Journal of Medical Genetics最新文献

{"title":"Response to: 'Commentary on Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank' by Møller <i>et al</i>.","authors":"Joaquín Castillo-Iturra, Ariadna Sánchez, Leticia Moreira, Maria Pellisé, Francesc Balaguer","doi":"10.1136/jmg-2024-110468","DOIUrl":"10.1136/jmg-2024-110468","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"151"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950245","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":"Homozygous missense variant in <i>C2orf69</i> causes early-onset neurodegeneration, leukoencephalopathy and autoinflammation.","authors":"Rachel Youjin Oh, Michael Maier, Susan Blaser, Jessie Cameron, Cynthia Hawkins, Bruno Reversade, Grace Yoon","doi":"10.1136/jmg-2024-110419","DOIUrl":"10.1136/jmg-2024-110419","url":null,"abstract":"<p><p>Biallelic pathogenic variants in <i>C2orf69</i> cause a fatal autosomal recessive multisystem disorder characterized by recurrent autoinflammation, hypomyelination, progressive neurodegeneration, microcephaly, failure to thrive, liver dysfunction, respiratory chain defects and accumulation of glycogen in skeletal muscle. No missense variants in <i>C2orf69</i> have been reported to date.We report a 6-year-old boy with microcephaly, global developmental delays, lower limb spasticity with hyperreflexia, epilepsy, abnormal brain MRI, failure to thrive, recurrent fevers and transaminitis. Whole-exome sequencing identified a homozygous missense c.320 C>G, p.(Pro107Arg) variant of uncertain significance (VUS) in <i>C2orf69</i> Skeletal muscle biopsy showed active and chronic muscle fibre degeneration with deposits of periodic acid-Schiff-positive material in affected tissues, consistent with abnormal glycogen storage. Mitochondrial respiratory assays were normal in muscle tissue. Primary patient fibroblasts showed normal levels of mRNA expression but significantly reduced levels of endogenous C2ORF69 protein and GBE1 by Western blot. We report a patient with a homozygous missense variant in <i>C2orf69</i>, causing loss of function. Depletion of endogenous GBE1 in affected cells can be considered a biomarker for this disorder and assist in the interpretation of VUS in <i>C2orf69</i> This expands the clinical and genetic spectrum of <i>C2orf69</i>-related disorder.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"206-209"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029005","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":"Sexual dimorphism in <i>SMAD3</i> pathogenic variant-harbouring individuals.","authors":"Julie Richer, Joe Davis Velchev, Sharan Goobie, Christie A Boswell-Patterson, Ingrid M B H van de Laar, Judith M A Verhagen, Marja W Wessels, Jolien W Roos-Hesselink, Ilse Luyckx, Hussein Al-Amodi, Michael W A Chu, Anne-Marie Laberge, Bekim Sadikovic, Tugce Balci, Aline Verstraeten, Bart Loeys","doi":"10.1136/jmg-2024-110219","DOIUrl":"10.1136/jmg-2024-110219","url":null,"abstract":"<p><strong>Background: </strong>Individuals harbouring <i>SMAD3</i> pathogenic variants are at risk for aneurysms/dissections throughout the arterial tree. Based on prior reports of sex differences in thoracic aortic aneurysm/dissection, we investigated the sexual dimorphism for vascular events in <i>SMAD3-</i>variant-harbouring patients.</p><p><strong>Methods: </strong>We analysed two large pedigrees comprising 84 individuals segregating pathogenic missense variants affecting the same p.Arg287 residue in <i>SMAD3</i>. We excluded individuals<40 years without vascular involvement, as they were too young to be classified. Individuals were subcategorised according to sex, the presence or absence and localisation (aneurysm/dissection with or without involvement of the aortic root/ascending aorta) of vascular lesions. We complemented our familial patient cohort with 178 <i>SMAD3</i> patients reported in the literature between 2011 and 2023.</p><p><strong>Results: </strong>In our two pedigrees, 11/30 (37%) variant-harbouring females had no vascular involvement, whereas none of the variant-harboring males (n=23) had no vascular involvement (p=0.001). While the two groups did not differ by age, males were at higher risk of vascular complications (p=0.037), there was no age difference between sexes. Of the 19 females with vascular involvement, six (32%) had vascular involvment sparing the aortic root/ascending aorta, whereas of the 23 males with vascular invovlement, only one (4%) had vascular involvement sparing the aortic root/ascending aorta (p=0.034). In the literature, we identified 116 male and 62 female additional patients. In the combined cohort of 220 patients, we demonstrated an over-representation of males (p<0.001) and non-penetrance in females for vascular pathology involving the aortic root/ascending aorta (p=0.028).</p><p><strong>Conclusions: </strong>Non-penetrance is more common in women, and normal echocardiography in at-risk females is not as reassuring for risk of vasculopathy in other locations. The higher non-penetrance in women creates an ascertainment bias and results in an over-representation of male patients in the literature.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"199-205"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921909","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":"Robust detection of pathogenic <i>HYDIN</i> variants that cause primary ciliary dyskinesia using RNA-seq of nasal mucosa.","authors":"Minako Hijikata, Kozo Morimoto, Masashi Ito, Keiko Wakabayashi, Akiko Miyabayashi, Naoto Keicho","doi":"10.1136/jmg-2024-110400","DOIUrl":"10.1136/jmg-2024-110400","url":null,"abstract":"<p><p>Primary ciliary dyskinesia (PCD, OMIM 244400) is a rare genetic disorder that affects motile cilia and is characterised by impaired mucociliary clearance of the airway epithelium, which results in chronic upper and lower airway infections. While short-read next-generation sequencing technology has been used for the genetic testing of PCD, its effectiveness is limited in identifying variants in the <i>HYDIN</i> gene because of the nearly identical pseudogene <i>HYDIN2</i> As we confirmed that the <i>HYDIN2</i> gene was not expressed in airway cells, we obtained nasal mucosa biopsy specimens for total RNA sequencing (RNA-seq) with library enrichment using exome oligos. Among the 34 nasal samples from patients suspected of having PCD, three aberrant splicing patterns in <i>HYDIN</i> were identified in two samples. Variant calls from RNA-seq combined with long-read amplicon sequencing of genomic DNA detected four pathogenic variants exclusively in the <i>HYDIN</i> gene. Therefore, RNA-seq in combination with long-read sequencing significantly facilitates the accurate genetic diagnosis of PCD caused by <i>HYDIN</i> variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"180-184"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978950","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":"Advances in research on the mechanism of tsRNA action in tumours.","authors":"Yan Gao, Yanzhao Huang, Kaiyun Guo, Jun Cheng, Yuting Luo, Yi Deng, Ming Lei","doi":"10.1136/jmg-2024-110437","DOIUrl":"10.1136/jmg-2024-110437","url":null,"abstract":"<p><p>tsRNA is a class of non-coding RNAs derived from mature or precursor tRNAs. In recent years, more and more studies have explored the correlation between tsRNAs and tumours. tsRNAs can affect the biological behaviours of tumour cells such as proliferation, apoptosis and metastasis by regulating gene expression, protein translation or post-transcriptional regulation. In this paper, we systematically review the production, biological function and research progress of tsRNA in tumour and discuss its prospects as biomarkers and therapeutic targets.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"152-159"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909688","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":"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":"210-218"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877031/pdf/","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":"OA","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":"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":"185-190"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","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}

{"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":"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":"219-226"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","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":"<i>PURA</i>-related neurodevelopmental disorders: a systematic review on genotype-phenotype correlations.","authors":"Noritaka Taniguchi, Keisuke Watanuki, Daisuke Nakato, Toshiki Takenouchi, Kenjiro Kosaki, Hiroshi Koga","doi":"10.1136/jmg-2024-110379","DOIUrl":"10.1136/jmg-2024-110379","url":null,"abstract":"<p><strong>Introduction: </strong>Genotype-phenotype correlations in <i>PURA</i>-related neurodevelopmental disorders (<i>PURA</i>-NDDs) remain unclear. This systematic review aimed to clarify these correlations.</p><p><strong>Methods: </strong>Searches of PubMed and Embase were conducted on 8 August 2024 to identify studies that had investigated genetically diagnosed <i>PURA-</i>NDDs (5q31.3 deletion syndrome and PURA syndrome). All types and languages of studies were included. Study quality was assessed using a 20-item criterion checklist. Genetic and clinical data were extracted from each article and genotype-phenotype correlations were explored.</p><p><strong>Results: </strong>Our analysis included 46 studies encompassing 230 patients with <i>PURA</i>-NDDs (5q31.3 deletion syndrome 18 (8%) and PURA syndrome 212 (92%)). Patients with 5q31.3 deletion syndrome exhibited more congenital defects (50% vs 12%, p<0.0001), respiratory difficulties (94% vs 63%, p=0.013) and walking disability (94% vs 55%, p=0.0026) than patients with PURA syndrome. In PURA syndrome, protein-truncating (nonsense or frameshift) variants were associated with more speech deficits (93% vs 80%, p=0.014) than non-protein-truncating (missense or in-frame) variants. <i>PURA</i> variant location had no effect on congenital defect occurrence or neurodevelopmental outcome. Overall, respiratory difficulties, walking disability and speech deficits were more commonly observed in the following order: 5q31.3 deletion (94%, 94% and 100%, respectively), multiple PUR-repeat deletions (68%, 60% and 95%, respectively), single PUR-repeat deletion or alteration (61%, 53% and 85%, respectively), and deletion or alteration located outside PUR repeats (38%, 33% and 43%, respectively).</p><p><strong>Conclusion: </strong>The clinical severity of <i>PURA</i>-NDDs appears to be associated with the deletion/alteration size including PUR repeats rather than the location of <i>PURA</i> variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"191-198"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006675","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":"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":"176-179"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","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}