing (GT) to guide cancer treatment, risk management and prevention has driven the demand for cancer genetic services. The global shortage of genetic counsellors (GCs) has led to the <i>mainstreaming</i> model. We evaluate the outcomes of the first GC-led service in Asia as a potential model for mainstreaming.</p><p><strong>Methods: </strong>A retrospective review of patients managed by the service from 2013 to 2023 was conducted. Output data relevant to patient consultations, GT uptake and pathogenic variant carriers identified were extracted. A progress chart outlines the efforts made in addressing barriers, improving uptake and service delivery.</p><p><strong>Results: </strong>Demand for GT has increased 18-fold. Uptake grew from 27% to an average of 81% from 2020, with no misconduct recorded. Carrier detection rate rose from 16% to 19-25% from 2015. The cost of GT has reduced significantly. Referral pathways for common hereditary cancer predisposition syndromes have been implemented. Support group events are held annually for carriers.</p><p><strong>Conclusion: </strong>Our findings highlight the feasibility and success of a GC-led mainstreaming model that is safe and scalable. GCs are more time and cost-efficient than doctors in meeting GT demands while supporting carriers psychosocially. Expanding the GC workforce should be a priority in meeting the global demand for GT.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000772","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":"Multiple early onset atypical cutaneous fibrous histiocytomas in multilocus inherited neoplasia allele syndrome involving TP53 and FLCN genes.","authors":"Schaida Schirwani, Sylvia Ghattas, Nicholas Wilson, Samantha Hunt, Alison Callaway, Lucy Side, Jessica Bate","doi":"10.1136/jmg-2025-110820","DOIUrl":"https://doi.org/10.1136/jmg-2025-110820","url":null,"abstract":"<p><p>Li-Fraumeni syndrome and Birt-Hogg-Dubé syndrome are distinct cancer predisposition syndromes caused by germline pathogenic variants (GPVs) in TP53 and FLCN, respectively. Multilocus inherited neoplasia alleles syndrome (MINAS) describes the co-occurrence of GPVs in two or more cancer predisposition genes. We present a unique case of a boy aged 16 years with multiple, very early onset atypical cutaneous fibrous histiocytomas (ACFHs), diagnosed with MINAS due to de novo TP53 and paternally inherited FLCN GPVs. This case is the first reported association of ACFH with germline TP53 and FLCN pathogenic variants. This paper highlights the importance of considering MINAS in patients with unusual tumour presentations. We discuss the clinical, histopathological and genetic findings, emphasising the need for comprehensive genetic testing and personalised surveillance in such cases.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992656","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":"Long-term efficacy of migalastat in females with Fabry disease.","authors":"Staci Kallish, Antonia Camporeale, Robert J Hopkin, Ana Jovanovic, Peter Nordbeck, Biliana O Veleva-Rotse, Eva Krusinska, Roser Torra","doi":"10.1136/jmg-2024-110596","DOIUrl":"https://doi.org/10.1136/jmg-2024-110596","url":null,"abstract":"<p><strong>Background: </strong>Fabry disease is a progressive, X-linked lysosomal disorder caused by reduced or absent α-galactosidase A activity due to <i>GLA</i> variants. Females with Fabry disease often experience diagnostic delays and an underappreciated disease burden owing to their variable disease presentation and progression.</p><p><strong>Methods: </strong>We conducted a <i>post hoc</i> analysis of all females from the clinical studies FACETS (NCT00925301) and ATTRACT (NCT01218659) and their open-label extensions, assessing baseline characteristics and long-term efficacy of migalastat regarding cardiac and renal function and Fabry-associated clinical events (FACEs).</p><p><strong>Results: </strong>Overall, 60 females had a median migalastat exposure of 5.1 years. At baseline, the median age was 47 years with multiorgan involvement in 70.0% of females (≥2 organ systems: renal, cardiac, central nervous system, peripheral nervous system and gastrointestinal). At baseline, 21.7% of females had left ventricular hypertrophy (LVH). In multiorgan involvement and LVH subgroups, the median baseline estimated glomerular filtration rate (eGFR) was in chronic kidney disease stage 2. Annualised rate of change in left ventricular mass index remained below 1 g/m²/year regardless of LVH or eGFR category at baseline. Mean (SD) eGFR annualised change was -1.1 (2.8) mL/min/1.73 m² overall. Ten FACEs were reported in eight females, seven of whom had prior events. Seven FACEs were cardiac; the remaining three were cerebrovascular (all transient ischaemic attacks). The incidence of renal, cardiac and cerebrovascular events was 0, 24.9 and 10.7 events per 1000 patient-years, respectively.</p><p><strong>Conclusion: </strong>These data show that females with Fabry disease experience considerable disease severity and burden and support the long-term efficacy of migalastat for the treatment of females.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957368","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":"Refined genotype-phenotype correlations in neurofibromatosis type 1 patients with <i>NF1</i> point variants.","authors":"Laurence Pacot, Marinus Blok, Dominique Vidaud, Laura Fertitta, Ingrid Laurendeau, Audrey Coustier, Theodora Maillard, Cécile Barbance, Djihad Hadjadj, Manuela Ye, Dominique Lallemand, Salah Ferkal, Benoit Funalot, Ariane Lunati-Rozie, Bérénice Hebrard, Rakia Bhouri, Liesbeth Spruijt, Didier Bessis, David Geneviève, Vivian Vernimmen, Martinus P G Broen, Sabine Sigaudy, Sylvie Odent, Léna Damaj, Chloé Quélin, Laurent Pasquier, Valérie Layet, Brigitte Gilbert-Dussardier, Gaël Nicolas, Anne-Marie Guerrot, Bruno Leheup, Anne-Claire Bursztejn, Florence Petit, Odile Boute-Bénéjean, Yline Capri, Anne Guimier, Stanislas Lyonnet, Genevieve Baujat, Emmanuelle Bourrat, Bertrand Isidor, Mathilde Nizon, Sébastien Barbarot, Annick Toutain, Sophie Blesson, Julien Van-Gils, Fanny Morice-Picard, Séverine Audebert-Bellanger, Juliette Mazereeuw-Hautier, Alban Ziegler, Yves Alembik, Juliette Piard, Elise Brischoux-Boucher, Léa Guerrini-Rousseau, Julia Morera, Véronique Paquis-Flucklinger, Bruno Delobel, Jean-Luc Alessandri, Béatrice Parfait, Pierre Wolkenstein, Eric Pasmant","doi":"10.1136/jmg-2025-110783","DOIUrl":"10.1136/jmg-2025-110783","url":null,"abstract":"<p><strong>Background: </strong>Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders. NF1 is caused by dominant loss-of-function pathogenic variants (PVs) of the tumour-suppressor gene <i>NF1</i>, which encodes neurofibromin, a negative regulator of rat sarcoma proteins. NF1 is an autosomal dominant disorder with complete penetrance, but a highly variable expression. Identification of genotype-phenotype correlations is challenging because of the wide clinical variability, the progressive nature of the disorder and the extreme diversity of the mutation spectrum. Only a few <i>NF1</i> point variants have been associated with a specific phenotype in NF1 patients.</p><p><strong>Methods: </strong>We investigated a large, well-phenotyped NF1 cohort.</p><p><strong>Results: </strong>We report analyses of genotype-phenotype correlations in 112 NF1 patients with specific <i>NF1</i> point variants: p.Arg1809 missense variants were associated with a mild form of NF1 (n=24), while a more severe phenotype was associated with codons 844-848 (n=27), p.Arg1276 (n=25) and p.Lys1423 (n=35) missense variants. We describe a new correlation for p.Arg1204 missense variants (n=11), with no neurofibroma observed in patients. Functional studies will be critical for drawing conclusions on the potential hypomorphic or dominant-negative effects of these variants.</p><p><strong>Conclusion: </strong>The current data confirms several genotype-phenotype correlations in NF1, which may be relevant to the management and surveillance of NF1 patients with specific <i>NF1</i> PVs.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784537","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>APC</i> I1307K and clinical management: insights from UK Biobank association analysis of colorectal and other cancer risks in Ashkenazi and non-Ashkenazi whites.","authors":"Sophie Allen, Charlie F Rowlands, Andrew Latchford, Clare Turnbull, Laura Valle","doi":"10.1136/jmg-2025-110911","DOIUrl":"https://doi.org/10.1136/jmg-2025-110911","url":null,"abstract":"<p><strong>Background: </strong><i>APC</i> c.3920T>A; p.Ile1307Lys (I1307K), prevalent in individuals of Ashkenazi Jewish (AJ) origin, has been associated with a modestly increased colorectal cancer (CRC) risk. Clinical recommendations for I1307K heterozygotes vary across countries and expert groups, reflecting differences in population frequencies, modest risk estimates and limited data in non-AJ individuals.</p><p><strong>Methods: </strong>We analysed UK Biobank data comprising 466 315 individuals (8944 with CRC), using genomic analysis to classify AJ and non-AJ ancestries.</p><p><strong>Results: </strong>I1307K was identified in 7.1% of AJ and 0.08% of non-AJ white participants. No significant association with CRC was observed in AJ (OR: 0.71; 95% CI: 0.17 to 2.95) or non-AJ white individuals (OR: 1.05; 95% CI: 0.50 to 2.22). The previously established OR of 1.7-1.8 for AJ individuals lies within our 95% CI, indicating underpowered results due to limited CRC cases. No significant associations were detected for other cancers. Unbiased, adequately powered CRC case-control studies in non-AJ populations would require cohorts far larger than current resources for feasible analysis.</p><p><strong>Conclusion: </strong>Clinical actionability of I1307K should prioritise risk stratification based on overall CRC risk and ancestry-dependent variant detection rates. However, management strategies need not differ by ancestry once a carrier is identified, as the biological impact of I1307K should be consistent across populations.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957463","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":"Reproductive carrier screening for genetic disorders: position statement of the Canadian College of Medical Geneticists.","authors":"Ritu B Aul, Karen Elizabeth Canales, Isabelle De Bie, Anne-Marie Laberge, Sylvie Langlois, Tanya N Nelson, Sakina Walji, Andrea C Yu, Joanna Lazier","doi":"10.1136/jmg-2025-110871","DOIUrl":"https://doi.org/10.1136/jmg-2025-110871","url":null,"abstract":"<p><strong>Purpose and scope: </strong>The aim of this position statement is to provide recommendations aimed at Canadian reproductive care clinicians and genetics professionals regarding the use of reproductive carrier screening for autosomal recessive and X-linked recessive conditions.</p><p><strong>Methods of statement development: </strong>A multidisciplinary expert group was assembled to review the existing literature on reproductive carrier screening for autosomal recessive and X-linked recessive conditions and make recommendations relevant to the Canadian context. The statement was circulated for comment to the membership of the Canadian College of Medical Geneticists (CCMG) and Canadian Association of Genetic Counsellors (CAGC), and multiple family physician reviewers. Feedback from these groups was incorporated, and the final position statement was approved by the CCMG Board of Directors on 5 December 2024 and the CAGC Board of Directors on 14 April 2025.</p><p><strong>Results and conclusions: </strong>Routinely offered pan-ethnic reproductive carrier screening via a provincial or territorial programme is recommended for a limited panel of relatively common and severe childhood onset genetic conditions, based on Canadian experience with ethnicity-based testing: cystic fibrosis, fragile X syndrome, spinal muscular atrophy, haemoglobinopathies and founder mutations for Tay-Sachs disease, Canavan disease and familial dysautonomia. Provincial/territorial programmes must be developed to provide oversight, ensure appropriate resourcing and manage education and roll-out. Maintaining regional ethnicity-based screening programmes is also recommended, where relevant. Publicly funded population-level expanded carrier screening is not recommended at this time.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957337","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}